Journal Cover
Bioorganic & Medicinal Chemistry
Journal Prestige (SJR): 0.871
Citation Impact (citeScore): 3
Number of Followers: 132  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0968-0896
Published by Elsevier Homepage  [3162 journals]
  • Veratridine binding to a transmembrane helix of sodium channel Nav1.4
           determined by solid-state NMR
    • Abstract: Publication date: Available online 17 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Ai Niitsu, Ayako Egawa, Keisuke Ikeda, Kazuo Tachibana, Toshimichi Fujiwara Multi-step ligand action to a target protein is an important aspect when understanding mechanisms of ligand binding and discovering new drugs. However, structurally capturing such complex mechanisms is challenging, particularly regarding interactions between large membrane proteins and small molecules. One of those large membrane proteins is Nav1.4, a eukaryotic voltage-gated sodium channel. Domain 4 segment 6 (D4S6) of Nav1.4 is a transmembrane α-helical segment playing a key role in channel gating regulation, and is targeted by a neurotoxin, veratridine (VTD). VTD has been suggested to show two step action to activate Nav1.4. Here, we show the NMR structure of a selectively 13C-labeled peptide corresponding to D4S6 and its VTD binding site in lipid bilayers determined by using magic-angle spinning solid-state NMR. By 13C NMR, we obtain NMR structural constraints as 13C chemical shifts and the 1H-2H dipolar couplings between the peptide and deuterated lipids. The peptide backbone structure and its location with respect to the membrane are determined under the obtained NMR structural constraints aided by replica exchange molecular dynamics simulations with an implicit membrane/solvent system. Further, by measuring the 1H-2H dipolar couplings to monitor the peptide-lipid interaction, we identify a VTD binding site on D4S6. When superimposed to a crystal structure of a bacterial sodium channel NavRh, the determined binding site is the only surface exposed to the protein exterior and localizes beside the second-step binding site reported previously. Based on these results, we propose that VTD initially binds to the newly determined residues on D4S6 from the membrane hydrophobic domain, which induces the first-step channel opening followed by the second-step blocking of channel inactivation of Nav1.4. Our findings provide new detailed insights of the VTD action mechanism, which could be useful in designing new drugs targeting D4S6.Graphical abstractGraphical abstract for this article
  • Kojyl cinnamate esters are peroxisome proliferator-activated receptor
           α/γ dual agonists
    • Abstract: Publication date: Available online 17 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Sae On Kim, Yujia Han, Sungjin Ahn, Seungchan An, Jeayoung C. Shin, Hyunjung Choi, Hyoung-June Kim, Nok Hyun Park, Yong-Jin Kim, Sun Hee Jin, Ho Sik Rho, Minsoo Noh Adiponectin is an adipocytokine with insulin-sensitizing, anti-inflammatory, anti-atherosclerotic, and anti-aging properties. Compounds with the ability to promote adiponectin secretion are of interest for the development of anti-aging drugs to improve skin-aging phenotypes. In the phenotypic assay to measure adiponectin secretion during adipogenesis in human adipose tissue-derived mesenchymal stem cells (hAT-MSCs), kojyl cinnamate ester derivatives increased adiponectin secretion. A target identification study showed that the kojyl cinnamate ester derivatives competitively bound to peroxisome proliferator-activated receptor α/γ (PPARα/γ). The upregulation of adiponectin production induced by kojyl cinnamate ester derivatives was significantly correlated with PPARα and PPARγ binding activities. Kojyl cinnamate ester derivatives significantly increased the transcription of genes encoding cholesterol and fatty acid synthesizing enzymes in hAT-MSCs. Notably, the kojyl cinnamate esters upregulated the gene transcription of lipid metabolic enzymes in human epidermal keratinocytes, which are important in the integrity of skin permeability barrier. In addition, the kojyl cinnamate esters that function as PPARα/γ dual modulators inhibited ultraviolet B irradiation-induced inflammation in human epidermal keratinocytes. Therefore, kojyl cinnamate ester derivatives are a novel class of PPARα/γ dual agonists with the potential to improve skin-aging phenotypes.Graphical abstractGraphical abstract for this article
  • Flexibility of small molecular CD4 mimics as HIV entry inhibitors
    • Abstract: Publication date: Available online 16 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Takuya Kobayakawa, Nami Ohashi, Yuki Hirota, Kohei Takahashi, Yuko Yamada, Tetsuo Narumi, Kazuhisa Yoshimura, Shuzo Matsushita, Shigeyoshi Harada, Hirokazu Tamamura CD4 mimics such as YIR-821 and its derivatives are small molecules which inhibit the interaction between the Phe43 cavity of HIV-1 gp120 with host CD4, an interaction that is involved in the entry of HIV to cells. Known CD4 mimics generally possess three structural features, an aromatic ring, an oxalamide linker and a piperidine moiety. We have shown previously that introduction of a cyclohexyl group and a guanidine group into the piperidine moiety and a fluorine atom at the meta-position of the aromatic ring leads to a significant increase in the anti-HIV activity. In the current study, the effects of conformational flexibility were investigated by introduction of an indole-type group in the junction between the oxalamide linker and the aromatic moiety or by replacement of the oxalamide linker with a glycine linker. This led to the development of compounds with high anti-HIV activity, showing the importance of the junction region for the expression of high anti-HIV activity. The present data are expected to be useful in the future design of novel CD4 mimic molecules.Graphical abstractGraphical abstract for this article
  • 4-N-Alkanoyl and 4-N-Alkyl Gemcitabine Analogues with NOTA Chelators for
           68-Gallium Labelling
    • Abstract: Publication date: Available online 12 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Jesse Pulido, Maria de Cabrera, Adam J. Sobczak, Alejandro Amor-Coarasa, Anthony J. McGoron, Stanislaw F. Wnuk The conjugation of 4-N-(3-aminopropanyl)-2'-deoxy-2',2'-difluorocytidine with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) ligand in 0.1 M Na2CO3 buffer (pH 11) at ambient temperature provided 4-N-alkylgemcitabine-NOTA chelator. Incubation of latter with excess of gallium(III) chloride (GaCl3) (0.6 N AcONa/H2O, pH = 9.3) over 15 min gave gallium 4-N-alkylgemcitabine-NOTA complex which was characterized by HRMS. Analogous [68Ga]-complexation of 4-N-alkylgemcitabine-NOTA conjugate proceeded with high labeling efficiency (94% to 96%) with the radioligand almost exclusively found in the aqueous layer (∼95%). The high polarity of the gallium 4-N-alkylgemctiabine-NOTA complex resulted in rapid renal clearance of the 68Ga-labelled radioligand in BALB/c mice.Graphical abstractGraphical abstract for this article
  • Monosaccharide inhibitors targeting Carbohydrate Esterase family 4
    • Abstract: Publication date: Available online 12 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Benjamin R. DiFrancesco, Zachary A. Morrison, Mark Nitz The Carbohydrate Esterase family 4 contains virulence factors which modify peptidoglycan and biofilm-related exopolysaccharides. Despite the importance of this family of enzymes, a potent mechanism-based inhibition strategy has yet to emerge. Based on the postulated tridentate binding mode of the tetrahedral de-N-acetylation intermediate, GlcNAc derivatives bearing metal chelating groups at the 2 and 3 positions were synthesized. These scaffolds include 2-C phosphonate, 2-C sulfonamide, 2-thionoacetamide warheads as well as derivatives bearing thiol, amine and azide substitutions at the 3-position. The inhibitors were assayed against a representative peptidoglycan deacetylase, Pgda from Streptococcus pneumonia, and a representative biofilm-related exopolysaccharide deacetylase, PgaB from Escherichia. coli. Of the inhibitors evaluated, the 3-thio derivatives showed weak to moderate inhibition of Pgda. The strongest inhibitor was (2,3-dideoxy-2-thionoacetamide-3-thio)-benzyl-β-D-glucoside, whose inhibitory potency showed an unexpected dependence on metal concentration and was found to have a partial mixed inhibition mode (Ki = 2.9 ± 0.6 μM).Graphical abstractGraphical abstract for this article
  • Synthesis, computational studies and antiproliferative activities of
           coumarin-tagged 1,3,4-oxadiazole conjugates against MDA-MB-231 and MCF-7
           human breast cancer cells
    • Abstract: Publication date: Available online 12 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Sanjeev Dhawan, Nagaraju Kerru, Paul Awolade, Ashona Singh-Pillay, Sourav Taru Saha, Mandeep Kaur, Sreekantha B. Jonnalagadda, Parvesh Singh A novel library of coumarin tagged 1,3,4 oxadiazole conjugates was synthesized and evaluated for their antiproliferative activities against MDA-MB-231 and MCF-7 breast cancer cell lines. The evaluation studies revealed that compound 9d was the most potent molecule with an IC50 value of
  • Design, synthesis, cholinesterase inhibition and molecular modelling study
           of novel tacrine hybrids with carbohydrate derivatives
    • Abstract: Publication date: Available online 9 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): João Paulo Bizarro Lopes, Luana Silva, Gabriela da Costa Franarin, Marco Antonio Ceschi, Diogo Seibert Lüdtke, Rafael Ferreira Dantas, Cristiane Martins Cardoso de Salles, Floriano Paes Silva-Jr, Mario Roberto Senger, Isabella Alvim Guedes, Laurent Emmanuel Dardenne A series of hybrids containing tacrine linked to carbohydrate-based moieties, such as D-xylose, D-ribose, and D-galactose derivatives, were synthesized by the nucleophilic substitution between 9-aminoalkylamino-1,2,3,4-tetrahydroacridines and the corresponding sugar-based tosylates. All compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the nanomolar IC50 scale. Most of the D-xylose derivatives (6a-e) were selective for AChE and the compound 6e (IC50 = 2.2 nM for AChE and 4.93 nM for BuChE) was the most active compound for both enzymes. The D-galactose derivative 8a was the most selective for AChE exhibiting an IC50 ratio of 7.6 for AChE over BuChE. Only two compounds showed a preference for BuChE, namely 7a (D-ribose derivative) and 6b (D-xylose derivative). Molecular docking studies indicated that the inhibitors are capable of interacting with the entire binding cavity and the main contribution of the linker is to enable the most favorable positioning of the two moieties with CAS, PAS, and hydrophobic pocket to provide optimal interactions with the binding cavity. This finding is reinforced by the fact that there is no linear correlation between the linker size and the observed binding affinities. The majority of the new hybrids synthesized in this work do not violate the Lipinski's rule-of-five according to FAF-Drugs4, and do not demonstrated predicted hepatotoxicity according ProTox-II.Graphical abstractGraphical abstract for this article
  • Synthesis, anticancer activity and cytotoxicity of galactosylated
           epothilone B
    • Abstract: Publication date: Available online 9 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Hui Gao, Gangliang Huang Epothilones are the 16-membered macrolide compounds, exhibit microtubule-promoting activity, have the same anti-tumor mechanism as paclitaxel, and are expected to be the ideal substitutes for paclitaxel. However, natural epothilone compounds have been found to have disadvantages such as high toxicity in vivo, poor selectivity to tumor cells, and susceptibility to drug resistance. Herein, epothilone B was synthesized by fermentation, and it was galactosylated by chemical method. The toxicity in vitro of epothilone B and its galactosylated derivative was investigated by the MTT method. The anticancer activity evaluation in vitro was performed using a method similar to the antibody-directed enzyme-prodrug therapy (ADEPT) method. It indicated that the ratio of cytotoxicity between the free epothilone B and the galactosylated epothilone B was about 150. This would lay the foundation for the targeted treatment of cancer with epothilone glycosides.Graphical abstractGraphical abstract for this article
  • Novel 5,6-disubstituted pyrrolo[2,3-d]pyrimidine derivatives as broad
           spectrum antiproliferative agents: Synthesis, cell based assays, kinase
           profile and molecular docking study
    • Abstract: Publication date: Available online 9 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Ju-Hyeon Lee, Ashraf Kareem El-Damasy, Seon Hee Seo, Changdev G. Gadhe, Ae NimPae, Nakcheol Jeong, Soon-Sun Hong, Gyochang Keum Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-d]pyrimidine octamides (4a–o and 5a–m) and their corresponding free amines 6a–g and 7a–g have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 6d–g as well as the amine derivative 7b have shown the best anticancer activity with single digit micromolar GI50 values over the tested cancer cells, and low cytotoxic effects (GI50> 10.0 µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-d]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 6f was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI50 and TGI values over multiple cancer cells. Kinase profile of compound 6f over 53 oncogenic kinases at 10 µM showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 6f against TrkA (IC50 = 2.25 µM), FGFR4 (IC50 = 6.71 µM) and Tie2 (IC50 = 6.84 µM) was explained by molecular docking study, which also proposed that 6f may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 6f may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.Graphical abstractGraphical abstract for this article
  • Graphical abstract TOC
    • Abstract: Publication date: 1 October 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 18Author(s):
  • Graphical abstract TOC
    • Abstract: Publication date: 1 October 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 18Author(s):
  • Graphical abstract TOC
    • Abstract: Publication date: 1 October 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 18Author(s):
  • Design, solid-phase synthesis and evaluation of enterobactin analogs for
           iron delivery into the human pathogen Campylobacter jejuni
    • Abstract: Publication date: Available online 16 April 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Cristina Y. Zamora, Amaël G.E. Madec, Wilma Neumann, Elizabeth M. Nolan, Barbara Imperiali The human enteropathogen Campylobacter jejuni, like many bacteria, employs siderophores such as enterobactin for cellular uptake of ferric iron. This transport process has been shown to be essential for virulence and presents an attractive opportunity for further study of the permissiveness of this pathway to small-molecule intervention and as inspiration for the development of synthetic carriers that may effectively transport cargo into Gram-negative bacteria. In this work, we have developed a facile and robust microscale assay to measure growth recovery of C. jejuni NCTC 11168 in liquid culture as a result of ferric iron uptake. In parallel, we have established the solid-phase synthesis of catecholamide compounds modeled on enterobactin fragments. Applying these methodological developments, we show that small synthetic iron chelators of minimal dimensions provide ferric iron to C. jejuni with equal or greater efficiency than enterobactin.Graphical abstractGraphical abstract for this article
  • Interfacial bioconjugation on emulsion droplet for biosensors
    • Abstract: Publication date: Available online 13 April 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Qifan Zhang, Anita Scigliano, Tarita Biver, Andrea Pucci, Timothy M. Swager Interfacial bioconjugation methods are developed for intact liquid emulsion droplets. Complex emulsion droplets having internal hydrocarbon and fluorocarbon immiscible structured phases maintain a dynamic interface for controlled interfacial reactivity. The internal morphological change after binding to biomolecules is readily visualized and detected by light transmission, which provides a platform for the formation of inexpensive and portable bio-sensing assays for enzymes, antibodies, nucleic acids and carbohydrates.Graphical abstractGraphical abstract for this article
  • Investigation of transition metal-catalyzed nitrene transfer reactions in
    • Abstract: Publication date: Available online 11 April 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Juliet M. Alderson, Joshua R. Corbin, Jennifer M. Schomaker Transition metal-catalyzed nitrene transfer is a powerful method for incorporating new CN bonds into relatively unfunctionalized scaffolds. In this communication, we report the first examples of site- and chemoselective CH bond amination reactions in aqueous media. The unexpected ability to employ water as the solvent in these reactions is advantageous in that it eliminates toxic solvent use and enables reactions to be run at increased concentrations with lower oxidant loadings. Using water as the reaction medium has potential to expand the scope of nitrene transfer to encompass a variety of biomolecules and highly polar substrates, as well as enable pH control over the site-selectivity of CH bond amination.Graphical abstractGraphical abstract for this article
  • Rational design and screening of peptide-based inhibitors of heat shock
           factor 1 (HSF1)
    • Abstract: Publication date: Available online 7 April 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Xu Ran, Eileen T. Burchfiel, Bushu Dong, Nicholas J. Rettko, Bryan M. Dunyak, Hao Shao, Dennis J. Thiele, Jason E. Gestwicki Heat shock factor 1 (HSF1) is a stress-responsive transcription factor that regulates expression of protein chaperones and cell survival factors. In cancer, HSF1 plays a unique role, hijacking the normal stress response to drive a cancer-specific transcriptional program. These observations suggest that HSF1 inhibitors could be promising therapeutics. However, HSF1 is activated through a complex mechanism, which involves release of a negative regulatory domain, leucine zipper 4 (LZ4), from a masked oligomerization domain (LZ1-3), and subsequent binding of the oligomer to heat shock elements (HSEs) in HSF1-responsive genes. Recent crystal structures have suggested that HSF1 oligomers are held together by extensive, buried contact surfaces, making it unclear whether there are any possible binding sites for inhibitors. Here, we have rationally designed a series of peptide-based molecules based on the LZ4 and LZ1-3 motifs. Using a plate-based, fluorescence polarization (FP) assay, we identified a minimal region of LZ4 that suppresses binding of HSF1 to the HSE. Using this information, we converted this peptide into a tracer and used it to understand how binding of LZ4 to LZ1-3 suppresses HSF1 activation. Together, these results suggest a previously unexplored avenue in the development of HSF1 inhibitors. Furthermore, the findings highlight how native interactions can inspire the design of inhibitors for even the most challenging protein-protein interactions (PPIs).Graphical abstractGraphical abstract for this article
  • Screening of ligands for redox-active europium using magnetic resonance
    • Abstract: Publication date: Available online 4 April 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Brooke A. Corbin, Lina A. Basal, Susan A. White, Yimin Shen, E. Mark Haacke, Kenneth W. Fishbein, Matthew J. Allen We report a screening procedure to predict ligand coordination to EuII and EuIII using magnetic resonance imaging in which bright images indicate complexation and dark images indicate no complexation. Here, paramagnetic GdIII is used as a surrogate for EuIII in the screening procedure to enable detection with magnetic resonance imaging. The screening procedure was tested using a set of eight ligands with known coordination to EuII and EuIII, and results were found to be consistent with expected binding. Validation of the screening procedure with known coordination chemistry enables use with new ligands in the future.Graphical abstractGraphical abstract for this article
  • Site-specific incorporation of quadricyclane into a protein and
           photocleavage of the quadricyclane ligation adduct
    • Abstract: Publication date: Available online 4 April 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Frederick M. Tomlin, Chelsea G. Gordon, Yisu Han, Taia S. Wu, Ellen M. Sletten, Carolyn R. Bertozzi The quadricyclane (QC) ligation is a bioorthogonal reaction between a quadricyclane moiety and a nickel bis(dithiolene) derivative. Here we show that a QC amino acid can be incorporated into a protein site-specifically using the pyrrolysine-based genetic code expansion platform, and subsequently used for ligation chemistry. Additionally, we exploited the photolability of the QC ligation product to render the adduct cleavable with a handheld UV lamp. We further developed a protein purification method that involves QC ligation of biotin to a protein of interest, capture on streptavidin resin, and finally release using only UV light. The QC ligation thus brings novel chemical manipulations to the realm of bioorthogonal chemistry.Graphical abstractGraphical abstract for this article
  • Medium throughput cage state stability screen of conditions for the
           generation of gold nanoparticles encapsulated within a mini-ferritin
    • Abstract: Publication date: Available online 26 March 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): T.A. Cornell, B.P. Orner Methods for the generation of nanoparticles encapsulated within cage proteins, such as ferritins, provide particles with low polydispersities due to size constraint by the cage. The proteins can provide enhanced water solubility to enable biological applications and affinity and identification tags to facilitate delivery or the assembly of advanced materials. Many effective methods have been developed, however, they are often impeded by cage protein instability in the presence of reagents or conditions for formation of the nanoparticles. Although the stability of ferritin cage quaternary structure can be enhanced, application of ferritins to materials science remains limited by unpredictable behaviour. Recently, we reported a medium throughput technique to directly detect the ferritin cage state. Herein, we expand this strategy to screen conditions commonly used for the formation of gold nanoparticles. Not only do we report nanoparticle formation conditions that permit ferritin stability, we establish a general screening strategy based on protein cage stability that could be applied to other protein cages or for the generation of other types of particles.Graphical abstractGraphical abstract for this article
  • l+alanine+and+its+incorporation+into+argyrin+C&rft.title=Bioorganic+&+Medicinal+Chemistry&rft.issn=0968-0896&">Painting argyrins blue: Negishi cross-coupling for synthesis of deep-blue
           tryptophan analogue β-(1-azulenyl)-l alanine and its incorporation into
           argyrin C
    • Abstract: Publication date: Available online 26 March 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Erik Stempel, Robert Franz-Xaver Kaml, Nediljko Budisa, Markus Kalesse The argyrins are a family of non-ribosomal peptides that exhibits different biological activities through only small structural changes. Ideally, a biologically active molecule can be tracked and observed in a variety of biological and clinical settings in a non-invasive manner. As a step towards this goal, we report here a chemical synthesis of unnatural deep blue amino acid β-(1-azulenyl)-l alanine with different fluorescence and photophysical properties, which allows a spectral separation from the native tryptophan signal. This might be especially useful for cell localization studies and visualizing the targeted proteins. In particular, the synthesis of β-(1-azulenyl)-l alanine was achieved through a Negishi coupling which proved to be a powerful tool for the synthesis of unnatural tryptophan analogs. Upon β-(1-azulenyl)-l alanine incorporation into argyrin C, deep blue octapeptide variant was spectrally and structurally characterized.Graphical abstractGraphical abstract for this article
  • ω-Hydroxylation of α-tocopheryl quinone reveals a dual function for
           cytochrome P450-4F2 in vitamin E metabolism
    • Abstract: Publication date: Available online 5 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Luke Taylor, Nick Krueger, Olga Malysheva, Jeffrey Atkinson, Robert S. Parker α-tocopherol (α-TOH) is the primary lipophilic radical trapping antioxidant in human tissues. Oxidative catabolism of α-tocopherol (αTOH) is initiated by ω-hydroxylation of the terminal carbon (C-13) of the isoprenoid sidechain followed by oxidative transformations that sequentially truncate the chain to yield the 2,5,7,8-tetramethyl(3’carboxyethyl)-6-hydroxychroman (α-CEHC). After conjugation to glucuronic acid, 3'-carboxyethyl-6-hydroxychroman glucuronide is excreted in urine. We report here that the same enzyme that accomplishes this task, the cytochrome P450 monooxygenase CYP-4F2, can also ω-hydroxylate the terminal carbon of α-tocopheryl quinone. A standard sample of ω-HO-α-tocopheryl quinone (ω-OH-α-TQ) was synthesized as a mixture of stereoisomers by allylic oxidation of α-tocotrienol using SeO2 followed by double-bond reduction and oxidation to the quinone. After incubating human liver microsomes or insect cell microsomes expressing only recombinant human CYP-4F2, cytochrome b5, and NADPH P450 reductase with d6-α-tocopheryl quinone (d6-αTQ), we showed that the ω-hydroxylated (13-OH) d6-α-TQ was produced. We further identified the production of the terminal carboxylic acid d6-13-COOH-αTQ. The ramifications of this discovery to the understanding of tocopherol utilization and metabolism, including the quantitative importance of the αTQ-ω-hydroxylase pathway in humans, are discussed.Graphical abstractGraphical abstract for this article
  • Molecular Tools that Block Maturation of the Nuclear Lamin A and
           Decelerate Cancer Cell Migration
    • Abstract: Publication date: Available online 4 October 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Alexios N. Matralis, Dimitrios Xanthopoulos, Geneviève Huot, Stéphane Lopes-Paciencia, Charles Cole, Hugo de Vries, Gerardo Ferbeyre, Youla S. Tsantrizos Lamin A contributes to the structure of nuclei in all mammalian cells and plays an important role in cell division and migration. Mature lamin A is derived from a farnesylated precursor protein, known as prelamin A, which undergoes post-translational cleavage catalyzed by the zinc metalloprotease STE24 (ZPMSTE24). Accumulation of farnesylated prelamin A in the nuclear envelope compromises cell division, impairs mitosis and induces an increased expression of inflammatory gene products. ZMPSTE24 has been proposed as a potential therapeutic target in oncology. A library of peptidomimetic compounds were synthesized and screened for their ability to induce accumulation of prelamin A in cancer cells and block cell migration in pancreatic ductal adenocarcinoma cells. The results of this study suggest that inhibitors of lamin A maturation may interfere with cell migration, the biological process required for cancer metastasis.Graphical abstractGraphical abstract for this article
  • 1H-pyrrolo[2,3-b]pyridine: a new scaffold for human neutrophil elastase
           (HNE) inhibitors
    • Abstract: Publication date: Available online 27 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Letizia Crocetti, Maria Paola Giovannoni, Igor A. Schepetkin, Mark T. Quinn, Andrei I. Khlebnikov, Niccolò Cantini, Gabriella Guerrini, Antonella Iacovone, Elisabetta Teodori, Claudia Vergelli Human neutrophil elastase (HNE) is a potent serine protease belonging to the chymotrypsin family. It is an important target for the development of novel and selective inhibitors for the treatment of inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis and biological evaluation of a new series of HNE inhibitors with a pyrrolo[2,3-b]pyridine scaffold, which is an isomer of our previously reported indazoles, in order to assess how shift of the nitrogen from position 2 to position 7 influences activity. The majority of new compounds were effective HNE inhibitors and had IC50 values in the micromolar/submicromolar range, with some compounds active in low nanomolar levels. For example, 2a and 2b inhibited HNE with IC50 values of 15 and 14 nM, respectively. Molecular modeling of compounds differing in the position of heteroatom(s) in the bicyclic moiety and in the oxadiazole ring demonstrated that the calculated geometries of enzyme-inhibitor complexes were in agreement with the observed biological activities. Docking experiments showed that orientation of the active pyrrolo[2,3-b]pyridines in the HNE catalytic triad Ser195-His57-Asp102 correlated with effectiveness of the inhibitor interaction with the enzyme. Thus, the pyrrolo[2,3-b]pyridine scaffold represents a novel scaffold for the development of potent HNE inhibitors.Graphical abstractGraphical abstract for this article
  • Design, synthesis, and systematic evaluation of 4-arylpiperazine- and
           4-benzylpiperidine napthyl ethers as inhibitors of monoamine
           neurotransmitters reuptake
    • Abstract: Publication date: Available online 26 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Suresh Paudel, Xiao Min, Srijan Acharya, Daulat Bikram Khadka, Goon Yoon, Kyeong-Man Kim, Seung Hoon Cheon Two series of 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers were designed based on structure-activity relationship (SAR) and docking model of reported monoamine neurotransmitters reuptake inhibitors. The compounds were synthesized in 3-simple steps and their biological activities were evaluated. Several compounds were proven to be potent inhibitors of serotonin and norepinephrine reuptake. Computer docking was performed to study the interaction of the most potent compound 35 with human serotonin transporter. The results of the analyses suggest that 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers might be promising antidepressants worthy of further studies.Graphical abstractGraphical abstract for this article
  • Synthesis and evaluation of 2-substituted 4(3H)-quinazolinone thioether
           derivatives as monoamine oxidase inhibitors
    • Abstract: Publication date: Available online 25 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Malikotsi A. Qhobosheane, Anél Petzer, Jacobus P. Petzer, Lesetja J. Legoabe In the present study, a series of fourteen 2-mercapto-4(3H)-quinazolinone derivatives was synthesised and evaluated as potential inhibitors of the human monoamine oxidase (MAO) enzymes. Quinazolinone is the oxidised form of quinazoline, and although this class has not yet been extensively explored as MAO inhibitors, it has been shown to possess a wide variety of biological activities. Among the quinazolinone derivatives investigated, seven compounds (IC50 < 1 µM) proved to be potent and specific MAO-B inhibitors, with the most potent inhibitor, 2-[(3-iodobenzyl)thio]quinazolin-4(3H)-one, exhibiting an IC50 value of 0.142 μM. Further investigation showed that this inhibitor is a reversible and competitive inhibitor of MAO-B with a Ki value of 0.068 µM. None of the test compounds were MAO-A inhibitors. Analysis of the structure-activity relationships (SARs) for MAO-B inhibition shows that substitution on the C2 position of quinazolinone with a benzylthio moiety bearing a Cl, Br or I on the meta position yields the most potent inhibitors of the series. In contrast, substitution with the unsubstituted benzylthio moiety (IC50 = 3.03 µM) resulted in significantly weaker inhibition activity towards MAO-B. This study suggests that quinazolinones are promising leads for the development of selective MAO-B inhibitors which may be used for the treatment of neurodegenerative disorders such as Parkinson’s disease.Graphical abstractGraphical abstract for this article
  • Design, Synthesis, Biological Evaluation and Cellular Imaging of
    • Abstract: Publication date: Available online 25 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Tom Baladi, Jessy Aziz, Florent Dufour, Valentina Abet, Véronique Stoven, François Radvanyi, Florent Poyer, Ting-Di Wu, Jean-Luc Guerquin-Kern, Isabelle Bernard-Pierrot, Sergio Marco Garrido, Sandrine Piguel The TAM kinase family arises as a new effective and attractive therapeutic target for cancer therapy, autoimmune and viral diseases. A series of 2,6-disubstituted imidazo[4,5-b]pyridines were designed, synthesized and identified as highly potent TAM inhibitors. Despite remarkable structural similarities within the TAM family, compounds 28 and 25 demonstrated high activity and selectivity in vitro against AXL and MER, with IC50 value of 0.77 nM and 9 nM respectively and a 120- to 900-fold selectivity. We also observed an unexpected nuclear localization for compound 10Bb, thanks to nanoSIMS technology, which could be correlated to the absence of cytotoxicity on three different cancer cell lines being sensitive to TAM inhibition.Graphical abstractGraphical abstract for this article
  • Longitudinal trend of global artemisinin research in chemistry subject
           areas (1983–2017)
    • Abstract: Publication date: Available online 24 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Wanqi Xu, Zhongmei Zou, Jin Pei, Linfang Huang Artemisinin, the initial and main drug for malaria prevention and treatment internationally, was first extracted from the plant Artemisia annua L. by Chinese scientists in 1972. Research on artemisinin in chemistry subject areas shows a rapid growth since the 1980s. To evaluate the evolutionary trends and draw the knowledge map of artemisinin research, 1316 relevant publications are analysed based on bibliometrics. The global research status, emerging trends and future directions are also visualised and discussed. Furthermore, a historical overview of chemical synthesis on artemisinin is illustrated via timeline in terms of industrialisation. Overall, this study provides a novel method to visualise further information about artemisinin research and a comprehensive perspective to understand the longitudinal trend over the last 30 years.Graphical abstractGraphical abstract for this article
  • A novel 2,4-diaminopyrimidine derivative as selective inhibitor of protein
           kinase C theta prevents allograft rejection in a rat heart transplant
    • Abstract: Publication date: Available online 24 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Shigeki Kunikawa, Akira Tanaka, Yuji Takasuna, Mamoru Tasaki, Noboru Chida Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and is an attractive target for the treatment of T cell-mediated diseases such as transplant rejection and autoimmune disease. To identify PKCθ inhibitors, we focused on the 2,6-diamino-3-carbamoyl-5-cyanopyrazine derivative 2, which exhibited moderate PKCθ inhibitory activity. Optimization of 2 identified the 2,4-diamino-5-cyanopyrimidine derivative 16c, which exhibited potent PKCθ inhibitory activity and showed good selectivity against other PKC isozymes. Compound 16c prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.Graphical abstractGraphical abstract for this article
  • Design and Synthesis of Cell-permeable Fluorescent Nitrilotriacetic Acid
    • Abstract: Publication date: Available online 24 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Genichiro Tsuji, Takayuki Hattori, Masashi Kato, Wataru Hakamata, Hideshi Inoue, Mikihiko Naito, Masaaki Kurihara, Yosuke Demizu, Takuji Shoda Fluorescence labeling of the target molecules using a small molecule-based probe is superior than a method using genetically expressed green fluorescence protein (GFP) in terms of convenience in its preparation and functionalization. Fluorophore-nitrilotriacetic acid (NTA) conjugates with several ester protecting groups were synthesized and evaluated for their cell membrane permeability by fluorescence microscopy analysis. One of the derivatives, acetoxymethyl (AM)-protected NTA conjugate is hydrolyzed, resulting in intracellular accumulation, thus providing localized fluorescence intensity in cells. This modification is expected as an effective method for converting a non-cell membrane permeable NTA-BODIPY conjugates to a cell membrane permeable derivatives.Graphical abstractGraphical abstract for this article
  • Discovery and Anti-inflammatory Evaluation of Benzothiazepinones (BTZs) as
           Novel Non-ATP Competitive Inhibitors of Glycogen Synthase Kinase-3β
    • Abstract: Publication date: Available online 22 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Yang Gao, Peng Zhang, Anfeng Cui, De-Yong Ye, Meng Xiang, Yong Chu Glycogen synthase kinase-3β (GSK-3β) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory mediated diseases in animal models. Non-ATP competitive inhibitors inherently have better therapeutical value due to their higher specificity than ATP competitive ones. In this paper, we designed and synthesized a series of new BTZ derivatives as non-ATP competitive GSK-3β inhibitors. Kinetic analysis revealed two typical compounds 6j and 3j showed the different non-ATP competitive mechanism of substrate competition or allosteric modulation to GSK-3β, respectively. As expected, the two compounds showed good specificity in a panel test of 16 protein kinases, even to the closest enzymes, like CDK-1/cyclin B and CK-II. The in vivo results proved that both compounds can greatly attenuate the LPS-induced acute lung injury (ALI) and diminish inflammation response in mice by inhibiting the mRNA expression of IL-1β and IL-6. Western blot analysis demonstrated that they negatively regulated GSK-3β, and the mechanism of the observed beneficial effects of the inhibitors may involve both the increased phosphorylation of the Ser9 residue on GSK-3β and protein expression of Sirtuin 1 (SIRT1). The results support that such novel BTZ compounds have a protective role in LPS-induced ALI, and might be attractive candidates for further development of inflammation pharmacotherapy, which greatly thanks to their inherently high selectivities by the non-ATP competitive mode of action. Finally, we proposed suggesting binding modes by Docking study to well explain the impacts of compounds on the target site.Graphical abstractGraphical abstract for this article
  • Chemistry-Driven Glycoscience
    • Abstract: Publication date: Available online 22 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Laura L. Kiessling Carbohydrates are the most prominent features of the cell’s exterior—they are the cell’s “face” and serve as the cell’s identification card. The features of cell surface glycans (e.g. glycoproteins, glycolipids, polysaccharides) can be read by proteins, other cells, or organisms. In all of these contexts, glycan-binding proteins typically recognize (“read”) glycan identity. This recognition mediates important host-microbe interactions, as well as critical physiological functions, including fertilization, development, and immune system function. This article focuses on how proteins recognize glycans with an emphasis on three objectives: 1) to understand the molecular basis for carbohydrate recognition, 2) to implement that understanding to develop functional probes of protein-carbohydrate interactions, and 3) to apply those probes to elucidate and exploit the physiological consequences of protein–carbohydrate interactions. In this context, our group has focused on two key aspects of carbohydrate recognition: CH-π and multivalent interactions. We are applying the foundational knowledge gained from our studies for purposes ranging from illuminating host-microbe interactions to probing immune system function.
  • Compromising the Plasma Membrane as a Secondary Target in Photodynamic
           Therapy-Induced Necrosis
    • Abstract: Publication date: Available online 22 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Sebastian A. Thompson, Amit Aggarwal, Sunaina Singh, Alejandro P. Adam, Joao P.C. Tome, Charles Michael Drain Photodynamic therapy (PDT) is a non-invasive treatment widely applied to different cancers. The goal of PDT is the photo-induced destruction of cancer cells by the activation of different cell death mechanisms, including apoptosis and/or necrosis. Recent efforts focusing on understanding the mechanisms of cell death activated by PDT find that it depends on the type of photosensitizer (PS), targeted organelles, and nature of the light used. It is generally accepted that very short incubation times are required to direct the PS to the plasma membrane (PM), while longer periods result in the accumulation of the PS in internal compartments such as the endoplasmic reticulum or mitochondria. Glycosylation of the PS targets cancer via saccharide receptors on the cell surface, and is generally assumed that these compounds rapidly internalize and accumulate, e.g. in the endoplasmic reticulum. Herein we demonstrate that a minor fraction of a glycosylated chlorin compound residing at the PM of cancer cells can activate necrosis upon illumination by compromising the PM independently of the length of the incubation period. The results presented here show that the PM can also be targeted by glycosylated PS designed to accumulate in internal organelles. PS activation to induce necrosis by compromising the plasma membrane has the benefits of fast cell death and shorter irradiation times. The findings described here expand our understanding of the cellular damage induced by phototherapies, presenting the possibility of activating another cell death mechanism based on the incubation time and type of light used.Graphical abstractGraphical abstract for this article
  • Sterically Induced Conformational Restriction: Discovery and Preclinical
           Evaluation of Novel Pyrrolo[3, 2-d]pyrimidines as Microtubule Targeting
    • Abstract: Publication date: Available online 21 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Roheeth Kumar Pavana, Khushbu Shah, Taylor Gentile, Nicholas F. Dybdal-Hargreaves, April L. Risinger, Susan L. Mooberry, Ernest Hamel, Aleem Gangjee The discovery, synthesis and biological evaluations of a series of nine N5-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds with microtubule depolymerizing activity were identified. Some of these compounds also circumvent clinically relevant tumor resistance mechanisms (expression of P-glycoprotein and βIII tubulin). Compounds 4, 5, and 8-13 were one to two-digit nanomolar (IC50) inhibitors of cancer cells in culture. Contrary to recent reports (Banerjee et al. J. Med. Chem.2018, 61, 1704-1718), the conformation of the most active compounds determined by 1H NMR and molecular modeling are similar to that reported previously and in keeping with recently reported x-ray crystal structures. Compound 11, freely water soluble as the HCl salt, afforded statistically significant inhibition of tumor growth in three xenograft models [MDA-MB-435, MDA-MB-231 and NCI/ADR-RES] compared with controls. Compound 11 did not display overt animal toxicity and is currently slated for further preclinical development.Graphical abstractGraphical abstract for this article
  • 4-Epi-Isofagomine Derivatives as Pharmacological Chaperones for the
           Treatment of Lysosomal Diseases Linked to β-Galactosidase Mutations:
           Improved Synthesis and Biological Investigations
    • Abstract: Publication date: Available online 21 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Sophie Front, Sofia Almeida, Vincent Zoete, Julie Charollais-Thoenig, Estelle Gallienne, Céline Marmy, Vincent Pilloud, Roger Marti, Tim Wood, Olivier R. Martin, Stéphane Demotz (5aR)-5a-C-pentyl-4-epi-isofagomine 1 is a powerful inhibitor of lysosomal β-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B. We report herein an improved synthesis of this compound and analogs (5a-C-methyl, pentyl, nonyl and phenylethyl derivatives), and a crystal structure of a synthetic intermediate that confirms its configuration resulting from the addition of a Grignard reagent. These compounds were evaluated as as glycosidase inhibitors and their potential as chaperones for mutant lysosomal galactosidases determined. Based on these results and on docking studies, the 5-C-pentyl derivative 1 was selected as the optimal structure for further investigations: this compound induces the maturation of mutated β-galactosidase in fibroblasts of a GM1-gangliosidosis patient and promote the decrease of keratan sulfate and oligosaccharide load in patient cells. Compound 1 is clearly capable of restoring β-galactosidase activity and of promoting maturation of the protein, which should result in significant clinical benefit. These properties strongly support the development of compound 1 for the treatment of GM1-gangliosidosis and Morquio disease type B patients harboring β-galactosidase mutations sensitive to pharmacological chaperoning.Graphical abstractGraphical abstract for this article
  • A new phenolic series of indenopyridinone as topoisomerase inhibitors:
           Design, synthesis, and structure-activity relationships
    • Abstract: Publication date: Available online 20 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Aarajana Shrestha, Seojeong Park, Hae Jin Jang, Pramila Katila, Ritina Shrestha, Youngjoo Kwon, Eung-Seok Lee DNA Topoisomerase IIα (topo IIα) is one of the most effective therapeutic targets to control cancer. In an effort to develop novel and effective topo IIα targeting anti-proliferative agent, a phenolic series of indenopyridinone and indenopyridinol were designed and prepared using efficient multi-component one pot synthetic method. Total twenty-two synthesized compounds were assessed for topo I and IIα inhibition, and anti-proliferation in three different human cancer cell lines. Overall structure-activity relationship study explored the significance of meta-phenolic group at 4-position and para-phenolic group at 2- and/or 4- position of indenopyridinone skeleton for strong topo IIα-selective inhibition and anti-proliferative activity against human cervix (HeLa) and colorectal (HCT15) cell lines. Compound 12 with excellent topo IIα inhibition (93.7%) was confirmed as a DNA intercalator that could be a new promising lead to develop effective topo IIα-targeted anticancer agents.Graphical abstractGraphical abstract for this article
  • Design, synthesis, and biological activity of substituted
           2-amino-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid derivatives as
           inhibitors of the inflammatory kinases TBK1 and IKKε for the treatment of
    • Abstract: Publication date: Available online 20 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Tyler S. Beyett, Xinmin Gan, Shannon M. Reilly, Andrew V. Gomez, Louise Chang, John J.G. Tesmer, Alan R. Saltiel, Hollis D. Showalter The non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and inhibitor of nuclear factor kappa-B kinase ε (IKKε) play a key role in insulin-independent pathways that promote energy storage and block adaptive energy expenditure during obesity. Utilizing docking calculations and the x-ray structure of TBK1 bound to amlexanox, an inhibitor of these kinases with modest potency, a series of analogues was synthesized to develop a structure activity relationship (SAR) around the A- and C-rings of the core scaffold. A strategy was developed wherein R7 and R8 A-ring substituents were incorporated late in the synthetic sequence by utilizing palladium-catalyzed cross-coupling reactions on appropriate bromo precursors. Analogues display IC50 values as low as 210 nM and reveal A-ring substituents that enhance selectivity toward either kinase. In cell assays, selected analogues display enhanced phosphorylation of p38 or TBK1 and elicited IL-6 secretion in 3T3-L1 adipocytes better than amlexanox. An analogue bearing a R7 cyclohexyl modification demonstrated robust IL-6 production in 3T3-L1 cells as well as a phosphorylation marker of efficacy and was tested in obese mice where it promoted serum IL-6 response, weight loss, and insulin sensitizing effects comparable to amlexanox. These studies provide impetus to expand the SAR around the amlexanox core toward uncovering analogues with development potential.Graphical abstractGraphical abstract for this article
  • Identification of N-(5-(phenoxymethyl)-1,3,4-thiadiazol-2-yl)acetamide
           derivatives as novel protein tyrosine phosphatase epsilon inhibitors
           exhibiting anti-osteoclastic activity
    • Abstract: Publication date: Available online 19 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Bonsu Ku, Hye-Yeoung Yun, Kyung Won Lee, Ho-Chul Shin, Sang-Rae Lee, Chang Hyen Kim, Hwangseo Park, Kyu Yang Yi, Chang Hoon Lee, Seung Jun Kim Cytosolic protein tyrosine phosphatase epsilon (cyt-PTPε) plays a central role in controlling differentiation and function of osteoclasts, whose overactivation causes osteoporosis. Based on our previous study reporting a number of cyt-PTPε inhibitory chemical compounds, we carried out a further and extended analysis of our compounds to examine their effects on cyt-PTPε-mediated dephosphorylation and on osteoclast organization and differentiation. Among five compounds showing target selectivity to cyt-PTPε over three other phosphatases in vitro, two compounds exhibited an inhibitory effect against the dephosphorylation of cellular Src protein, the cyt-PTPε substrate. Moreover, these two compounds caused destabilization of the podosome structure that is necessary for the bone-resorbing activity of osteoclasts, and also attenuated cellular differentiation of monocytes into osteoclasts, without affecting cell viability. Therefore, these findings not only verified anti-osteoclastic effects of our cyt-PTPε inhibitory compounds, but also showed that cyt-PTPε expressed in osteoclasts could be a putative therapeutic target worth considering.Graphical abstractGraphical abstract for this article
  • Development of 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and Their
           Salts as Potent Cytotoxic Agents and Topoisomerase I/ IIα Inhibitors
    • Abstract: Publication date: Available online 18 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Sateesh Kumar Arepalli, Chaerim Lee, Seongrak Sim, Kiho Lee, Hyunji Jo, Kyu-Yeon Jun, Youngjoo Kwon, Jong-Soon Kang, Jae-Kyung Jung, Heesoon Lee A novel series of 35 angularly fused pentacyclic 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridin-5-ium chlorides were designed and synthesized. Their cytotoxic activities were investigated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Among all screened compounds; 28, 30, 34, 35, 46, 48, 52, and 53 compounds exhibited potential cytotoxic activities against all tested human cancer cell lines. Further, these potent lead cytotoxic agents were evaluated against human Topoisomerase I and IIα inhibition. Among them, the compound 48 exhibited dual Topoisomerase I and IIα inhibition especially at 20 μM concentrations the compound 48 exhibited 1.25 times more potent Topoisomerase IIα inhibitory activity (38.3%) than the reference drug etoposide (30.6 %). The compound 52 also exhibited excellent (88.4 %) topoisomerase I inhibition than the reference drug camptothecin (66.7 %) at 100 μM concentrations. Molecular docking studies of the compounds 48 and 52 with topo I discovered that they both intercalated into the DNA single-strand cleavage site where the compound 48 have van der Waals interactions with residues Arg364, Pro431, and Asn722 whilst the compound 52 have with Arg364, Thr718, and Asn722 residues. Both the compounds 48 and 52 have π- π stacking interactions with the stacked DNA bases. The docking studies of the compound 48 with topo IIα explored that it was bound to the topo IIα DNA cleavage site where etoposide was situated. The benzo[f]chromeno[4,3-b][1,7]naphthyridine ring of the compound 48 was stacked between the DNA bases of the cleavage site with π- π stacking interactions and there were no hydrogen bond interactions with topo IIα.Graphical abstractGraphical abstract for this article
  • A truncated rhamm protein for discovering novel therapeutic peptides
    • Abstract: Publication date: Available online 18 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Alexandra Hauser-Kawaguchi, Cornelia Tolg, Teresa Peart, Mark Milne, Eva Turley, Leonard G. Luyt The receptor for hyaluronan mediated motility (RHAMM, gene name HMMR) belongs to a group of proteins that bind to hyaluronan (HA), a high-molecular weight anionic polysaccharide that has pro-angiogenic and inflammatory properties when fragmented. We propose to use a chemically synthesized, truncated version of the protein (706-767), 7 kDa RHAMM, as a target receptor in the screening of novel peptide-based therapeutic agents. Chemical synthesis by Fmoc-based solid-phase peptide synthesis, and optimization using pseudoprolines, results in RHAMM protein of higher purity and yield than synthesis by recombinant protein production. 7 kDa RHAMM was evaluated for its secondary structure, ability to bind the native ligand, HA, and its bioactivity. This 62-amino acid polypeptide replicates the HA binding properties of both native and recombinant RHAMM protein. Furthermore, tubulin-derived HA peptide analogues that bind to recombinant RHAMM and were previously reported to compete with HA for interactions with RHAMM, bind with a similar affinity and specificity to the 7 kDa RHAMM. Therefore, in terms of its key binding properties, the 7 kDa RHAMM mini-protein is a suitable replacement for the full-length recombinant protein.Graphical abstractGraphical abstract for this article
  • N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery,
           lead optimization and demonstration of off-target effect in a diabetes
    • Abstract: Publication date: Available online 18 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Hamid R. Hoveyda, Graeme L. Fraser, Ludivine Zoute, Guillaume Dutheuil, Didier Schils, Cyrille Brantis, Alexey Lapin, Julien Parcq, Sandra Guitard, François Lenoir, Mohamed El Bousmaqui, Sarah Rorive, Sandrine Hospied, Sébastien Blanc, Jérôme Bernard, Frédéric Ooms, Joanne C. McNelis, Jerrold M. Olefsky Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLE = 0.3, ΔFsp3 = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.Graphical abstractGraphical abstract for this article
  • Novel autophagy modulators: Design and synthesis of (+)-epogymnolactam
           analogues and structure-activity relationship
    • Abstract: Publication date: Available online 17 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Kazuki Ueda, Yuji Okado, Kengo Shigetomi, Makoto Ubukata (+)-Epogymnolactam (1) was discovered as a novel autophagy inducer from a culture of Gymnopus sp. in our laboratory. To determine structure-activity relationships among (+)-epogymnolactam analogues comparing with cerulenin (2), we synthesized 5 analogues including (–)-epogymnolactam (3) having each different functional group, and 3 analogues with different side-chain lengths. Five analogues, 3, 4, 5, 6, and 7 did not significantly increase the ratio of LC3-II to LC3-I as an autophagy marker in NIH3T3 cells. These results suggest that presence and stereochemistry of (2R,3S)-epoxy group and cyclic syn-form (1b) of 1 are important for the activity as autophagy inducer. Hexyl analogue (8) as well as 1 having butyl side-chain dose-dependently increased the ratio of LC3-II to LC3-I, whereas octyl analogue (9) and 2 rather decreased the ratio. Decyl analogue (10) did not give a change in the ratio. Although 8 seemed to be an excellent autophagy inducer, it dose-dependently increased SQSTM1 (p62) as in the case of 2, whereas 1 showed a slight dose-dependent decrease of p62 as an index of autophagic protein degradation. These observations suggest that 8 is an autophagy modulator with different molecular target from 1 or 2.Graphical abstractGraphical abstract for this article
  • Design and synthesis of thiazolylhydrazone dervatives as inhibitors of
           chitinolytic N-acetyl-β-D-hexosaminidase
    • Abstract: Publication date: Available online 17 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Huibin Yang, Tian Liu, Huitang Qi, Zhisong Huang, Zesheng Hao, Junwu Ying, Qing Yang, Xuhong Qian N-acetyl-β-D-hexosaminidase (Hex) is potential target for pesticide design. Here, a series of thiazolylhydrazone derivatives were designed, synthesized and evaluated as competitive inhibitors of OfHex1, a Hex from the agricultural pest Ostrinia furnacalis. The derivative 3k, with a (benzyloxy)methyl group at the N3 atom, demonstrated greater potency with a Ki of 10.2 µM. Molecular docking analysis indicated that the (benzyloxy)methyl group of 3k was bound to a previously unexplored pocket formed by Loop478-496. Then further optimization around naphthalene ring led to find the more potency substituent phenyl. The derivative 7, with phenoxyethyl group at R1 and a phenyl group at R2, demonstrated an augmented potency with a Ki of 2.1 µM. Molecular docking analysis indicated that 7 was bound to the active pocket of OfHex1 more favorably than 3k. This work suggests a novel scaffold for developing specific Hex inhibitors.Graphical abstractGraphical abstract for this article
  • Nanomolar Binding Affinity of Quinine-Based Antimalarial Compounds by the
           Cocaine-Binding Aptamer
    • Abstract: Publication date: Available online 17 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Sladjana Slavkovic, Zachary R. Churcher, Philip E. Johnson An unusual feature of the cocaine-binding aptamer is that it binds quinine much tighter than the ligand it was selected for, cocaine. Here we expand the repertoire of ligands that this aptamer binds to include the quinine-based antimalarial compounds amodiaquine, mefloquine, chloroquine and primaquine. Using isothermal titration calorimetry (ITC) we show that amodiaquine is bound by the cocaine-binding aptamer with an affinity of (7 ± 4) nM, one of the tightest aptamer-small molecule affinities currently known. Amodiaquine, mefloquine and chloroquine binding are driven by both a favorable entropy and enthalpy of binding, while primaquine, quinine and cocaine binding are enthalpy driven with unfavorable binding entropy. Using nuclear magnetic resonance (NMR) and ITC methods we show that these ligands compete for the same binding sites in the aptamer. Our identification of such a tight binding ligand for this aptamer should prove useful in developing new biosensor techniques and applications using the cocaine-binding aptamer as a model system.Graphical abstractGraphical abstract for this article
  • Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling
           and colorectal cancer growth
    • Abstract: Publication date: Available online 17 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Jiangbo Wang, Robert A. Mook, Xiu-rong Ren, Qingfu Zhang, Genevieve Jing, Min Lu, Ivan Spasojevic, H. Kim Lyerly, David Hsu, Wei Chen The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide’s anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.Graphical abstractGraphical abstract for this article
  • Structure-based design and synthesis of
           1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 17Author(s): Yuan Yin, Cheng-Juan Chen, Ru-Nan Yu, Zhi-Jian Wang, Tian-Tai Zhang, Da-Yong Zhang Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2 nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4 μM). Further, compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological mechanisms research on 1,2,3-triazole
           derivatives of Jiyuan Oridonin A
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 17Author(s): Yu Ke, Wang Wang, Long-Fei Zhao, Jian-Jia Liang, Ying Liu, Xiao Zhang, Kai Feng, Hong-Min Liu Two series of derivatives with 1,2,3-triazole as heterocyclic moiety of Jiyuan Oridonin A, a new ent-kaurene diterpenoid which was isolated from genus Isodon rubescens, were synthesized and biologically evaluated. All the derivatives possessed good anti-proliferative activities. Among them, compound 8g was found to significantly induce cell apoptosis and cell cycle arrest in MGC-803 via a series of signals activated by the increased intracellular ROS levels.Graphical abstractGraphical abstract for this article
  • Graphical abstract TOC
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 17Author(s):
  • Graphical abstract TOC
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 17Author(s):
  • Graphical abstract TOC
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 17Author(s):
  • Design, synthesis, and biological evaluation of novel selective peptide
           inhibitors of 11β-hydroxysteroid dehydrogenase 1
    • Abstract: Publication date: Available online 12 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Stephanie Boudon, Marc Heidl, Anna Vuorinen, Eliane Wandeler, Remo Campiche, Alex Odermatt, Eileen Jackson The enzyme 11β-HSD1 plays a crucial role in the tissue-specific regulation of cortisol levels and it has been associated with various diseases. Inhibition of 11β-HSD1 is an attractive intervention strategy and the discovery of novel selective 11β-HSD1 inhibitors is of high relevance. In this study, we identified and evaluated a new series of selective peptide 11β-HSD1 inhibitors with potential for skin care applications. This novel scaffold was designed with the aid of molecular modeling and two previously reported inhibitors. SAR optimization yielded highly active peptides (IC50 below 400 nM) that were inactive at 1 µM concentration against structurally related enzymes (11β-HSD2, 17β-HSD1 and 17β-HSD2). The best performing peptides inhibited the conversion of cortisone into cortisol in primary human keratinocytes and the most active compound, 5d, was further shown to reverse cortisone-induced collagen damage in human ex-vivo tissue.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of anthranilamide derivatives
           as potential factor Xa (fXa) inhibitors
    • Abstract: Publication date: Available online 11 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Junhao Xing, Lingyun Yang, Jinpei Zhou, Huibin Zhang Factor Xa (fXa) is a crucial player in various thromboembolic disorders. Inhibition of fXa can provide safe and effective antithrombotic effects. In this study, a series of anthranilamide compounds were designed by utilizing structure-based design strategies. Optimization at P1 and P4 groups led to the discovery of compound 16g: a highly potent, selective fXa inhibitor with pronounced in vitro anticoagulant activity. Moreover, 16g also displayed excellent in vivo antithrombotic activity in the rat venous thrombosis (VT) and arteriovenous shunt (AV-SHUNT) models. The bleeding risk evaluation showed that 16g had a safer profile than that of betrixaban at 1 mg/kg and 5 mg/kg dose. Additionally, 16g also exhibited satisfactory PK profiles. Eventually, 16g was selected to investigate its effect on hypoxia-reoxygenation- induced H9C2 cell viability. MTT results showed that H9C2 cell viability can be remarkably alleviated by 16g.Graphical abstractGraphical abstract for this article
  • Pyrrolo[2,1–c][1,4] benzodiazepine-3,11-diones protect SHSY-5Y cells
           from Cd-induced apoptosis involving suppression of endoplasmic reticulum
    • Abstract: Publication date: Available online 11 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Chao Ma, Ke Du, Ying Zhao, Linkui Zhang, Baichun Hu, Maosheng Cheng Cadmium (Cd) is a potent toxic heavy metal, some studies showed that Cd-induced apoptosis is through ER stress pathway. Compounds of pyrrolo[2,1–c][1,4]benzodiazepine (PBD)-3,11-diones were discovered as potent neuroprotective agents against Cd-induced toxicity in SH-SY5Y cells for the first time. In this study, twenty-six PBD-3,11-dione derivatives were synthesized and evaluated for their neuroprotective activity against Cd-induced toxicity by CCK-8 assay. Their preliminary SARs studies indicated that various substituents were tolerated on the benzene ring, and alkyl heterocycles groups at the N10-position of the PBD-3,11-dione scaffold were important for the activities. Among them, compound 13c exhibited the best activity (cell viability = 68.6%, 25μM). Furthermore, we found that the compound 13c could inhibit cadmium-induced cell apoptosis with the downregulation of the ER stress markers GRP78, CHOP, cleaved-caspase12 and cleaved-caspase3 through western blotting. The results of in silico evaluation of ADME/T properties showed that 13c exhibited medium BBB penetration level and promising toxicity profiles. These results proved the potential of 13c as a promising lead compound against Cd-induced neurotoxicity.Graphical abstractGraphical abstract for this article
  • Discovery of natural flavonoids as activators of Nrf2-mediated defense
           system: structure-activity relationship and inhibition of intracellular
           oxidative insults
    • Abstract: Publication date: Available online 11 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Yan-Ru Li, Guo-Hui Li, Ming-Xing Zhou, Lan Xiang, Dong-Mei Ren, Hong-Xiang Lou, Xiao-Ning Wang, Tao Shen Continuous overproduction of reactive oxygen species (ROS), termed as oxidative stress, plays a crucial role in the onset and progression of many human diseases. Activation of nuclear transcription factor erythroid 2-related factor (Nrf2) by small molecules could eliminate ROS, and thus block the pathogenesis of oxidative stress-induced diseases. In this study, a natural flavonoid library was established and tested for their potential Nrf2 inducing effects. Based on QR inducing effect of flavonoids, their structure-activity relationship (SAR) on Nrf2 induction was summarized, and twenty flavonoids were firstly identified to be potential activators of Nrf2-mediated defensive response. Then, 7-O-methylbiochanin A (7-MBA) was further investigated for its capability on the Nrf2 activation and prevention against oxidative insults in human lung epithelial cells. Further studies indicated that 7-MBA activated Nrf2 signaling pathway and protected human lung epithelial Beas-2B cells against sodium arsenite [As(III)]-induced cytotoxicity in an Nrf2-dependent manner. Activation of Nrf2 by 7-MBA upregulated intracellular antioxidant capacity, which was produced by enhancement of Nrf2 stabilization, blockage of Nrf2 ubiquitination, as well as Nrf2 phosphorylation by mitogen-activated protein kinase (MAPK), protein kinase C (PKC), protein kinase R-like endoplasmic reticulum kinase (PERK), and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Taken together, 7-MBA is a novel isoflavone-type Nrf2 activator displaying potential preventive effect against oxidative damages in human lung epithelial cells.Graphical abstractGraphical abstract for this article
  • Discovery of DS-6930, a Potent Selective PPARγ Modulator. Part I:
           Lead Identification
    • Abstract: Publication date: Available online 8 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Tsuyoshi Shinozuka, Tomoharu Tsukada, Kunihiko Fujii, Eri Tokumaru, Kousei Shimada, Yoshiyuki Onishi, Yumi Matsui, Satoko Wakimoto, Masanori Kuroha, Tsuneaki Ogata, Kazushi Araki, Jun Ohsumi, Ryoko Sawamura, Nobuaki Watanabe, Hideki Yamamoto, Kazunori Fujimoto, Yoshiro Tani, Makoto Mori, Jun Tanaka The lead identification of a novel potent selective PPARγ agonist, DS-6930 is reported. To avoid PPARγ-related adverse effects, a partial agonist was designed to prevent the direct interaction with helix 12 of PPARγ-LBD. Because the TZD group is known to interact with helix 12, the TZD in efatutazone (CS-7017) was replaced to discover novel PPARγ intermediate partial agonist 8i. The optimization of 8i yielded 13ac with high potency in vitro. Compound 13ac exhibited robust plasma glucose lowering effects comparable to those of rosiglitazone (3 mg/kg) in Zucker diabetic fatty rats. Upon toxicological evaluation, compound 13ac (300 mg/kg) induced hemodilution to a lower extent than rosiglitazone; however, 13ac elevated liver enzyme activities. X-ray crystallography revealed no direct interaction of 13ac with helix 12, and the additional lipophilic interactions are also suggested to be related to the maximum transcriptional activity of 13ac.Graphical abstractGraphical abstract for this article
  • Discovery of DS-6930, a Potent Selective PPARγ Modulator. Part II:
           Lead Optimization
    • Abstract: Publication date: Available online 8 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Tsuyoshi Shinozuka, Tomoharu Tsukada, Kunihiko Fujii, Eri Tokumaru, Kousei Shimada, Yoshiyuki Onishi, Yumi Matsui, Satoko Wakimoto, Masanori Kuroha, Tsuneaki Ogata, Kazushi Araki, Jun Ohsumi, Ryoko Sawamura, Nobuaki Watanabe, Hideki Yamamoto, Kazunori Fujimoto, Yoshiro Tani, Makoto Mori, Jun Tanaka Attempts were made to reduce the lipophilicity of previously synthesized compound (II) for the avoidance of hepatotoxicity. The replacement of the left-hand side benzene with 2-pyridine resulted in the substantial loss of potency. Because poor membrane permeability was responsible for poor potency in vitro, the adjustment of lipophilicity was examined, which resulted in the discovery of dimethyl pyridine derivative (I, DS-6930). In preclinical studies, DS-6930 demonstrated high PPARγ agonist potency with robust plasma glucose reduction. DS-6930 maintained diminished PPARγ-related adverse effects upon toxicological evaluation in vivo, and demonstrated no hepatotoxicity. Cofactor recruitment assay showed that several cofactors, such as RIP140 and PGC1, were significantly recruited, whereas several canonical factors was not affected. This selective cofactor recruitment was caused due to the distinct binding mode of DS-6930. The calcium salt, DS-6930b, which is expected to be an effective inducer of insulin sensitization without edema, could be evaluated clinically in T2DM patients.Graphical abstractGraphical abstract for this article
  • Structure-Activity Relationship of Novel (Benzoylaminophenoxy)phenol
           Derivatives as Anti-prostate Cancer Agents
    • Abstract: Publication date: Available online 6 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Yuko Kazui, Shinya Fujii, Ayumi Yamada, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Aya Tanatani The androgen receptor (AR) is a ligand-inducible transcription factor belonging to the nuclear receptor superfamily, and is a target molecule for development of drugs to treat prostate cancer. However, AR antagonists in clinical use, such as flutamide (3a) and bicalutamide (4), encounter resistance after several years of hormone therapy, predominantly due to mutations of AR. Thus, although some new-generation AR antagonists have been developed, novel types of AR antagonists are still required to treat drug-resistant prostate cancer. We previously reported a novel (benzoylaminophenoxy)phenol derivative 10a, which is structurally distinct from conventional AR antagonists. Here, we systematically examined the structure-activity relationship of (benzoylaminophenoxy)phenol derivatives on the inhibitory activity on the prostate cancer cell proliferations. We found that the 4-[4-(benzoylamino)phenoxy]phenol backbone is important for anti-prostate cancer activity. Introduction of a small substituent at the 2 position of the central benzene ring (B ring) increases the activity. Among the synthesized compounds, 19a and 19b exhibited the most potent inhibitory activity toward dihydrotestosterone-induced proliferation of several androgen-dependent cell lines, SC-3 (wild-type AR), LNCaP (T877A AR), and 22Rv1 (H874Y AR), but interestingly also inhibited proliferation of AR-independent PC-3 cells. These compounds, which have a different pharmacophore from conventional AR antagonists, are promising drug candidates for the treatment of prostate cancer.Graphical abstractGraphical abstract for this article
  • Synthesis of oxidative metabolites of CRA13 and their analogs:
           Identification of CRA13 active metabolites and analogs thereof with
           selective CB2R affinity
    • Abstract: Publication date: Available online 6 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Ahmed H.E. Hassan, Min Chang Cho, Hye In Kim, Ji Seul Yang, Kyung Tae Park, Ji Young Hwang, Choon-Gon Jang, Ki Duk Park, Yong Sup Lee CRA13; a peripheral dual CB1R/CB2R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB1R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB1R affinity. Metabolism produces less lipophilic metabolites that could be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB1R and CB2R activity revealed the alcohol metabolite (8c) as a more potent and more effective CB2R ligand with attenuated CB1R affinity relative to CRA13. Also, the alcohol analogue (8b) and methyl ester (12a) possessed enhanced CB2R affinity and reduced CB1R affinity. The CB2R binding affinity of alcohol analogue 8b was similar to CRA13 while that of methyl ester 12a was more potent. In silico study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.Graphical abstractGraphical abstract for this article
  • Thiazole- and selenazole-comprising high-affinity inhibitors possess
           bright microsecond-scale photoluminescence in complex with protein kinase
    • Abstract: Publication date: Available online 5 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Jürgen Vahter, Kaido Viht, Asko Uri, Ganesh babu Manoharan, Erki Enkvist A previously disclosed protein kinase (PK) CK2-selective inhibitor 4-(2-amino-1,3-thiazol-5-yl)benzoic acid (ATB) and its selenium-containing counterpart (ASB) revealed remarkable room temperature phosphorescence when bound to the ATP pocket of the protein kinase CK2. Conjugation of these fragments with a mimic of CK2 substrate peptide resulted in bisubstrate inhibitors with increased affinity towards the kinase. Attachment of the fluorescent acceptor dye 5-TAMRA to the conjugates led to significant enhancement of intensity of long-lifetime (microsecond-scale) photoluminescence of both sulfur- and selenium-containing compounds. The developed photoluminescent probes make possible selective determination of the concentration of CK2 in cell lysates and characterization of CK2 inhibitors by means of time-gated measurement of photoluminescence.Graphical abstractGraphical abstract for this article
  • Antifungal Benzo[b]thiophene 1,1-dioxide IMPDH Inhibitors Exhibit
           Pan-Assay Interference (PAINS) Profiles
    • Abstract: Publication date: Available online 5 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Lalith K. Kummari, Mark S. Butler, Emily Furlong, Ross Blundell, Amanda Nouwens, Alberto B. Silva, Ulrike Kappler, James A. Fraser, Bostjan Kobe, Matthew A. Cooper, Avril A.B. Robertson Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor.Graphical abstractGraphical abstract for this article
  • 4-(3-Alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides as new
           antimitotic prodrugs activated by cytochrome P450 1A1 in breast cancer
    • Abstract: Publication date: Available online 4 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Atziri Corin Chavez Alvarez, Mitra Zarifi Khosroshahi, Marie-France Côté, Mathieu Gagné-Boulet, Sébastien Fortin The role and the importance of the sulfonate moiety in phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were assessed using its bioisosteric sulfonamide equivalent leading to new cytochrome P450 1A1 (CYP1A1)-activated prodrugs designated as 4-(3-alkyl-2-oxoimidazolidin-1-yl)-N-phenylbenzenesulfonamides (PAIB-SAs). PAIB-SAs are active in the submicromolar to low micromolar range showing selectivity toward CYP1A1-expressing MCF7 cells as compared to cells devoid of CYP1A1 activity such as MDA-MB-231 and HaCaT cells. The most potent PAIB-SA 13 bearing a trimethoxyphenyl group on ring B blocks the cell cycle progression in G2/M phase, disrupts the microtubule dynamics and is biotransformed by CYP1A1 into CEU-638, its potent antimicrotuble counterpart. Structure-activity relationships related to PAIB-SOs and PAIB-SAs evidenced that PAIB-SOs and PAIB-SAs are true bioisosteric equivalents fully and selectively activatable by CYP1A-expressing cells into potent antimitotics.Graphical abstractGraphical abstract for this article
  • Andrographolide Derivative as STAT3 Inhibitor that Protects Acute Liver
           Damage in Mice
    • Abstract: Publication date: Available online 4 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Shao-Ru Chen, Feng Li, Mo-Yu Ding, Decai Wang, Qi Zhao, Yitao Wang, Guo-Chun Zhou, Ying Wang Sustained activation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway contributed to the progression of cancer and liver diseases. STAT3 signaling inhibitor has been extensively investigated for pharmacological use. We synthesized a series of andrographolide derivatives, and characterized their activity against STAT3 signaling pathway both in vitro and in the CCl4-induced acute liver damage mice model. Among these derivatives, compound 24 effectively inhibited phosphorylation and dimerization of STAT3 but not its DNA binding activity. Compound 24 significantly ameliorated carbon tetrachloride-induced acute liver damage in vivo without changing mice body weight. Treatment with 24 attenuated hepatic pathologic damage and promoted hepatic proliferation and activation of STAT3. Compound 24 inhibited elevated expression of α-smooth muscle actin and serum pro-inflammatory cytokines downstream of STAT3 but not those factors that are regulated by NF-κB or SMADs. In summary, our results suggest that compound 24 may serve as a potential therapeutic agent for the treatment of hepatic damage or a liver protection agent via regulating STAT3 activation.Graphical abstractGraphical abstract for this article
  • Discovery and structural characterization of peficitinib (ASP015K) as a
           novel and potent JAK inhibitor
    • Abstract: Publication date: Available online 4 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Hisao Hamaguchi, Yasushi Amano, Ayako Moritomo, Shohei Shirakami, Yutaka Nakajima, Kazuo Nakai, Naoko Nomura, Misato Ito, Yasuyuki Higashi, Takayuki Inoue Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3–b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.Graphical abstractGraphical abstract for this article
  • Oximes short-acting CB1 receptor agonists
    • Abstract: Publication date: Available online 2 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Michael S. Malamas, Jimit Girish Raghav, Xiaoyu Ma, Chandrashekhar Honrao, JodiAnne T. Wood, Othman Benchama, Han Zhou, Srikrishnan Mallipeddi, Alexandros Makriyannis New oximes short-acting CB1 agonists were explored by the introduction of an internal oxime and polar groups at the C3 alkyl tail of Δ8-THC. The scope of the research was to drastically alter two important physicochemical properties hydrophobicity (log P) and topological surface area (tPSA) of the compound, which play a critical role in tissue distribution and sequestration (depot effect). Key synthesized analogs demonstrated sub-nanomolar affinity for CB1, marked reduction in hydrophobicity (ClogP∼2.5–3.5 vs 9.09 of Δ8-THC-DMH), and found to function as either agonists (trans-oximes) or neutral antagonists (cis-oximes) in a cAMP functional assay. All oxime analogs showed comparable affinity at the CB2 receptor, but surprisingly they were found to function as inverse agonists for CB2. In behavioral studies (i.e. analgesia, hypothermia) trans-oxime 8a exhibited a predictable fast onset (∼20 min) and short duration of pharmacological action (∼180 min), in contrast to the very prolonged duration of Δ8-THC-DMH (>24 h), thus limiting the potential for severe psychotropic side-effects associated with persistent activation of the CB1 receptor. We have conducted 100 ns molecular dynamic (MD) simulations of CB1 complexes with AM11542 (CB1 agonist) and both trans-8a and cis-8b isomeric oximes. These studies revealed that the C3 alkyl tail of cis-8b orientated within the CB1 binding pocket in a manner that triggered a conformational change that stabilized the CB1 receptor at its inactive-state (antagonistic functional effect). In contrast, the trans-8a isomer’s conformation was coincided with that of the AM11542 CB1 agonist-bound structure, stabilizing the CB1 receptor at the active-state (agonistic functional effect). We have selected oxime trans-8a based on its potency for CB1, and favorable pharmacodynamic profile, such as fast onset and predictable duration of pharmacological action, for evaluation in pre-clinical models of anorexia nervosa.Graphical abstractGraphical abstract for this article
  • Discovery and biological evaluation of thiobarbituric derivatives as
           potent p300/CBP inhibitors
    • Abstract: Publication date: Available online 27 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Wenchao Lu, Huan Xiong, Yu Chen, Chen Wang, Hao Zhang, Pan Xu, Jie Han, Senhao Xiao, Hong Ding, Zhifeng Chen, Tian Lu, Jun Wang, Yuanyuan Zhang, Liyan Yue, Yu-Chih Liu, Chenhua Zhang, Yaxi Yang, Hualiang Jiang, Kaixian Chen, Bing Zhou Histone acetyltransferases (HATs) relieve transcriptional repression by preferentially acetylation of ε-amino group of lysine residues on histones. Dysregulation of HATs is strongly correlated with etiology of several diseases especially cancer, thus highlighting the utmost significance of the development of small molecule inhibitors against this potential therapeutic target. In the present study, through virtual screening and iterative optimization, we identified DCH36_06 as a bona fide, potent p300/CBP inhibitor. DCH36_06 mediated p300/CBP inhibition leading to hypoacetylation on H3K18 in leukemic cells. The suppression of p300/CBP activity retarded cell proliferation in several leukemic cell lines. In addition, DCH36_06 arrested cell cycle at G1 phase and induced apoptosis via activation of capase3, caspase9 and PARP that elucidated the molecular mechanism of its anti-proliferation activity. In transcriptome analysis, DCH36_06 altered downstream gene expression and apoptotic pathways-related genes verified by real-time PCR. Importantly, DCH36_06 blocked the leukemic xenograft growth in mice supporting its potential for in vivo use that underlies the therapeutic potential for p300/CBP inhibitors in clinical translation. Taken together, our findings suggest that DCH36_06 may serve as a qualified chemical tool to decode the acetylome code and open up new opportunities for clinical intervention.Graphical abstractGraphical abstract for this article
  • Synthesis, in vitro and in vivo biological evaluation, COX-1/2 inhibition
           and molecular docking study of indole-N-acylhydrazone derivatives
    • Abstract: Publication date: Available online 17 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Ana Daura Travassos de Oliveira Moraes, Mirelly Dianne Santos de Miranda, Íris Trindade Tenório Jacob, Cézar Augusto da Cruz Amorim, Ricardo Olímpio de Moura, Simone Ângela Soares da Silva, Milena Botelho Pereira Soares, Sinara Mônica Vitalino de Almeida, Túlio Ricardo Couto de Lima Souza, Jamerson Ferreira de Oliveira, Teresinha Gonçalves da Silva, Cristiane Moutinho Lagos de Melo, Diogo Rodrigo Magalhães Moreira, Maria do Carmo Alves de Lima The objective of this work was to obtain and evaluate anti-inflammatory in vitro, in vivo and in silico potential of novel indole-N-acylhydrazone derivatives. In total, 10 new compounds (3a-j) were synthesized in satisfactory yields, through a condensation reaction in a single synthesis step. In the lymphoproliferation assay, using mice splenocytes, 3a and 3b showed inhibition of lymphocyte proliferation of 62.7% (±3.5) and 50.7% (±2), respectively, while dexamethasone presented an inhibition of 74.6% (±2.4). Moreover, compound 3b induced higher Th2 cytokines production in mice splenocytes cultures. The results for COX inhibition assays showed that compound 3b is a selective COX-2 inhibitor, but with less potency when compared to celecoxib, and compound 3a not presented selectivity towards COX-2. The molecular docking results suggest compounds 3a and 3b interact with the active site of COX-2 in similar conformations, but not with the active site of COX-1, and this may be the main reason to the COX-2 selectivity of compound 3b. In vivo carrageenan-induced paw edema assays were adopted for the confirmation of the anti-inflammatory activity. Compound 3b showed better results in suppressing edema at all tested concentrations and was able to induce an edema inhibition of 100% after 5 hours of carrageenan injection at the 30 mg kg-1 dosage, corroborating with the COX inhibition and lymphoproliferation results. I addition to our experimental results, in silico analysis suggest that compounds 3a and 3b present a well-balanced profile between pharmacodynamics and pharmacokinetics. Thus, our preliminary results revealed the potentiality of a new COX-2 selective derivative in the modulation of the inflammatory process.Graphical abstractGraphical abstract for this article
  • Kinetic analyses and structure-activity relationship studies of synthetic
           lysine acetylation catalysts
    • Abstract: Publication date: Available online 7 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Kenzo Yamatsugu, Masahiro Furuta, Siqi Xi, Yoshifumi Amamoto, Jiaan Liu, Shigehiro A. Kawashima, Motomu Kanai Lysine acylation of proteins is a crucial chemical reaction, both as a post-translational modification and as a method for bioconjugation. We previously developed a chemical catalyst, DSH, which activates a chemically stable thioester including acyl-CoA, allowing the site-selective lysine acylation of histones under physiological conditions. However, a more active catalyst is required for efficient lysine acylation in more complex biological milieu, such as in living cells, but there are no rational guidelines for developing efficient lysine acylation catalysts for use under physiological conditions as opposed to in organic solvents. We, herein, conducted a kinetic analysis of the ability of DSH and several derivatives to mediate lysine acetylation to better understand the structural elements essential for high acetylation activity under physiological conditions. Interestingly, the obtained trend in reactivity was different from that observed in organic solvents, suggesting that a different principle is necessary for designing chemical catalysts specifically for use under physiological conditions compared to catalysts for use in organic solvents. Based on the obtained information, we identified a new catalyst scaffold with high activity and structural flexibility for further modification to improve this catalyst system.Graphical abstractGraphical abstract for this article
  • Structure-guided engineering of TGF-βs for the development of novel
           inhibitors and probing mechanism
    • Abstract: Publication date: Available online 7 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Andrew P. Hinck The increasing availability of detailed structural information on many biological systems provides an avenue for manipulation of these structures, either for probing mechanism or for developing novel therapeutic agents for treating disease. This has been accompanied by the advent of several powerful new methods, such as the ability to incorporate non-natural amino acids or perform fragment screening, increasing the capacity to leverage this new structural information to aid in these pursuits. The abundance of structural information also provides new opportunities for protein engineering, which may become more and more relevant as treatment of diseases using gene therapy approaches become increasingly common. This is illustrated by example with the TGF-β family of proteins, for which there is ample structural information, yet no approved inhibitors for treating diseases, such as cancer and fibrosis that are promoted by excessive TGF-β signaling. The results presented demonstrate that through several relatively simple modifications, primarily involving the removal of an α-helix and replacement of it with a flexible loop, it is possible to alter TGF-βs from being potent signaling proteins into inhibitors of TGF-β signaling. The engineered TGF-βs have improved specificity relative to kinase inhibitors and a much smaller size compared to monoclonal antibodies, and thus may prove successful as either as an injected therapeutic or as a gene therapy-based therapeutic, where other classes of inhibitors have failed.Graphical abstractGraphical abstract for this article
  • Molecular dynamics simulations of viral neuraminidase inhibitors with the
           human neuraminidase enzymes: Insights into isoenzyme selectivity
    • Abstract: Publication date: Available online 23 May 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Michele R. Richards, Tianlin Guo, Carmanah D. Hunter, Christopher W. Cairo Inhibitors of viral neuraminidase enzymes have been previously developed as therapeutics. Humans can express multiple forms of neuraminidase enzymes (NEU1, NEU2, NEU3, NEU4) that share a similar active site and enzymatic mechanism with their viral counterparts. Using a panel of purified human neuraminidase enzymes, we tested the inhibitory activity of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir, oseltamivir, and peramivir against each of the human isoenzymes. We find that, with the exceptions of DANA and zanamivir, these compounds show generally poor activity against the human neuraminidase enzymes. To provide insight into the interactions of viral inhibitors with human neuraminidases, we conducted molecular dynamics simulations using homology models based on coordinates reported for NEU2. Simulations revealed that an organized water is displaced by zanamivir in binding to NEU2 and NEU3 and confirmed the critical importance of engaging the binding pocket of the C7–C9 glycerol sidechain. Our results suggest that compounds designed to target the human neuraminidases should provide more selective tools for interrogating these enzymes. Furthermore, they emphasize a need for additional structural data to enable structure-based drug design in these systems.Graphical abstractGraphical abstract for this article
  • Halogenated trimethoprim derivatives as multidrug-resistant Staphylococcus
           aureus therapeutics
    • Abstract: Publication date: Available online 19 May 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Napon Nilchan, Wanida Phetsang, Taechin Nowwarat, Soraya Chaturongakul, Chutima Jiarpinitnun Incorporation of halogen atoms to drug molecule has been shown to improve its properties such as enhanced in membrane permeability and increased hydrophobic interactions to its target. To investigate the effect of halogen substitutions on the antibacterial activity of trimethoprim (TMP), we synthesized a series of halogen substituted TMP and tested for their antibacterial activities against global predominant methicillin resistant Staphylococcus aureus (MRSA) strains. Structure-activity relationship analysis suggested a trend in potency that correlated with the ability of the halogen atom to facilitate in hydrophobic interaction to saDHFR. The most potent derivative, iodinated trimethoprim (TMP-I), inhibited pathogenic bacterial growth with MIC as low as 1.25 μg/mL while the clinically used TMP derivative, diaveridine, showed resistance. Similar to TMP, synergistic studies indicated that TMP-I functioned synergistically with sulfamethoxazole. The simplicity in the synthesis from an inexpensive starting material, vanillin, highlighted the potential of TMP-I as antibacterial agent for MRSA infections.Graphical abstractGraphical abstract for this article
  • l-homoserine+lactone+analogs+in+two+Pseudomonas+aeruginosa+quorum+sensing+receptors+that+share+a+common+native+ligand+yet+inversely+regulate+virulence&rft.title=Bioorganic+&+Medicinal+Chemistry&rft.issn=0968-0896&">A comparative study of non-native N-acyl l-homoserine lactone analogs in
           two Pseudomonas aeruginosa quorum sensing receptors that share a common
           native ligand yet inversely regulate virulence
    • Abstract: Publication date: Available online 14 May 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Michelle E. Boursier, Daniel E. Manson, Joshua B. Combs, Helen E. Blackwell Certain bacteria can coordinate group behaviors via a chemical communication system known as quorum sensing (QS). Gram-negative bacteria typically use N-acyl l-homoserine lactone (AHL) signals and their cognate intracellular LuxR-type receptors for QS. The opportunistic pathogen Pseudomonas aeruginosa has a relatively complex QS circuit in which two of its LuxR-type receptors, LasR and QscR, are activated by the same natural signal, N-(3-oxo)-dodecanoyl l-homoserine lactone. Intriguingly, once active, LasR activates virulence pathways in P. aeruginosa, while activated QscR can inactivate LasR and thus repress virulence. We have a limited understanding of the structural features of AHLs that engender either agonistic activity in both receptors or receptor-selective activity. Compounds with the latter activity profile could prove especially useful tools to tease out the roles of these two receptors in virulence regulation. A small collection of AHL analogs was assembled and screened in cell-based reporter assays for activity in both LasR and QscR. We identified several structural motifs that bias ligand activation towards each of the two receptors. These findings will inform the development of new synthetic ligands for LasR and QscR with improved potencies and selectivities.Graphical abstractGraphical abstract for this article
  • Synthesis of the ABC framework of tamulamides A and B
    • Abstract: Publication date: Available online 22 April 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Elizabeth H. Kelley, Timothy F. Jamison Synthesis of the fused tetrahydrofuran motif comprising the ABC rings of the marine ladder polyethers tamulamides A and B has been achieved via two different polyepoxide cascade strategies. Investigations into a triepoxide cascade under aqueous conditions revealed the importance of the electronic nature of the cascade end-group with this initial approach. Ultimately, a diepoxide cascade under basic conditions proved most successful, providing the ABC tetrahydropyran triad in 41% yield.Graphical abstractGraphical abstract for this article
  • Screening serine/threonine and tyrosine kinase inhibitors for histidine
           kinase inhibition
    • Abstract: Publication date: Available online 22 April 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Kaelyn E. Wilke, Conrad A. Fihn, Erin E. Carlson Histidine kinases of bacterial two-component systems are promising antibacterial targets. Despite their varied, numerous roles, enzymes in the histidine kinase superfamily share a catalytic core that may be exploited to inhibit multiple histidine kinases simultaneously. Characterized by the Bergerat fold, the features of the histidine kinase ATP-binding domain are not found in serine/threonine and tyrosine kinases. However, because each kinase family binds the same ATP substrate, we sought to determine if published serine/threonine and tyrosine kinase inhibitors contained scaffolds that would also inhibit histidine kinases. Using select assays, 222 inhibitors from the Roche Published Kinase Set were screened for binding, deactivation, and aggregation of histidine kinases. Not only do the results of our screen support the distinctions between ATP-binding domains of different kinase families, but the lead molecule identified also presents inspiration for further histidine kinase inhibitor development.Graphical abstractGraphical abstract for this article
  • Synthesis of (E)-cinnamyl ester derivatives via a greener
           Steglich esterification
    • Abstract: Publication date: Available online 20 April 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Andrew B. Lutjen, Mackenzie A. Quirk, Allycia M. Barbera, Erin M. Kolonko Cinnamic acid derivatives are known antifungal, antimicrobial, antioxidant, and anticancer compounds. We have developed a facile and mild methodology for the synthesis of (E)-cinnamate derivatives using a modified Steglich esterification of (E)-cinnamic acid. Using acetonitrile as the solvent, rather than the typical chlorinated solvent, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as the coupling agent enables ester conversion in 45 min with mild heating (40–45 °C) and an average yield of 70% without need for further purification. These conditions were used to couple (E)-cinnamic acid with 1° and 2° aliphatic alcohols, benzylic and allylic alcohols, and phenols. This work demonstrates a facile and greener methodology for Steglich esterification reactions.Graphical abstractGraphical abstract for this article
  • Synthesis and biological evaluation of novel heteroring-annulated
           pyrrolino-tetrahydroberberine analogues as antioxidant agents
    • Abstract: Publication date: Available online 1 September 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Giacomo Mari, Simona Catalani, Elena Antonini, Lucia De Crescentini, Fabio Mantellini, Stefania Santeusanio, Paolo Lombardi, Antonella Amicucci, Serafina Battistelli, Serena Benedetti, Francesco Palma Tetrahydroberberine (THB), otherwise known as canadine, is a natural alkaloid showing significant pharmacological properties and antioxidant protection against oxidative damage. Herein, we synthetized structurally complex THB analogues, namely pyrrolino-tetrahydroberberines (PTHBs) 4a-g, containing the pyrrolino[2,3-b]pyridine system, by means of the reactions of 1,2-diaza-1,3-dienes and 7,8-dihydroberberine. Aim of the study was to explore the in vitro antioxidant properties of PTHBs in comparison to THB thus to identify the most effective against free radical-induced oxidative injury, by using three different antioxidant tests: the ORAC method, the DNA nicking assay, and the DCFH-DA cellular assay. As a result, PTHB 4d emerged among the other THB analogues by exhibiting the best antioxidant properties. First, it was the only compound having an ORAC value completely comparable to that of THB, indicating the same ability to neutralize peroxyl radicals. Secondly, 4d showed an even better antioxidant capacity than THB in protecting DNA against ferrous ion-induced strand breaks. These observations were also confirmed in NCTC-2544 human keratinocytes exposed to hydrogen peroxide. Indeed, 4d protected cells against oxidation more efficiently than THB both in the short (1 and 3 h) and long (24 h) period of incubation, possibly suggesting increased cell membrane permeability and/or intracellular stability of 4d as compared to THB.Graphical abstractGraphical abstract for this article
  • Novel 4-(2-Pyrimidinylamino)benzamide Derivatives as Potent Hedgehog
           Signaling Pathway Inhibitors
    • Abstract: Publication date: Available online 31 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Minhang Xin, Liandi Zhang, Chongxing Tu, Feng Tang, Jun Wen A series of novel hedgehog signaling pathway inhibitors have been designed and synthesized based on our previously reported scaffold of 4-(2-pyrimidinylamino)benzamide. The Hh signaling pathway inhibitory activities were evaluated by Gli-luciferase reporter method and most compounds showed more potent inhibitory activities than vismodegib. Three compounds were picked out to evaluated in vivo for their PK properties, and compound 23b bearing a 2-pyridyl A-ring and (morpholin-4-yl)methylene at 3-position of D-ring demonstrated satisfactory PK properties. This study suggested the 4-(2-pyrimidinylamino)benzamides were a series of potent Hh signaling pathway inhibitors, deserving to further structural optimization.Graphical abstractGraphical abstract for this article
  • Efflux pump inhibition by 11H-pyrido[2,1-b]quinazolin-11-one analogues in
    • Abstract: Publication date: Available online 29 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Tejosmita Sen, Kashmiri Neog, Sangita Sarma, Prasenjit Manna, Hari Prasanna Deka Boruah, Pranjal Gogoi, Anil Kumar Singh Mycobacterium tuberculosis infection causes 1.8 million deaths worldwide, of which half a million has been diagnosed with resistant tuberculosis (TB). Emergence of multi drug resistant and extensive drug resistant strains has made all the existing anti-TB therapy futile. The major involvement of efflux pump in drug resistance has made it a direct approach for therapeutic exploration against resistant M. tuberculosis. This study demarcates the role of 11H-pyrido[2,1-b]quinazolin-11-one (quinazolinone) analogues as efflux pump Mycobacterium smegmatis. Sixteen quinazolinone analogues were synthesized by treating 2-aminopyridine and 2-fluorobenzonitrile with KtOBu. Analogues were tested, and 3a, 3b, 3c, 3g, 3j, 3l, 3m, and 3p were found to modulate EtBr MIC by>4 whereas 3a, 3g, 3i and 3o showed>4 modulation on norfloxacin MIC. 3l and 3o in addition to their very low toxicity they showed high EtBr and norfloxacin accumulation respectively. Time kill curve showed effective log reduction in colony forming unit in presence of these analogues, thus confirming their role as efflux pump inhibitor. Through docking and alignment studies, we have also shown that the LfrA amino acid residues that the analogues are interacting with are present in Rv2333c and Rv2846c of M. tuberculosis. This study have shown for the first time the possibility of developing the 11H-pyrido[2,1-b]quinazolin-11-one analogues as efflux pump inhibitors for M. smegmatis and hence unbolts the scope to advance this study against resistant M. tuberculosis as well.Graphical abstractGraphical abstract for this article
  • Design, Synthesis, and Biological Evaluation of selective and potent
           Carbazole-Based Butyrylcholinesterase Inhibitors
    • Abstract: Publication date: Available online 29 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Roshanak Ghobadian, Hamid Nadri, Alireza Moradi, Syed Nasir Abbas Bukhari, Mohammad Mahdavi, Mehdi Asadi, Tahmineh Akbarzadeh, Hossein Khaleghzadeh-Ahangar, Mohammad Sharifzadeh, Mohsen Amini Alzheimer’s disease (AD) is the most common form of dementia. Inhibition of BChE might be a useful therapeutic target for AD. A new series of Carbazole-Benzyl Pyridine derivatives were designed synthesized and evaluated as butyrylcholinesterase (BChE) inhibitors. In vitro assay revealed that all of the derivatives had selective and potent anti- BChE activities. 3-((9H-Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride (compound 8f) had the most potent anti-BChE activity (IC50 value = 0.073 μM), the highest BChE selectivity and mixed-type inhibition. Docking study revealed that 8f interacted with the peripheral site, the choline binding site, catalytic site and the acyl pocket of BChE. Physicochemical properties were accurate to Lipinski's rule. In addition, compound 8f demonstrated neuroprotective activity at 10 µM. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation at concentration of 100 µM and 10 µM respectively. The in-vivo study showed that compound 8f in 10 mg/kg increased the time spent in target quadrant in the probe day and decreased mean training period scape latency in rats. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.Graphical abstractGraphical abstract for this article
  • Amphipathic sulfonamidobenzamides mimicking small antimicrobial marine
           natural products; investigation of antibacterial and anti-biofilm activity
           against antibiotic resistant clinical isolates
    • Abstract: Publication date: Available online 28 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Elizaveta M. Igumnova, Ekaterina Mishchenko, Tor Haug, Hans-Matti Blencke, Johanna U. Ericson Sollid, Elizabeth G. Aarag Fredheim, Silje Lauksund, Klara Stensvåg, Morten B. Strøm There is an urgent need for novel antimicrobial agents to address the threat of bacterial resistance to modern society. We have used a structural motif found in antimicrobial marine hit compounds as a basis for synthesizing a library of antimicrobial sulfonamidobenzamide lead compounds. Potent in vitro antimicrobial activity against clinically relevant bacterial strains was demonstrated for two compounds, G6 and J18, with minimal inhibitory concentrations (MIC) of 4–16 μg/ml against clinical methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). The two compounds G6 and J18, together with several other compounds of this library, also caused ≥90% eradication of pre-established biofilm of methicillin-resistant S. epidermidis (MRSE) at 40 μg/ml. Using a luciferase assay, the mechanism of action of G6 was shown to resemble the biocide chlorhexidine by targeting the bacterial cell membrane.Graphical abstractGraphical abstract for this article
  • A reusable magnetic nickel nanoparticle based catalyst for the aqueous
           synthesis of diverse heterocycles and their evaluation as potential
           anti-bacterial agent
    • Abstract: Publication date: Available online 28 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Deboshikha Bhattacharjee, Sanjoy Kumar Sheet, Snehardinarayan Khatua, Koel Biswas, Sataram Joshi, Bekington Myrboh A library of biologically important heterocycles, viz. pyrazolyl pyrimidine-triones, bis(heterocyclyl)methanes were succesfully synthesised by the condensation of barbituric acid, pyrazolone with an aldehyde and dimedone/4-hydoxy coumarin with various substituted aldehydes in aqueous medium at room temperature catalysed by nickel nanoparticles which proved to be an efficient magnetically recyclable catalyst. The method is simple, eco-friendly and gave excellent yields of the products without taking recourse to column chromatographic separation procedures. Computational method was employed to elucidate the selective formation of uncyclised product in reaction course. The biological activity of the synthesized compounds were investigated and the results demonstrated profound antibacterial activity.Graphical abstractGraphical abstract for this article
  • Genetically-encoded Fragment-based Discovery of Glycopeptide Ligands for
    • Abstract: Publication date: Available online 28 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Simon Ng, Nicholas James Bennett, Jessica Schulze, Nan Gao, Christoph Rademacher, Ratmir Derda We have employed genetically-encoded fragment-based discovery to identify novel glycopeptides with affinity for the dendritic cell receptor DC-SIGN. Starting from libraries of 108 mannose-conjugated peptides, we identified glycopeptides that exhibited up to a 650-fold increase in multivalent binding affinity for DC-SIGN, which is also preserved in cells. Monovalently, our most potent glycopeptides have a similar potency to a Man3 oligosaccharide, representing a 15-fold increase in activity compared to mannose. These compounds represent the first examples of glycopeptide ligands that target the CRD of DC-SIGN. The natural framework of glycopeptide conjugates and the simplicity of orthogonal conjugation to make these glycopeptides anticipates a promising future for development of DC-SIGN-targeting moieties.Graphical abstractGraphical abstract for this article
  • Novel Multi-target Compounds in the Quest for New Chemotherapies against
           Alzheimer’s Disease: An Experimental and Theoretical Study
    • Abstract: Publication date: Available online 25 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Alberto Martínez, Mai Zahran, Miguel Gomez, Coreen Cooper, Johnny Guevara, Erik Ekengard, Ebbe Nordlander, Ralph Alcendor, Sarah Hambleton The lack of any effective therapy along with the aging world population anticipates a growth of the worldwide incidence of Alzheimer’s disease (AD) to more than 100 million cases by 2050. Accumulation of extracellular amyloid-β (A β) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. In the amyloidogenic process, a β -secretase, known as BACE 1, plays a fundamental role in the production of A β fragments, and therefore, inhibition of such enzymes represents a major strategy for the rational design of anti-AD drugs. In this work, a series of four multi-target compounds (1-4), inspired by previously described ionophoric polyphenols, have been synthesized and studied. These compounds have been designed to target important aspects of AD, including BACE 1 enzymatic activity, A β aggregation, toxic concentrations of Cu2+ metal ions and/or ROS production. Two other compounds (5 and 6), previously reported by some of us as anti-malarial agents, have also been studied because of their potential as multi-target species against AD. Interestingly, compounds 3 and 5 showed moderate to good ability to inhibit BACE 1 enzymatic activity in a FRET assay, with IC50’s in the low micromolar range (4.4 ± 0.3 and 1.7 ± 0.3µM, respectively), comparable to other multi-target species, and showing that the observed activity was in part due to a competitive binding of the compounds at the active site of the enzyme. Theoretical docking calculations overall agreed with FRET assay results, displaying the strongest binding affinities for 3 and 5 at the active site of the enzyme. In addition, all compounds selectively interacted with Cu2+ metal ions forming 2:1 complexes, inhibited the production of A β -Cu2+ catalyzed hydroxyl radicals up to a ∼100% extent, and scavenged AAPH-induced peroxyl radical species comparably to resveratrol, a compound used as reference in this work. Our results also show good anti-amyloidogenic ability: compounds 1-6 inhibited both the Cu2+-induced and self-induced A β (1-40) fibril aggregation to an extent that ranges from 31% to 77%, while they disaggregated pre-formed A β (1-40) mature fibrils up to a 37% and a 69% extent in absence and presence of Cu2+, respectively. Cytotoxicity was additionally studied in Tetrahymena thermophila and HEK293 cells, and compared to that of resveratrol, showing that compounds 1-6 display lower toxicity than that of resveratrol, a well-known non-toxic polyphenol.Graphical abstractGraphical abstract for this article
  • Synthesis of DNA interactive C3-trans-cinnamide linked β-carboline
           conjugates as potential cytotoxic and DNA topoisomerase I inhibitors
    • Abstract: Publication date: Available online 25 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Manda Sathish, Sabanis Chetan Dushantrao, Shalini Nekkanti, Ramya Tokala, Soujanya Thatikonda, Yellaiah Tangella, Gunda Srinivas, Shirisha Cherukommu, Namballa Hari Krishna, Nagula Shankaraiah, Narayana Nagesh, Ahmed Kamal A series of new C3-trans-cinnamide linked β-carboline conjugates has been synthesized by coupling between various β-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC50 values 13–45 nM. Moreover, the conjugates 8v and 8x were the most active against MCF-7 cells (14.05 nM and 13.84 nM respectively) and also even potent on other cell lines tested. Further, detailed investigations such as cell cycle analysis, apoptosis induction study, topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive topoisomerase I inhibitors.Graphical abstractGraphical abstract for this article
  • Large-Stokes-shift-based folded DNA probing systems targeting DNA and
           miRNA 21 with signal amplification
    • Abstract: Publication date: Available online 25 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Binh Huy Le, Thuy-Van Thi Nguyen, Han Na Joo, Young Jun Seo Large-Stokes-shift based simple folded DNA probing system (LSFP) had a simple folded DNA structure and exhibited a large Stokes-shifted (194 nm) fluorescence signal upon excitation at a single wavelength (386 nm). This Stokes shift was achieved through a simple combination of donor and acceptor fluorophores and employing multi-FRET systematically. This unique large Stokes-shifted fluorescence signal was used to detect target DNA with large increases in the fluorescence signal (9.7–14.2 fold). This LSFP exhibited enough selectivity, distinguishing a perfectly matched sequence from the probe itself and mismatched sequences. Surprisingly, when DSN was used for signal amplification with miR21P probing system whose target is miRNA 21, it showed high sensitivity (13.7 aM) and selectivity (one base mismatch discrimination). This system has several advantages over other molecular beacons (MBs): (i) it is easy to design and synthesize the probing system that does not require the construction of a finely designed stem and loop, as in most MBs (this can prevent the degradation of miR21P itself by DSN enzyme without special backbone modification); (ii) it can control unique fluorescence, such as large Stokes-shifted fluorescence through a simple combination of donor and acceptor fluorophores; and (iii) through signal amplification using DSN, it can efficiently detect extremely small amounts of target miRNA with high sensitivity (13.7 aM).Graphical abstractGraphical abstract for this article
  • Discovery and Development of Substituted Tyrosine Derivatives as
           Bcl-2/Mcl-1 Inhibitors
    • Abstract: Publication date: Available online 24 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Renshuai Liu, LuLu Liu, Tingting Liu, Xinying Yang, Yichao Wan, Hao Fang Anti-apoptotic Bcl-2 family proteins are vital for cancer cells to escape apoptosis, which make them attractive targets for cancer therapy. Recently, a lead compound 1 was found to modestly inhibit the binding of BH3 peptide to Bcl-2 protein with a Ki value of 5.2 µM. Based on this, a series of substituted tyrosine derivatives were developed and tested for their binding affinities to Bcl-2 protein. Results indicated that these compounds exhibited potent binding affinities to Bcl-2 and Mcl-1 protein but not to Bcl-XL protein. Promisingly, compound 6i inhibited the binding of BH3 peptide to Bcl-2 and Mcl-1 protein with a Ki value of 450 and 190 nM respectively, and showed obvious anti-proliferative activities against tested cancer cells.Graphical abstractGraphical abstract for this article
  • In vitro and in vivo anti-inflammatory properties of
           imine resveratrol analogues
    • Abstract: Publication date: Available online 24 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Danielle Cristina Zimmermann-Franco, Bruna Esteves, Leticia Moroni Lacerda, Isabela de Oliveira Souza, Juliana Alves dos Santos, Nicolas de Castro Campos Pinto, Elita Scio, Adilson David da Silva, Gilson Costa Macedo Resveratrol is a natural polyphenol found mainly on red grapes and in red wine, pointed as an important anti-inflammatory/immunomodulatory molecule. However, its bioavailability problems have limited its use encouraging the search for new alternatives agents. Thus, in this study, we synthetize 12 resveratrol analogues (6 imines, 1 thioimine and 5 hydrazones) and investigated its cytotoxicity, antioxidant activity and in vitro anti-inflammatory/immunomodulatory properties. The most promising compounds were also evaluated in vivo. The results showed that imines presented less cytotoxicity, were more effective than resveratrol on DPPH scavenger and exhibited an anti-inflammatory profile. Among them, the imines with a radical in the para position, on the ring B, not engaged in an intramolecular hydrogen-interaction, showed more prominent anti-inflammatory activity modulating, in vivo, the edema formation, the inflammatory infiltration and cytokine levels. An immunomodulatory activity also was observed in these molecules. Thus, our results suggest that imines with these characteristics presents potential to control inflammatory disorders.Graphical abstractGraphical abstract for this article
  • Design, synthesis and structure-activity relationship study of novel
           naphthoindolizine and indolizinoquinoline-5,12-dione derivatives as IDO1
    • Abstract: Publication date: Available online 24 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Rui Yang, Yu Chen, Liangkun Pan, Yanyan Yang, Qiang Zheng, Yue Hu, Yuxi Wang, Liangren Zhang, Yang Sun, Zhongjun Li, Xiangbao Meng Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as a promising target for cancer immunotherapy. Many naphthoquinone derivatives have been reported as IDO1 inhibitors so far. Herein, two series of naphthoquinone derivatives, naphthoindolizine and indolizinoquinoline- 5,12-dione derivatives, were synthesized and evaluated for their IDO1 inhibitory activity. Most of the target compounds showed significant inhibition potency and high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). The structure-activity relationship was also summarized. The most potent compounds 5c (IC50 23 nM, IDO1 enzyme), and 5b′ (IC50 372 nM, HeLa cell) were identified as promising lead compounds.Graphical abstractGraphical abstract for this article
  • Optimization of 5-Arylidene Barbiturates as Potent, Selective, Reversible
           LSD1 Inhibitors for the Treatment of Acute Promyelocytic Leukemia
    • Abstract: Publication date: Available online 22 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Siyuan Xu, Chen Zhou, Rongfeng Liu, Qihua Zhu, Yungen Xu, Fei Lan, Xiaoming Zha Histone lysine specific demethylase 1 (LSD1) is overexpressed in diverse hematologic disorders and recognized as a promising target for blood medicines. In this study, molecular docking-based virtual screening united with bioevaluation was utilized to identify novel skeleton of 5-arylidene barbiturate as small-molecule inhibitors of LSD1. Among the synthesized derivatives, 12a exhibited reversible and potent inhibition (IC50 = 0.41 μM) and high selectivity over the MAO-A and MAO-B. Notably, 12a strongly induced differentiation effect on acute promyelocytic leukemia NB4 cell line and distinctly escalated the methylation level on histone 3 lysine 4 (H3K4). Our findings indicate that 5-arylidene barbiturate may represent a new skeleton of LSD1 inhibitors and 12a deserve as a promising agent for the further research.Graphical abstractGraphical abstract for this article
  • Design, synthesis and in vitro study of densely functionalized oxindoles
           as potent α-glucosidase inhibitors
    • Abstract: Publication date: Available online 22 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Tania Luthra, K. Naga Lalitha, A. Uma, Subhabrata Sen Diabetes a non-communicable disease occurs either due to the lack of insulin or the inability of the human body to recognize it. The recent data indicated an increase in the trend of people diagnosed with type 2 diabetes mainly due to unhealthy life style. Here in we report a new class of oxindole derivatives 6a-kvia scaffold hopping of known α -glucosidase inhibitors 1-4. When molecular docking was performed against a homology model of α -glucosidase the resulting compound 6d revealed binding interactions comparable to 1-4. The compounds were accessed through a unique condensation-ring opening protocol of pyridofuranone building blocks. Overall the compounds exhibited decent binding to the yeast α -glucosidase, where the most potent compound 6h, inhibited the enzyme with IC50 of 0.6 µM. This was nearly threefold improvement from the original known compounds 1-4, selected to design the newer analogs. The reaction kinetics of 6h indicated competitive inhibition.Graphical abstractGraphical abstract for this article
  • Development of matrix metalloproteinase-13 inhibitors – A
           structure-activity/structure-property relationship study
    • Abstract: Publication date: Available online 20 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Rita Fuerst, Jun Yong Choi, Anna M. Knapinska, Lyndsay Smith, Michael D. Cameron, Claudia Ruiz, Gregg B. Fields, William R. Roush A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20 min, kinetic solubility higher than 20 μM, and a permeability coefficient greater than 20 x 10-6 cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (Cmax = 56.8 μM, T1/2 (plasma) = 3.0 h, Cl = 0.23 mL/min/kg) and thus is a suitable candidate for in vivo efficacy studies in an OA animal model.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of lazabemide derivatives as
           inhibitors of monoamine oxidase
    • Abstract: Publication date: Available online 19 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Shiyang Zhou, Guangying Chen, Gangliang Huang In the studied a series novel of lazabemide derivatives were designed, synthesized and evaluated as inhibitors of monoamine oxidase (MAO-A or MAO-B). These compounds used lazabemide as the lead compound, and the chemistry structures were modified by used the bioisostere and modification of compound with alkyl principle. The two types of inhibitors (inhibition of MAO-A and inhibition of MAO-B) were screened by inhibition activity of MAO. In vitro experiments showed that compounds 3a, 3d and 3f had intensity inhibition the biological activity of MAO-A, while compounds 3i and 3m had intensity inhibition the biological activity of MAO-B. It could be seen from the data of inhibition activity experiments in vitro, that the compound 3d was IC50=3.12±0.05 μmol/mL of MAO-A and compound 3m was IC50=5.04±0.06 μmol/mL. In vivo inhibition activity experiments were conducted to evaluate the inhibitory activity of compounds 3a, 3d, 3f, 3i and 3m by detecting the contents of 5-HT, NE, DA and activity of MAO-A and MAO-B in plasma and brain tissue. In vivo inhibition activity evaluation results showed that the compounds 3a, 3d, 3f, 3i and 3m had increased the contents of 5-HT, NE and DA in plasma and brain tissues. Meanwhile, the determination results activity of MAO in plasma and brain tissue showed that the compounds 3a, 3d, and 3f had a significant inhibitory effect on the activity of MAO-A, while the compounds 3i and 3m showed inhibitory effect on the activity of MAO-B. This study provided a new inhibitors for inhibiting of MAO activity.Graphical abstractGraphical abstract for this article
  • Synthesis and SAR of new isoxazole-triazole bis-heterocyclic compounds as
           analogues of natural lignans with antiparasitic activity
    • Abstract: Publication date: Available online 19 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Lara A. Zimmermann, Milene H. de Moraes, Rafael da Rosa, Eduardo B. de Melo, Fávero R. Paula, Eloir P. Schenkel, Mario Steindel, Lílian S.C. Bernardes Despite the impressive scientific and technological advances of recent decades, no effective treatment is currently available for Chagas disease. Our research group has been studying the design and synthesis of analogues of natural lignans aiming to identify compounds with antiparasitic activity. This article reports the synthesis of 42 novel bis-heterocyclic derivatives and the structure-activity relationship study conducted based on results of biological assays against Trypanosoma cruzi amastigotes. Thirty-seven compounds were active, and eight of them had GI50 values lower than 100 μM (GI50 88.4–12.2 μM). A qualitative structure activity relationship study using three dimensional descriptors was carried out and showed a correlation between growth inhibitory potency and the presence of bulky hydrophobic groups located at rings A and D of the compounds. Compound 3-(3,4-dimethoxyphenyl)-5-((4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)methyl)isoxazole (31) was the most active in the series (GI50 12.2 μM), showing, in vitro, low toxicity and potency similar to benznidazole (GI50 10.2 μM). These results suggest that this compound can be a promising scaffold for the design of new trypanocidal compounds.Graphical abstractGraphical abstract for this article
  • Discovery of a Non-toxic [1,2,4]Triazolo[1,5-A]Pyrimidin-7-One (WS-10)
           that Modulates ABCB1-Mediated Multidrug Resistance (MDR)
    • Abstract: Publication date: Available online 18 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Liming Chang, Mengwu Xiao, Linlin Yang, Shuai Wang, Sai-Qi Wang, Andreas Bender, Aixi Hu, Zhe-Sheng Chen, Bin Yu, Hong-Min Liu Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied. In this work, we report the discovery of non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) from our structurally diverse in-house compound collection that selectively modulates ABCB1-mediated multidrug resistance. WS-10 enhanced the intracellular accumulation of paclitaxel in SW620/Ad300 cells, but did not affect the expression of ABCB1 Protein and ABCB1 localization. The cellular thermal shift assay (CETSA) showed that WS-10 was able to bind to ABCB1, which could be responsible for the reversal effect of WS-10 toward paclitaxel and doxorubicin in SW620/Ad300 cells. Docking simulations were performed to show the possible binding modes of WS-10 within ABCB1 transporter. To conclude, WS-10 could be used as a template for designing new ABCB1 modulators to overcome ABCB1-mediated multidrug resistance.Graphical abstractGraphical abstract for this article
  • An antimycobacterial pleuromutilin analogue effective against dormant
    • Abstract: Publication date: Available online 18 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Maddie R. Lemieux, Shajila Siricilla, Katsuhiko Mitachi, Shakiba Eslamimehr, Yuehong Wang, Dong Yang, Jeffrey D. Pressly, Ying Kong, Frank Park, Scott G. Franzblau, Michio Kurosu Pleuromutilin is a promising pharmacophore to design new antibacterial agents for Gram-positive bacteria. However, there are limited studies on the development of pleuromutilin analogues that inhibit growth of Mycobacterium tuberculosis (Mtb). In screening of our library of pleuromutilin derivatives, UT-800 (1) was identified to kill replicating- and non-replicating Mtb with the MIC values of 0.83 and 1.20 μg/mL, respectively. UT-800 also kills intracellular Mtb faster than rifampicin at 2xMIC concentrations. Pharmacokinetic studies indicate that 1 has an oral bioavailability with an average F-value of 27.6%. Pleuromutilin may have the potential to be developed into an orally administered anti-TB drug.Graphical abstractGraphical abstract for this article
  • The synthesis of novel chromogenic enzyme substrates for detection of
           bacterial glycosidases and their applications in diagnostic microbiology
    • Abstract: Publication date: Available online 17 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Michael Burton, John D. Perry, Stephen P. Stanforth, Hayley J. Turner The preparation and evaluation of chromogenic substrates for detecting bacterial glycosidase enzymes is reported. These substrates are monoglycoside derivatives of the metal chelators catechol, 2,3-dihydroxynaphthalene (DHN) and 6,7-dibromo-2,3-dihydroxynaphthalene (6,7-dibromo-DHN). When hydrolysed by appropriate bacterial enzymes these substrates produced coloured chelates in the presence of ammonium iron(III) citrate, thus enabling bacterial detection. A β-D-riboside of DHN and a β-D-glucuronide derivative of 6,7-dibromo-DHN were particularly effective for the detection of S. aureus and E. coli respectively.Graphical abstractGraphical abstract for this article
  • Design and Synthesis of a Luminescent Iridium Complex-Peptide Hybrid (IPH)
           that Detects Cancer Cells and Induces Their Apoptosis
    • Abstract: Publication date: Available online 14 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Abdullah-Al Masum, Kenta Yokoi, Yosuke Hisamatsu, Kana Naito, Babita Shashni, Shin Aoki Tumor necrosis factor related apoptosis inducing ligand (TRAIL) triggers the cell-extrinsic apoptosis pathway by complexation with its signaling receptors such as death receptors (DR4 and DR5). TRAIL is a C3-symmetric type II transmembrane protein, consists of three monomeric units. Cyclometalated iridium(III) complexes such as fac-Ir(tpy)3 (tpy = 2-(4-tolyl)pyridine) also possess a C3-symmetric structure and are known to have excellent luminescence properties. In this study, we report on the design and synthesis of a C3-symmetric and luminescent Ir complex-peptide hybrid (IPH), which contains a cyclic peptide that had been reported to bind to death receptor (DR5). The results of MTT assay of Jurkat, K562 and Molt-4 cells with IPH and co-staining experiments with IPH and an anti-DR5 antibody indicate that IPH binds to DR5 and induces apoptosis in a manner parallel to the DR5 expression level. Mechanistic studies of cell death suggest that apoptosis and necrosis-like cell death are differentiated by the position of the hydrophilic part that connects Ir complex and the peptide units. These findings suggest that IPHs could be a promising tool for controlling apoptosis and necrosis by activation of the extra-and intracellular cell death pathway and to develop new anticancer drugs that detect cancer cells and induce their cell death.Graphical abstractGraphical abstract for this article
  • [18F]DAA1106: automated radiosynthesis using spirocyclic iodonium ylide
           and preclinical evaluation for positron emission tomography imaging of
           translocator protein (18 KDa)
    • Abstract: Publication date: Available online 12 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Katsushi Kumata, Yiding Zhang, Masayuki Fujinaga, Takayuki Ohkubo, Wakana Mori, Tomoteru Yamasaki, Masayuki Hanyu, Lin Xie, Akiko Hatori, Ming-Rong Zhang DAA1106 (N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide), is a potent and selective ligand for the translocator protein (18 KDa, TSPO) in brain mitochondrial fractions of rats and monkey (Ki = 0.043 and 0.188 nM, respectively). In this study, to translate [18F]DAA1106 for clinical studies, we performed automated syntheses of [18F]DAA1106 using the spirocyclic iodonium ylide (1) as a radiolabelling precursor and conducted preclinical studies including positron emission tomography (PET) imaging of TSPO in ischemic rat brains. Radiofluorination of the ylide precursor 1 with [18F]F-, followed by HPLC separation and formulation, produced the [18F]DAA1106 solution for injection in 6% average (n = 10) radiochemical yield (based on [18F]F-) with> 98% radiochemical purity and molar activity of 100–160 GBq/μmol at the end of synthesis. The synthesis time was 87 min from the end of bombardment. The automated synthesis achieved [18F]DAA1106 with sufficient radioactivity available for preclinical and clinical use. Biodistribution study of [18F]DAA1106 showed a low uptake of radioactivity in the mouse bones. Metabolite analysis showed that> 96% of total radioactivity in the mouse brain at 60 min after the radiotracer injection was unmetabolized [18F]DAA1106. PET study of ischemic rat brains visualized ischemic areas with a high uptake ratio (1.9 ± 0.3) compared with the contralateral side. We have provided evidence that [18F]DAA1106 could be routinely produced for clinical studies.Graphical abstractGraphical abstract for this article
  • Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic
           glutamate subtypes 2 and 4
    • Abstract: Publication date: Available online 10 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Christina Gates, Donald S. Backos, Philip Reigan, Hye Jin Kang, Chris Koerner, Joseph Mirzaei, N.R. Natale Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR1a, mGLuR5 or mGluR8. Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR5 site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR2 and mGluR4 are distinct: the compounds which select for mGluR2 all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABAA, nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc- Antiporter. A homology model based on Conn’s mGluR1 crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis.Graphical abstractGraphical abstract for this article
  • Resveratrol-Maltol Hybrids as Multi-Target-Directed Agents for
           Alzheimer’s Disease
    • Abstract: Publication date: Available online 9 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Gang Cheng, Ping Xu, Minkui Zhang, Jing Chen, Rong Sheng, Yongmin Ma The 3-hydroxypyran-4-one moiety (maltol) was incorporated into the structure of resveratrol to achieve a series of resveratrol-maltol hybrids (8a–8k) as novel multi-target-directed ligands (MTDLs). In vitro biological evaluation of the MTDLs revealed these compounds to have a triple function, namely inhibition of self-induced Aβ1-42 aggregation, antioxidation, and metal chelating activity. Among all the evaluated MTDLs, compounds 8i and 8j showed the most promise, demonstrating micromolar IC50 values for Aβ1-42 aggregation inhibition, more potent ABTS•+ scavenging activity than Trolox, and good metal chelating activities.Graphical abstractGraphical abstract for this article
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
Home (Search)
Subjects A-Z
Publishers A-Z
Your IP address:
About JournalTOCs
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-