for Journals by Title or ISSN
for Articles by Keywords
help
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  [3159 journals]
  • 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 AokiTumor 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
       
  • Optimization of diarylpentadienones as chemotherapeutics for prostate
           cancer
    • Abstract: Publication date: Available online 13 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Manee Patanapongpibul, Changde Zhang, Guanglin Chen, Shanchun Guo, Qiang Zhang, Shilong Zheng, Guangdi Wang, Qiao-Hong ChenOur earlier studies indicate that (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones and (1E,4E)-1,5-bis(1-alkyl-1H-benzo[d] imidazol-2-yl)penta-1,4-diene-3-ones exhibit up to 121-fold greater antiproliferative potency than curcumin in human prostate cancer cell models, but only 2-10 fold increase in mouse plasma concentrations. The present study aims to further optimize them as anti-prostate cancer agents with both good potency and bioavailability. (1E,4E)-1,5-Bis(1H-imidazol-2-yl)penta-1,4-diene-3-one, the potential metabolic product of (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones, was synthesized and evaluated for its anti-proliferative activity. The promising potency of 1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones was completely abolished by removing the 1-alkyl group, suggesting the critical role of an appropriate group on the N1 position. We then envisioned that N-aryl substitution to exclude the C-H bond on the carbon adjacent to the N1 position (α-H) may increase the metabolic stability. Consequently, seven (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones and three (1E,4E)-1,5-bis(1-aryl-1H-benzo[d]imidazol-2-yl)penta-1,4-dien-3-ones, as well as three (1E,4E)-1,5-bis(1-aryl-1H-pyrrolo[3,2-b]pyridine-2-yl)penta-1,4-dien-3-ones, were synthesized through a three-step transformation, including N-arylation via Ullmann condensation, formylation, and Horner-Wadsworth-Emmons reaction. Six optimal (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones exhibit 24- to 375-fold improved potency as compared with curcumin. Replacement of the imidazole with bulkier benzoimidazole and 4-azaindole results in a substantial decrease in the potency. (1E,4E)-1,5-Bis(1-(2-methoxyphenyl)-1H-imidazol-2-yl)penta-1,4-dien-3-one (17d) was established as an optimal compound with both superior potency and good bioavailability that is sufficient to provide the therapeutic efficacy necessary to suppress in vivo tumor growth.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 ZhangDAA1106 (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
       
  • A latent green fluorescent styrylcoumarin probe for the selective growth
           and detection of Gram negative bacteria
    • Abstract: Publication date: Available online 12 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Linda Váradi, Miaoyi Wang, Ramesh R. Mamidi, Jia L. Luo, John D. Perry, David E. Hibbs, Paul W. GroundwaterA novel, green fluorescent β-alanylstyrylcoumarin derivative was synthesized and evaluated for its performance as a fluorogenic enzyme substrate on a range of clinically relevant microorganisms. The substrate was selectively hydrolysed by β-alanyl aminopeptidase producing P. aeruginosa resulting in an on-to-off fluorescent signal. Growth inhibitory effect of the substrate was observed on Gram positive bacteria and yeasts. Meanwhile, Gram negative species, despite their extremely protective cell envelope, showed ready uptake and accumulation of the substrate within their healthy growing colonies displaying intense green fluorescence.Graphical abstractGraphical abstract for this article
       
  • Characterization of crystal water molecules in a high-affinity inhibitor
           and hematopoietic prostaglandin D synthase complex by interaction energy
           studies
    • Abstract: Publication date: Available online 11 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Daisuke Takaya, Koji Inaka, Akifumi Omura, Kenji Takenuki, Masashi Kawanishi, Yukako Yabuki, Yukari Nakagawa, Keiko Tsuganezawa, Naoko Ogawa, Chiduru Watanabe, Teruki Honma, Kosuke Aritake, Yoshihiro Urade, Mikako Shirouzu, Akiko TanakaHematopoietic prostaglandin D synthase (H-PGDS) is one of the two enzymes that catalyze prostaglandin D2 synthesis and a potential therapeutic target of allergic and inflammatory responses. To reveal key molecular interactions between a high-affinity ligand and H-PGDS, we designed and synthesized a potent new inhibitor (KD: 0.14 nM), determined the crystal structure in complex with human H-PGDS, and quantitatively analyzed the ligand-protein interactions by the fragment molecular orbital calculation method. In the cavity, 10 water molecules were identified, and the interaction energy calculation indicated their stable binding to the surface amino acids in the cavity. Among them, 6 water molecules locating from the deep inner cavity to the peripheral part of the cavity contributed directly to the ligand binding by forming hydrogen bonding interactions. Arg12, Gly13, Gln36, Asp96, Trp104, Lys112 and an essential co-factor glutathione also had strong interactions with the ligand. A strong repulsive interaction between Leu199 and the ligand was canceled out by forming a hydrogen bonding network with the adjacent conserved water molecule. Our quantitative studies including crystal water molecules explained that compounds with an elongated backbone structure to fit from the deep inner cavity to the peripheral part of the cavity would have strong affinity to human H-PGDS.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and structure-activity relationship of diaryl-ureas with
           novel isoxazol[3,4-b]pyridine-3-amino-structure as multi-target inhibitors
           against receptor tyrosine kinase
    • Abstract: Publication date: Available online 11 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Zhi-Hao Shi, Feng-Tao Liu, Hao-Zhong Tian, Yan-Min Zhang, Nian-Guang Li, Tao LuInspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor β (PDGFR-β) with its IC50 values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several caner cells.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. NataleIsoxazolo[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 MaThe 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
       
  • Synthesis, antitumor activity evaluation and mechanistic study of novel
           hederacolchiside A1 derivatives bearing an aryl triazole moiety
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Hui-ning Li, Hui Wang, Zhi-peng Wang, Hai-ning Yan, Miao Zhang, Yang Liu, Mao-sheng ChengIn an attempt to arrive at a more potent antitumor agent than the parent natural saponin hederacolchiside A1, 23 hederacolchiside A1 derivatives (4a-4w) were synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and screened in vitro for cytotoxicity against six human cancer cell lines. The structure-activity relationship of these compounds was elucidated, and the biological screening results showed that most of the compounds exhibited moderate to high levels of antitumor activities against the tested cell lines and some of them displayed more potent inhibitory activities compared with hederacolchiside A1. Compound 4f showed a 2- to 7-fold more potent activity than hederacolchiside A1. The mechanistic study of 4f revealed that this compound can induce cell apoptosis in HepG2 cells via mitochondrial-mediated intrinsic pathways.Graphical abstractGraphical abstract for this article
       
  • Development of efficient one-pot three-component assembly of trityl
           olmesartan medoxomil
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Renata Toplak Časar, Zdenko ČasarWe have elaborated a one-pot three-component assembly of trityl olmesartan medoxomil starting from commercially available ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate, 5-(4′-(bromomethyl)-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one intermediates. The developed and optimized one-pot process provides 72–75% yield of trityl olmesartan medoxomil over three steps, which represents in average ca. 90% yield per synthetic step, on a 300 g scale. The process is conducted in simple fashion and provides highly pure trityl olmesartan medoxomil (up to 97.5% by HPLC), which can be easily converted to olmesartan medoxomil that fully complies with all ICH requirements. Furthermore, the described process significantly improves the primary process to trityl olmesartan medoxomil by drastic reduction of required unit operations and application of single reaction solvent through the reaction sequence. Moreover, the amount of used organic solvents was notably reduced. The developed process has provided solid bases for industrial production of trityl olmesartan medoxomil.Graphical abstractGraphical abstract for this article
       
  • Route design, the foundation of successful chemical development
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Philip Cornwall, Louis J. Diorazio, Natalie MonksRoute Design is the first step in the strategic development process for manufacture of a new active pharmaceutical ingredient (API). Numerous benefits can be realised for the project and the broader performance of the company. We present an appreciation of some of the potential challenges and describe the principles and practices that have shaped the Route Design culture within AstraZeneca. This is exemplified with case histories and we describe some of the activities that have supported our scientists and the simple messages used to educate the broader organisation.Graphical abstractGraphical abstract for this article
       
  • A short synthesis of Dronedarone
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Barbara Piotrkowska, Sven Nerdinger, Erwin Schreiner, Lovro Selič, Piotr P. GraczykA modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine 20 and 1,3-diketone 14 (R = CH2CH2CH2NBu2) in a two-stage process in almost 55% overall yield. Our results represent significant improvement over other state-of-the-art methods as no extra steps for the decoration of the benzofuran core are required.Graphical abstractGraphical abstract for this article
       
  • Forewords BMC
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Fabrice Gallou
       
  • Terpenoids with vasorelaxant effects from the Chinese liverwort
           Scapania carinthiaca
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Yanan Qiao, Hongbo Zheng, Lin Li, Jiaozhen Zhang, Yi Li, Siwen Li, Rongxiu Zhu, Jinchuan Zhou, Shengtian Zhao, Yuehua Jiang, Hongxiang LouFour new diterpenoids scapanacins A–D (1–4) including one kaurane and three clerodane derivatives, along with eleven known compounds (9–15), were isolated from the Chinese liverwort Scapania carinthiaca J.B. Jack ex Lindb. Their structures were determined based on extensive spectroscopic analyses, and electronic circular dichroism (ECD) calculations. Vasorelaxant activity assays of the clerodane-type diterpenoids 2, and 4–8 revealed that they relaxed 3rd-order rat mesenteric arterioles pre-contracted with norepinephrine (NE). Further assays with scapanacin D (4) confirmed that the vasodilatation was mediated through inhibition of Ca2+ influx via voltage-dependent Ca2+ channels (VDCs), and this Ca2+ channel blocking effect was also confirmed by inhibiting the extracellular Ca2+ influx in MOVAS cells. Besides, very little decrease of the relaxant activity caused by 4 on endothelium-denuded mesenteric arterioles with NE also suggested the vasodilatation was mainly produced by inhibiting Ca2+-induced contraction of smooth muscle. In addition, cytotoxicity testing showed that compounds 1 and 9 with α,β-unsaturated ketone exhibited inhibitory activities against a small panel of human cancer cell lines.Graphical abstractGraphical abstract for this article
       
  • Selective inhibition of human cathepsin S by 2,4,6-trisubstituted
           1,3,5-triazine analogs
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Zahira Tber, Mylène Wartenberg, Jean-Eddy Jacques, Vincent Roy, Fabien Lecaille, Dawid Warszycki, Andrzej J. Bojarski, Gilles Lalmanach, Luigi A. AgrofoglioWe report herein the synthesis and biological evaluation of a new series of 2,4,6-trisubstituted 1,3,5-triazines as reversible inhibitors of human cysteine cathepsins. The desired products bearing morpholine and N-Boc piperidine, respectively, were obtained in three to four steps from commercially available trichlorotriazine. Seventeen hitherto unknown compounds were evaluated in vitro against various cathepsins for their inhibitory properties. Among them, compound 7c (4-(morpholin-4-yl)-6-[4-(trifluoromethoxy)anilino]-1,3,5-triazine-2-carbonitrile) was identified as the most potent and selective inhibitor of cathepsin S (Ki  =  2  ±  0.3 nM). Also 7c impaired the autocatalytic maturation of procathepsin S. Molecular docking studies support that 7c bound within the active site of cathepsin S, by interacting with Gly23, Cys25 and Trp26 (S1 subsite), with Asn67, Gly69 and Phe70 (S2 subsite) and with Gln19 (S1′ pocket).Graphical abstractGraphical abstract for this article
       
  • Small molecule scaffolds that disrupt the Rev1-CT/RIR protein-protein
           interaction
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Zuleyha Ozen, Radha C. Dash, Kaitlyn R. McCarthy, Samantha A. Chow, Alessandro A. Rizzo, Dmitry M. Korzhnev, M. Kyle HaddenTranslesion synthesis (TLS) is a DNA damage tolerance mechanism that allows replicative bypass of DNA lesions, including DNA adducts formed by cancer chemotherapeutics. Previous studies demonstrated that suppression of TLS can increase sensitivity of cancer cells to first-line chemotherapeutics and decrease mutagenesis linked to the onset of chemoresistance, marking the TLS pathway as an emerging therapeutic target. TLS is mediated by a heteroprotein complex consisting of specialized DNA polymerases, including the Y-family DNA polymerase Rev1. Previously, we developed a screening assay to identify the first small molecules that disrupt the protein–protein interaction between the C-terminal domain of Rev1 (Rev1-CT) and the Rev1-interacting region (RIR) present in multiple DNA polymerases involved in TLS. Herein we report additional hit scaffolds that inhibit this key TLS PPI. In addition, through a series of biochemical, computational, and cellular studies we have identified preliminary structure–activity relationships and determined initial pharmacokinetic parameters for our original hits.Graphical abstractGraphical abstract for this article
       
  • Curcumin derivatives and Aβ-fibrillar aggregates: An interactions’
           study for diagnostic/therapeutic purposes in neurodegenerative diseases
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Giulia Orteca, Francesco Tavanti, Zuzana Bednarikova, Zuzana Gazova, Giovanna Rigillo, Carol Imbriano, Valentina Basile, Mattia Asti, Luca Rigamonti, Monica Saladini, Erika Ferrari, Maria Cristina MenzianiSeveral neurodegenerative diseases, like Alzheimer’s (AD), are characterized by amyloid fibrillar deposition of misfolded proteins, and this feature can be exploited for both diagnosis and therapy design. In this paper, structural modifications of curcumin scaffold were examined in order to improve its bioavailability and stability in physiological conditions, as well as its ability to interfere with β-amyloid fibrils and aggregates. The acid-base behaviour of curcumin derivatives, their pharmacokinetic stability in physiological conditions, and in vitro ability to interfere with Aβ fibrils at different incubation time were investigated. The mechanisms governing these phenomena have been studied at atomic level by means of molecular docking and dynamic simulations. Finally, biological activity of selected curcuminoids has been investigated in vitro to evaluate their safety and efficiency in oxidative stress protection on hippocampal HT-22 mouse cells.Two aromatic rings, π-conjugated structure and H-donor/acceptor substituents on the aromatic rings showed to be the sine qua non structural features to provide interaction and disaggregation activity even at very low incubation time (2h). Computational simulations proved that upon binding the ligands modify the conformational dynamics and/or interact with the amyloidogenic region of the protofibril facilitating disaggregation. Significantly, in vitro results on hippocampal cells pointed out protection against glutamate toxicity and safety when administered at low concentrations (1 μM). On the overall, in view of its higher stability in physiological conditions with respect to curcumin, of his rapid binding to fibrillar aggregates and strong depolymerizing activity, phtalimmide derivative K2F21 appeared a good candidate for both AD diagnostic and therapeutic purposes.Graphical abstractGraphical abstract for this article
       
  • Regio- and stereospecific synthesis of rac-carbasugar-based cyclohexane
           pentols; Investigations of their α- and β-glucosidase inhibitions
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Emel Karakılıç, Sümeyye Durmuş, Sedat Sevmezler, Onur Şahin, Arif BaranIn the present study, (3aR,7aS)-1,3,3a,4,7,7a-hexahydroisobenzofuran was submitted to photooxygenation and two isomeric hydroperoxides were successfully obtained. Without any further purification, reduction of the hydroperoxides with titanium tetraisopropoxide catalyzed by dimethyl sulfide gave two alcohol isomers in high yields. After acetylation of alcohol with Ac2O in pyridine, epoxidation reaction of formed monoacetates with m-CPBA, then chromatographed and followed by hydrolysis of the acetate groups with NH3 in CH3OH resulted in the formation of epoxy alcohol isomers respectively. These epoxy alcohol isomers were subjected to trans-dihydroxylation reaction with acid (H2SO4) in the presence of water to afford triols. Acetylation of the free hydroxyl groups produced benzofuran triacetates in high yields. Ring-opening reaction of furan triacetates with sulfamic acid catalyzed in the presence of acetic acid/acetic anhydrate and subsequently hydrolysis of the acetate groups with ammonia gave the targeted cyclohexane carbasugar-based pentols. All products were separated and purified by chromatographic and crystallographic methods. Structural analyses of all compounds were conducted by spectral techniques including NMR and X-ray analyses. The biological inhibition activity of the target compounds was tested against glycosidase enzymes, α- and β-glucosidase.Graphical abstractGraphical abstract for this article
       
  • Design and biological evaluation of novel hybrids of 1, 5-diarylpyrazole
           and Chrysin for selective COX-2 inhibition
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Shen-Zhen Ren, Zhong-Chang Wang, Xiao-Hua Zhu, Dan Zhu, Zhang Li, Fa-Qian Shen, Yong-Tao Duan, Han Cao, Jing Zhao, Hai-Liang ZhuThe overexpress of COX-2 was clearly associated with carcinogenesis and COX-2 as a possible target has long been exploited for cancer therapy. In this work, we described the design and synthesis of a series of diarylpyrazole derivatives integrating with chrysin. Among them, compound e9 exhibited the most potent inhibitory activity against COX-2 and antiproliferative activity against Hela cells with IC50 value of 1.12 μM. Further investigation revealed that e9 could induce apoptosis of Hela cells by mitochondrial depolarization and block the G1 phase of cell cycle in a dose-dependent manner. Besides, molecular docking simulation results was further confirmed that e9 could bind well with COX-2. In summary, compound e9 may be promising candidates for cancer therapy.Graphical abstractA series of novel COX-2 inhibitors (compound e1–e30) have been designed and synthesized. Compound e9 exhibited the most potent inhibitory activity against COX-2 and anticancer. Docking simulation results was further confirmed that e9 could bind well with COX-2.Graphical abstract for this article
       
  • Structural optimization and in vitro profiling of N-phenylbenzamide-based
           farnesoid X receptor antagonists
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Jurema Schmidt, Simone Schierle, Leonie Gellrich, Astrid Kaiser, Daniel MerkActivation of the nuclear farnesoid X receptor (FXR) which acts as cellular bile acid sensor has been validated as therapeutic strategy to counter liver disorders such as non-alcoholic steatohepatitis by the clinical efficacy of obeticholic acid. FXR antagonism, in contrast, is less well studied and potent small molecule FXR antagonists are rare. Here we report the systematic optimization of a novel class of FXR antagonists towards low nanomolar potency. The most optimized compound antagonizes baseline and agonist induced FXR activity in a full length FXR reporter gene assay and represses intrinsic expression of FXR regulated genes in hepatoma cells. With this activity and a favorable toxicity-, stability- and selectivity-profile it appears suitable to further study FXR antagonism in vitro and in vivo.Graphical abstractGraphical abstract for this article
       
  • Synthetic molecules for disruption of the MYC protein-protein interface
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Nicholas T. Jacob, Pedro O. Miranda, Ryan J. Shirey, Ritika Gautam, Bin Zhou, M. Elena de Orbe Izquierdo, Mark S. Hixon, Jonathan R. Hart, Lynn Ueno, Peter K. Vogt, Kim D. JandaMYC is a key transcriptional regulator involved in cellular proliferation and has established roles in transcriptional elongation and initiation, microRNA regulation, apoptosis, and pluripotency. Despite this prevalence, functional chemical probes of MYC function at the protein level have been limited. Previously, we discovered 5a, that binds to MYC with potency and specificity, downregulates the transcriptional activities of MYC and shows efficacy in vivo. However, this scaffold posed intrinsic pharmacokinetic liabilities, namely, poor solubility that precluded biophysical interrogation. Here, we developed a screening platform based on field-effect transistor analysis (Bio-FET), surface plasmon resonance (SPR), and a microtumor formation assay to analyze a series of new compounds aimed at improving these properties. This blind SAR campaign has produced a new lead compound of significantly increased in vivo stability and solubility for a 40-fold increase in exposure. This probe represents a significant advancement that will not only enable biophysical characterization of this interaction and further SAR, but also contribute to advances in understanding of MYC biology.Graphical abstractGraphical abstract for this article
       
  • Stereospecific reduction of the butenolide in strigolactones in plants
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Misa Yamauchi, Kotomi Ueno, Toshio Furumoto, Takatoshi Wakabayashi, Masaharu Mizutani, Hirosato Takikawa, Yukihiro SugimotoReductive metabolism of strigolactones (SLs) in several plants was investigated. Analysis of aquaculture filtrates of cowpea and sorghum each fed with four stereoisomers of GR24, the most widely used synthetic SL, revealed stereospecific reduction of the double bond at C-3′ and C-4′ in the butenolide D-ring with preference for an unnatural 2′S configuration. The cowpea metabolite converted from 2′-epi-GR24 and the sorghum metabolite converted from ent-GR24 had the methyl group at C-4′ in the trans configuration with the substituent at C-2′, different from the cis configuration of the synthetic H2-GR24 reduced with Pd/C catalyst. The plants also reduced the double bond in the D-ring of 5-deoxystrigol isomers with a similar preference. The metabolites and synthetic H2-GR24 stereoisomers were much less active than were the GR24 stereoisomers in inducing seed germination of the root parasitic weeds Striga hermonthica, Orobanche crenata, and O. minor. These results provide additional evidence of the importance of the D-ring for bioactivity of SLs.Graphical abstractGraphical abstract for this article
       
  • Synthesis and anticancer activity of novel bisindolylhydroxymaleimide
           derivatives with potent GSK-3 kinase inhibition
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Hannah J. Winfield, Michael M. Cahill, Kevin D. O'Shea, Larry T. Pierce, Thomas Robert, Sandrine Ruchaud, Stéphane Bach, Pascal Marchand, Florence O. McCarthySynthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates.Graphical abstractGraphical abstract for this article
       
  • Mechanism underlying inhibitory effect of six dicaffeoylquinic acid
           
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Ji Hoon Ha, Soo Nam ParkDicaffeoylquinic acid (DCQA), which contain 2 caffeic acids and a quinic acid, is 6 isomeric compounds (1,3-, 1,4-, 1,5-, 3,4-, 3,5-, and 4,5-DCQA). In this study, the mechanism underlying the inhibitory effect of DCQA isomers on melanogenesis in B16F1 murine melanoma cells stimulated by melanocyte stimulating hormone (α-MSH) was evaluated. DCQA isomers showed inhibitory effects on melanogenesis in α-MSH-stimulated B16F1 cells. Furthermore, the anti-melanogenesis activities of 1,5-DCQA and 4,5-DCQA were 61% and 84%, respectively, which were greater than that of arbutin (35%). For cell-free tyrosinase, 3,4-DCQA and 4,5-DCQA indicated high inhibitory effects, similar to the activity to arbutin (35%) at 25 μM. DCQA isomers inhibited the melanogenic enzymes including tyrosinase and dopachrome tautomerase (DCT) on α-MSH-stimulated B16F1 cells. Interestingly, 4,5-DCQA, the most potent inhibitor of melanogenesis among the six DCQA isomers, significantly downregulated the expression of microphthalmia-associated transcription factor (MITF), tyrosinase-related protein 1 (TRP1) containing tyrosinase, and DCT. In particular, the inhibitory mechanism of 4,5-DCQA on MITF expression was elucidated, revealing that 4,5-DCQA inhibits the phosphorylation of cAMP response element-binding protein (CREB) by attenuating cAMP generation during melanogenesis. A molecular docking study was conducted to elucidate the inhibitory mechanism of 4,5-DCQA on cAMP production. DCQA isomers dock to the residues of adenylyl cyclase with a distance of
       
  • Anti-acute myeloid leukemia activity of
           2-chloro-3-alkyl-1,4-naphthoquinone derivatives through inducing mtDNA
           damage and GSH depletion
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Kun Li, Kun Yang, Lifang Zheng, Yuanyuan Li, Qi Wang, Ruili Lin, Dian He2-Chloro-3-alkyl-1,4-naphthoquinone derivatives were synthesized and tested as the anti-acute myeloid leukaemia agents. The compound 9b (2-chloro-3-ethyl-5,6,7-trimethoxy-1,4-naphthoquinone) was the most potent toward HL-60 leukaemia cells. In mechanistic study for 9b, the protein levels of mtDNA-specific DNA polymerase γ (poly-γ) and mtDNA transcription factor A (mt-TFA) were decreased after the 24 h treatment, showing the occurrence of mtDNA damage. And 9b triggered cell cycle arrest at S phase accompanied by a secondary block in G2/M phase which had a direct link to the process of mtDNA damage. The dissipations of mitochondrial membrane potential and ATP also proceeded. On the other hand, 9b promoted the generation of ROS and resulted in the oxidation of intracellular GSH to GSSG. This process was coupled to the formation of adduct between 9b and GSH, detected by the UV–Vis spectrum and HRMS analysis. Depletion of GSH by buthionine sulfoximine enhanced ROS level and produced higher cytotoxicity, suggesting GSH was involved in the anti-leukemic mechanism of 9b. Together, our results provide new insights on the molecular mechanism of the derivatives of 2-chloro-1,4-naphthoquinone and 9b might be useful for the further development into an anti-leukemia agent.Graphical abstractGraphical abstract for this article
       
  • Activation studies with amines and amino acids of the α-carbonic
           anhydrase from the pathogenic protozoan Trypanosoma cruzi
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Andrea Angeli, Marianne Kuuslahti, Seppo Parkkila, Claudiu T. SupuranThe activation of a α-class carbonic anhydrase (CAs, EC 4.2.1.1) from Trypanosoma cruzi (TcCA) was investigated with the best known classes of activators, the amino acids and aromatic/heterocyclic amines. The best TcCA activators were l-/d-DOPA and 4-amino-l-phenylalanine, which had activation constants in the range of 0.38–0.83 µM. Low micromolar activators were also l-/d-Trp, l-/d-Tyr, l-Gln, histamine and serotonin (KAs of 1.79–4.92 µM), whereas l-/d-His, l-/d-Phe and l-Asp were less effective activators (KAs of 6.39–18.7 µM). Amines such as dopamine, pyridyl-alkylamines, aminoethyl-piperazine or l-adrenaline, were devoid of activating effects on TcCA. Since the role of autacoids as many of these compounds investigated here is not known for the life cycle of T. cruzi, our work provides new tools for further investigations of factors connected with this protozoan pathogen infection.Graphical abstractGraphical abstract for this article
       
  • Novel amino acid-substituted diphenylpyrimidine derivatives as potent BTK
           inhibitors against B cell lymphoma cell lines
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Changyuan Wang, Si Li, Qiang Meng, Xiuli Sun, Hua Li, Xiaohong Shu, Huijun Sun, Kexin Liu, Zhihao Liu, Xiaodong MaA new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent BTK inhibitors. Among them, compound 7b, which features an l-proline substituent, was identified as the strongest BTK inhibitor, with an IC50 of 8.7 nM. Compound 7b also displayed similar activity against B-cell lymphoma cell lines as ibrutinib. Moreover, 7b exhibited low cytotoxic activity against normal PBMC cells. In addition, the acridine orange/ethidium bromide (AO/EB) staining assay, Western blot analysis and flow cytometry analysis also showed its effectiveness in interfering with B-cell lymphoma cell growth. The molecular simulation performance showed that 7b forms additional strong hydrogen bonds with the BTK protein. All these findings provided new clues about the pyrimidine scaffold as an effective BTK inhibitor for the treatment of B-cell lymphoma.Graphical abstractGraphical abstract for this article
       
  • The genome-wide sequence specificity of DNA cleavage by bleomycin
           analogues in human cells
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Vincent Murray, Jon K. Chen, Dong Yang, Ben ShenBleomycin (BLM) is a cancer chemotherapeutic agent that cleaves cellular DNA at specific sequences. Using next-generation Illumina sequencing, the genome-wide sequence specificity of DNA cleavage by two BLM analogues, 6′-deoxy-BLM Z and zorbamycin (ZBM), was determined in human HeLa cells and compared with BLM. Over 200 million double-strand breaks were examined for each sample, and the 50,000 highest intensity cleavage sites were analysed. It was found that the DNA sequence specificity of the BLM analogues in human cells was different to BLM, especially at the cleavage site (position “0”) and the “+1” position. In human cells, the 6′-deoxy-BLM Z had a preference for 5′-GTGY*MC (where * is the cleavage site, Y is C or T, M is A or C); it was 5′-GTGY*MCA for ZBM; and 5′-GTGT*AC for BLM. With cellular DNA, the highest ranked tetranucleotides were 5′-TGC*C and 5′-TGT*A for 6′-deoxy-BLM Z; 5′-TGC*C, 5′-TGT*A and 5′-TGC*A for ZBM; and 5′-TGT*A for BLM. In purified human genomic DNA, the DNA sequence preference was 5′-TGT*A for 6′-deoxy-BLM, 5′-RTGY*AYR (where R is G or A) for ZBM, and 5′-TGT*A for BLM. Thus, the sequence specificity of the BLM analogue, 6′-deoxy-BLM Z, was similar to BLM in purified human DNA, while ZBM was different.Graphical abstractGraphical abstract for this article
       
  • l-phenylglycine+derivatives+as+potential+PPARγ+lead+compounds&rft.title=Bioorganic+&+Medicinal+Chemistry&rft.issn=0968-0896&rft.date=&rft.volume=">Design, synthesis, and evaluation of novel l-phenylglycine derivatives as
           potential PPARγ lead compounds
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Jinyu Liu, Xiaoyan Su, Huachong Li, Li Fan, Yuanyuan Li, Xuemei Tang, Jufang Yan, Xin Chen, Feifei Chen, Jie Liu, Dacheng YangIn accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l-phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator-activated receptor gamma (PPARγ) activated activity, α-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105.04% at 10 μg·mL−1 compared with the positive control pioglitazone, with 100% activity). Therefore, M5 was selected as the hit compound from which the TM3 and TM4 series of compounds were further designed and synthesized. Based on the PPRE relative activities of TM3 and TM4, we discovered another new molecule, TM4h, which had the strongest PPRE relative activity (120.42% at 10 μg·mL−1). In addition, the concentration-dependent activity of the highly active compounds was determined by assaying their half-maximal effective concentration (EC50) values. The molecular physical parameter calculation and the molecular toxicity prediction were used to theoretically evaluate the lead-likeness and safety of the active compounds. In conclusion, we identified a potential PPARγ lead molecule and developed a tangible strategy for antidiabetic drug development.Graphical abstractGraphical abstract for this article
       
  • The synthesis and evaluation of phenoxyacylhydroxamic acids as potential
           agents for Helicobacter pylori infections
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Wei-Wei Ni, Qi Liu, Shen-Zhen Ren, Wei-Yi Li, Li-Li Yi, Heng Jing, Li-Xin Sheng, Qin Wan, Ping-Fu Zhong, Hai-Lian Fang, Hui Ouyang, Zhu-Ping Xiao, Hai-Liang ZhuTwo series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC50 = 0.061 ± 0.003 μM) and intact cell (IC50 = 0.89 ± 0.05 μM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of novel sophoridinic imine derivatives
           containing conjugated planar structure as potent anticancer agents
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Yiming Xu, Dewang Jing, Rui Chen, Haroon Ur Rashid, Jun Jiang, Xu Liu, Lisheng Wang, Peng XieBased on our previous study and the binding mode of camptothecin with Topo I, a series of novel sophoridine imine derivatives containing conjugated planar structure were designed, synthesized and tested for their in vitro anticancer activity. The results showed that most of the derivatives displayed potent activity. In particular, compounds 10b exhibited excellent anti-proliferative activities with IC50 5.7 µM and 8.5 µM against HepG-2 and HeLa cell lines, respectively. Molecular docking studies revealed that the introduction of conjugated planar structure could form π-π stacking interaction with DNA, leading to the improvement of biological activity. Its mode of action was to inhibit the activity of DNA Topo I, followed by the G0/G1 phase arrest. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound and 10b could emerge as promising lead compounds for the development of novel Topo I inhibitors.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and docking study of 4-arylpiperazine carboxamides as
           monoamine neurotransmitters reuptake inhibitors
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Suresh Paudel, Ningning Sun, Daulat Bikram Khadka, Goon Yoon, Kyeong-Man Kim, Seung Hoon CheonRational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound 9 displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of 9 was also studied.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological properties of aryl methyl sulfones
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Lorena Navarro, Gloria Rosell, Silvia Sánchez, Núria Boixareu, Klaus Pors, Ramon Pouplana, Josep M. Campanera, M. Dolors PujolA novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC50 COX-1 = 0.04 and COX-2 = 0.10 μM, and naproxen: IC50 COX-1 = 11.3 and COX-2 = 3.36 μM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies.The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.Graphical abstractGraphical abstract for this article
       
  • Indenone derivatives as inhibitor of human DNA dealkylation repair enzyme
           AlkBH3
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Richa Nigam, Kaki Raveendra Babu, Topi Ghosh, Bhavini Kumari, Deepa Akula, Subha Narayan Rath, Prolay Das, Roy Anindya, Faiz Ahmed KhanThe mammalian AlkB homologue-3 (AlkBH3) is a member of the dioxygenase family of enzymes that in humans is involved in DNA dealkylation repair. Because of its role in promoting tumor cell proliferation and metastasis of cancer, extensive efforts are being directed in developing selective inhibitors for AlkBH3. Here we report synthesis, screening and evaluation of panel of arylated indenone derivatives as new class of inhibitors of AlkBH3 DNA repair activity. An efficient synthesis of 2,3-diaryl indenones from 2,3-dibromo indenones was achieved via Suzuki-Miyaura cross-coupling. Using a robust quantitative assay, we have obtained an AlkBH3 inhibitor that display specific binding and competitive mode of inhibition against DNA substrate. Finally, we established that this compound could prevent the proliferation of lung cancer cell line and enhance sensitivity to DNA damaging alkylating agent.Graphical abstractGraphical abstract for this article
       
  • Identification of natural product compounds as quorum sensing inhibitors
           in Pseudomonas fluorescens P07 through virtual screening
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Ting Ding, Tingting Li, Jianrong LiPseudomonas fluorescens, a Gram-negative psychrotrophic bacteria, is the main microorganism causing spoilage of chilled raw milk and aquatic products. Quorum sensing (QS) widely exists in bacteria to monitor their population densities and regulate numerous physiological activities, such as the secretion of siderophores, swarming motility and biofilm formation. Thus, searching for quorum sensing inhibitors (QSIs) may be another promising way to control the deterioration of food caused by P. fluorescens. Here, we screened a traditional Chinese medicine (TCM) database to discover potential QSIs with lesser toxicity. The gene sequences of LuxI- and LuxR-type proteins of P. fluorescens P07 were obtained through whole-genome sequencing. In addition, the protein structures built by homology modelling were used as targets to screen for QSIs. Twenty-one compounds with a dock score greater than 6 were purchased and tested by biosensor strains (Chromobacterium violaceum CV026 and Agrobacterium tumefaciens A136). The results showed that 10 of the compounds were determined as hits (hit rate: 66.67%). Benzyl alcohol, rhodinyl formate and houttuynine were effective QSIs. The impact of the most active compound (benzyl alcohol) on the phenotypes of P. fluorescens P07, including swimming and swarming motility, production of extracellular enzymes and siderophores, N-acylhomoserine lactone (AHLs) content and biofilm formation were determined. The inhibitory mechanism of benzyl alcohol on the QS system of P. fluorescens P07 is further discussed. This study reveals the feasibility of searching for novel QSIs through virtual screening.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of novel pyrimido[5,4-d]pyrimidine derivatives as
           GPR119 agonist for treatment of type 2 diabetes
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Yuanying Fang, Jun Xu, Zhifeng Li, Zunhua Yang, Lijuan Xiong, Yi Jin, Qi Wang, Saisai Xie, Wufu Zhu, Sheng ChangWe described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC50 values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC0–2h) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC0–2h at the dose of 300 mg/kg.Graphical abstractGraphical abstract for this article
       
  • Discovery of novel leucyladenylate sulfamate surrogates as leucyl-tRNA
           synthetase (LRS)-targeted mammalian target of rapamycin complex 1 (mTORC1)
           inhibitors
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Suyoung Yoon, Dongxu Zuo, Jong Hyun Kim, Ina Yoon, Jihyae Ann, Sung-Eun Kim, Dasol Cho, Won Kyung Kim, Sangkook Lee, Jiyoun Lee, Sunghoon Kim, Jeewoo LeeAccording to recent studies, leucyl-tRNA synthetase (LRS) acts as a leucine sensor and modulates the activation of the mammalian target of rapamycin complex 1 (mTORC1) activation. Because overactive mTORC1 is associated with several diseases, including colon cancer, LRS-targeted mTORC1 inhibitors represent a potential option for anti-cancer therapy. In this work, we developed a series of simplified leucyladenylate sulfamate analogues that contain the N-(3-chloro-4-fluorophenyl)quinazolin-4-amine moiety to replace the adenine group. We identified several compounds with comparable activity to previously reported inhibitors and exhibited selective mTORC1 inhibition and anti-cancer activity. This study further supports the hypothesis that LRS is a promising target to modulate the mTORC1 pathway.Graphical abstractGraphical abstract for this article
       
  • Quinoxaline derivatives as potential antitrypanosomal and antileishmanial
           agents
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Juliana Cogo, Juan Cantizani, Ignacio Cotillo, Diego Pereira Sangi, Arlene Gonçalves Corrêa, Tânia Ueda-Nakamura, Benedito Prado Dias Filho, José Julio Martín, Celso Vataru NakamuraContinuous efforts have been made to discover new drugs for the treatment of Chagas’ disease, human African trypanosomiasis, and leishmaniasis. We have previously reported the synthesis and antileishmanial and antitrypanosomal (Y strain) properties of 2,3-disubstituted quinoxalines. Considering their promising antiparasitic potential, the present study was conducted to expand our search and take advantage of high-throughput assays to investigate the effects of quinoxaline derivatives against Leishmania donovani, Trypanosoma brucei, and Trypanosoma cruzi (Tulahuen strain). These compounds were active against the kinetoplastid parasites that were evaluated. The 2-chloro-3-methylsulfoxylsulfonyl and 2-chloro-3-methylsulfinyl quinoxalines were the most potent, and some of these derivatives were even more active than the reference drugs. Although the 2,3-diaryl-substituted quinoxalines were not active against all of the parasites, they were active against T. brucei and intracellular amastigotes of T. cruzi, without interfering with mammalian cell viability. These compounds presented encouraging results that will guide our future studies on in vivo bioassays towards the mode of action.Graphical abstractGraphical abstract for this article
       
  • Activity of steroid 4 and derivatives 4a–4f as inhibitors of the enzyme
           5α-reductase 1
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Yazmín Arellano, Eugene Bratoeff, Yvonne Heuze, Marisol Bravo, Juan Soriano, Marisa CabezaIt is known that the growth of prostate metastatic bone tumor depends on androgens, and tumor formation can start from migratory malignant cells produced in that organ. These cells exhibit grater type 1 5α-reductase (5α-R1) activity than type 2 5α-reductase. Noteworthy, both isozymes convert testosterone (T) to the more active androgen dihydrotestosterone (DHT) in the target tissues.Thus, in order to potentially improve the prognosis of this disease, in this work, seven derivatives of 17-(1H-benzimidazol-1-yl)-16-formillandrosta-5,16-dien-3β-yl benzoate (4a–f) and 17-(1H-benzimidazol-1-yl)-3-hydroxy-16-formylandrost-5,16-diene (4) were synthesized, characterized and identified as inhibitors of type 1 5α-reductase (5αR1). These derivatives having the advantage of improved plasma half-life.The inhibitory activity of the compounds towards 5α-R1 isoenzyme was determined by conversion of T into DHT in the presence or absence of compounds 4, 4a–f. Further, in vivo experiments were also carried out, treating gonadectomized hamsters with T and/or 4, 4a–f and evaluating their effect on the diameter of hamster flank organs and on the weight of the prostatic and seminal vesicles. Results indicated that compounds 4, 4b, 4c, served as in vitro inhibitors of the enzyme 5α-R1 and pharmacological experiments showed that 4 and derivatives 4a–f decreased the diameter of the flank glands, the weight of the prostate and seminal vesicles of treated hamsters without any appreciable toxicity during observation. Noteworthy the fact that compound 4 is the product, in all cases, of the hydrolysis of the series of esters 4a–f, thus they can serve as precursors (prodrugs) of the active form 4.Graphical abstractGraphical abstract for this article
       
  • Synthesis and characterization of some atypical sphingoid bases
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Essa M. Saied, Thuy Linh-Stella Le, T. Hornemann, Christoph ArenzSphingolipids are ubiquitous and abundant components of all eukaryotic and some prokaryotic organisms. Sphingolipids show a large structural variety not only between the different species, but also within an individual cell. This variety is not limited to alterations in the polar headgroups of e.g. glycosphingolipids, but also affects the lipophilic anchors comprised of different fatty acids on the one hand and different sphingoid bases on the other hand. The structural variations within different sphingoid bases e.g. in pathogens can be used to identify novel biomarkers and drug targets and the specific change in the profile of common and uncommon sphingolipids are associated with pathological conditions like diabetes or cancer. Therefore, the emerging field of sphingolipidomics is dedicated to collect data on the sphingolipidome of a cell and hence to assign changes therein to certain states of a cell or to pathological conditions. This powerful tool however is still limited by the availability of structural information about the individual lipid species as well as by the availability of appropriate internal standards for quantification. Herein we describe the synthesis of a variety of 1-deoxy-sphingoid bases. 1-DeoxySphingolipids have recently acquired significant attention due to its pathological role in the rare inherited neuropathy, HSAN1 but also as predictive biomarkers in diabetes type II. Some of the compounds synthesized and characterized herein, have been used and will be used to elucidate the correct structure of these disease-related lipids and their metabolites.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, and biological evaluation of novel oxadiazole- and
           thiazole-based histamine H3R ligands
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Mohammad A. Khanfar, David Reiner, Stefanie Hagenow, Holger StarkHistamine H3 receptor (H3R) is largely expressed in the CNS and modulation of the H3R function can affect histamine synthesis and liberation, and modulate the release of many other neurotransmitters. Targeting H3R with antagonists/inverse agonists may have therapeutic applications in neurodegenerative disorders, gastrointestinal and inflammatory diseases. This prompted us to design and synthesize azole-based H3R ligands, i.e. having oxadiazole- or thiazole-based core structures. While ligands of oxadiazole scaffold were almost inactive, thiazole-based ligands were very potent and several exhibited binding affinities in a nanomolar concentration range. Ligands combining 4-cyanophenyl moiety as arbitrary region, para-xylene or piperidine carbamoyl linkers, and/or pyrrolidine or piperidine basic heads were found to be the most active within this series of thiazole-based H3R ligands. The most active ligands were in silico screened for ADMET properties and drug-likeness. They fulfilled Lipinski’s and Veber’s rules and exhibited potential activities for oral administration, blood–brain barrier penetration, low hepatotoxicity, combined with an overall good toxicity profile.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s):
       
  • Identification of PKMYT1 inhibitors by screening the GSK published protein
           kinase inhibitor set I and II
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Charlott Platzer, Abdulkarim Najjar, Alexander Rohe, Frank Erdmann, Wolfgang Sippl, Matthias SchmidtAs a member of the Wee-kinase family protein kinase PKMYT1 is involved in G2/M checkpoint regulation of the cell cycle. Recently, a peptide microarray approach led to the identification of a small peptide; EFS247–259 as substrate of PKMYT1, which allowed for subsequent development of an activity assay. The developed activity assay was used to characterize the PKMYT1 catalyzed phosphorylation of EFS247–259. For the first time kinetic parameters for PKMYT1, namely Km, Km, ATP and vmax were determined. The optimized assay was used to screen the published protein kinase inhibitor sets (PKIS I and II), two sets of small molecule ATP-competitive kinase inhibitors reported by GlaxoSmithKline. We identified ten inhibitors, providing different scaffolds. The inhibitors were further characterized by using binding assay, activity and functional assay. In addition, docking studies were carried out in order to rationalize the observed biological activities. The derived results provide the basis for further chemical optimization of PKMYT1 inhibitors and for further analysis of PKMYT1 as target for anti-cancer therapy.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and pharmacology of aortic-selective acyl-CoA:
           Cholesterol O-acyltransferase (ACAT/SOAT) inhibitors
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Kimiyuki Shibuya, Katsumi Kawamine, Toru Miura, Chiyoka Ozaki, Toshiyuki Edano, Ken Mizuno, Yasunobu Yoshinaka, Yoshihiko TsunenariWe describe our molecular design of aortic-selective acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also abbreviated as SOAT) inhibitors, their structure–activity relationships (SARs) and their pharmacokinetic (PK) and pharmacological profiles. The connection of two weak ligands—N-(2,6-diisopropylphenyl)acetamide (50% inhibitory concentration [IC50] = 8.6 μM) and 2-(methylthio)benzo[d]oxazole (IC50 = 31 μM)—via a linker comprising a 6 methylene group chains yielded a highly potent molecule, 9-(benzo[d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide (3h) that exhibited high potency (IC50 = 0.004 μM) toward aortic ACAT. This head-to-tail design made it possible to markedly enhance the activity to 2150- to 7750-fold and to discriminate the isoform-selectivity based on the double-induced fit mechanism. At doses of 1 and 3 mg/kg, 3h significantly decreased the lipid-accumulation areas in the aortic arch to 74 and 69%, respectively without reducing the plasma total cholesterol level in high fat- and cholesterol-fed F1B hamsters. Here, we demonstrate the antiatherosclerotic effect of 3hin vivo via its direct action on aortic ACAT and its powerful modulator of cholesterol level. This molecule is a potential therapeutic agent for the treatment of diseases involving ACAT-1 overexpression.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of alkyl substituted pyridino[2,3-D]pyrimidine
           compounds as PI3Kα/mTOR dual inhibitors with improved pharmacokinetic
           properties and potent in vivo antitumor activity
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Yinyin Liu, Qinhua Xia, Lei FangUsing pyridino[2,3-D]pyrimidine as the core, total 13 pyridino[2,3-D]pyrimidine derivatives with different alkyl substituents at C2 site have been designed and synthesized to search for novel PI3Kα/mTOR dual inhibitors. Most of the target compounds showed potent mTOR inhibition activity with IC50 values ranging from single to double digit nanomole. Five target compounds exhibited pronounced PI3Kα inhibition activity. In vitro cellular assay indicated that most of the target compounds showed excellent antiproliferative activity, especially 3j whose potency against SKOV3 was 8-fold higher than the positive control AZD8055. In vitro metabolic stability study found that 3j had a comparable stability to that of AZD8055. More importantly, 3j showed better antitumor activity and pharmacokinetic properties in vivo as compared with AZD8055.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel series of
           2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold
           derivatives as PI3Kα inhibitors
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Fu-Dan Dong, Dan-Dan Liu, Cheng-Long Deng, Xiao-chun Qin, Kai Chen, Jian Wang, Hong-Rui Song, Huai-Wei DingThe abnormal activation of PI3K signaling pathway leads to the occurrence of various cancers. The PI3Kα is frequently mutated and overexpressed in many human cancers. Therefore, the PI3Kα was considered as a promising target in therapeutic treatment of cancer. In this study, two series of compounds containing 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold were synthesized and evaluated antiproliferative activities against three cancer cell lines, including HCT-116, MDA-MB-231 and SNU638. Compound 7f with the most potent antiproliferative activity was selected for further evaluation on normal cells and PI3K kinase. Studies indicated that compound 7f could decrease the phospho-Akt (T308) in a dose-dependent manner. Four key hydrogen bonding interactions were found in the docking of 7f with PI3K enzyme. All the results suggested that 7f was a potent PI3Kα inhibitor.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, in vitro and in vivo evaluation, and structure-activity
           relationship (SAR) discussion of novel dipeptidyl boronic acid proteasome
           inhibitors as orally available anti-cancer agents for the treatment of
           multiple myeloma and mechanism studies
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Meng Lei, Huayun Feng, Enhe Bai, Hui Zhou, Jia Wang, Jingmiao Shi, Xueyuan Wang, Shihe Hu, Zhaogang Liu, Yongqiang ZhuA series of novel dipeptidyl boronic acid inhibitors of 20S proteasome were designed and synthesized. Aliphatic groups at R1 position were designed for the first time to fully understand the SAR (structure–activity relationship). Among the screened compounds, novel inhibitor 5c inhibited the CT-L (chymotrypsin-like) activity with IC50 of 8.21 nM and the MM (multiple myeloma) cells RPMI8226, U266B and ARH77 proliferations with the IC50 of 8.99, 6.75 and 9.10 nM, respectively, which showed similar in vitro activities compared with the compound MLN2238 (biologically active form of marketed MLN9708). To investigate the oral availability, compound 5c was esterified to its prodrug 6a with the enzymatic IC50 of 6.74 nM and RPMI8226, U266B and ARH77 cell proliferations IC50 of 2.59, 4.32 and 3.68 nM, respectively. Furthermore, prodrug 6a exhibited good pharmacokinetic properties with oral bioavailability of 24.9%, similar with MLN9708 (27.8%). Moreover, compound 6a showed good microsomal stabilities and displayed stronger in vivo anticancer efficacy than MLN9708 in the human ARH77 xenograft mouse model. Finally, cell cycle results showed that compound 6a had a significant inhibitory effect on CT-L and inhibited cell cycle progression at the G2M stage.Graphical abstractGraphical abstract for this article
       
  • Synthesis and pharmacological evaluation of pyrazolo[4,3-c]quinolinones as
           high affinity GABAA-R ligands and potential anxiolytics
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Marisa J. López Rivilli, Anahí V. Turina, Elena A. Bignante, Victor H. Molina, María A. Perillo, Margarita C. Briñon, Elizabeth L. MoyanoThe synthesis, in vitro ligand binding study and in vivo Elevated Plus Maze test (EPM) of a series of pyrazolo[4,3-c]quinolin-3-ones (PQs) are reported. Multistep synthesis of PQs started from anilines and diethyl 2-(ethoxymethylene)malonate to give the quinolin-4-one nucleus, via the Gould-Jacobs reaction. These quinolinones were transformed to 4-chloroquinolines, which react with aryl-hydrazines affording the final compounds. PQs exhibited different potency in displacing specific [3H]Flunitrazepam binding from the benzodiazepine binding site at the γ-aminobutyric acid receptor (GABAA-R) depending on the substitution of the pyrazoloquinolone nucleus. PCA helped determine how different substituents contributed to the differential behavior of the PQs studied. Compounds with high affinity for the GABAA-R were tested regarding their anxiolytic properties in Wistar adult male rats using the Elevated Plus Maze (EPM). Thus, PQs with a p-methoxy phenyl group at N-1 (7b-ii and 7c-ii) displayed a remarkable anxiolytic activity at low doses (0.5–1.0 mg/kg). Meanwhile, PQs featuring an unsubstituted phenyl (7b-i) or p-fluoro phenyl group (7b-iii) at the N-1 showed anxiogenic effects in the EPM test.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and anticancer evaluation of acridine hydroxamic acid
           derivatives as dual Topo and HDAC inhibitors
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Jiwei Chen, Dan Li, Wenlu Li, Jingxian Yin, Yueying Zhang, Zigao Yuan, Chunmei Gao, Feng Liu, Yuyang JiangMultitarget inhibitors design has generated great interest in cancer treatment. Based on the synergistic effects of topoisomerase and histone deacetylase inhibitors, we designed and synthesized a new series of acridine hydroxamic acid derivatives as potential novel dual Topo and HDAC inhibitors. MTT assays indicated that all the hybrid compounds displayed good antiproliferative activities with IC50 values in low micromolar range, among which compound 8c displayed potent activity against U937 (IC50 = 0.90 μM). In addition, compound 8c also displayed the best HDAC inhibitory activity, which was several times more potent than HDAC inhibitor SAHA. Subsequent studies indicated that all the compounds displayed Topo II inhibition activity at 50 μM. Moreover, compound 8c could interact with DNA and induce U937 apoptosis. This study provides a suite of compounds for further exploration of dual Topo and HDAC inhibitors, and compound 8c can be a new dual Topo and HDAC inhibitory anticancer agent.Graphical abstractGraphical abstract for this article
       
  • Identification by Inverse Virtual Screening of magnolol-based scaffold as
           new tankyrase-2 inhibitors
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Simone Di Micco, Luana Pulvirenti, Ines Bruno, Stefania Terracciano, Alessandra Russo, Maria C. Vaccaro, Dafne Ruggiero, Vera Muccilli, Nunzio Cardullo, Corrado Tringali, Raffaele Riccio, Giuseppe BifulcoThe natural product magnolol (1) and a selection of its bioinspired derivatives 2–5, were investigated by Inverse Virtual Screening in order to identify putative biological targets from a panel of 308 proteins involved in cancer processes. By this in silico analysis we selected tankyrase-2 (TNKS2), casein kinase 2 (CK2) and bromodomain 9 (Brd9) as potential targets for experimental evaluations. The Surface Plasmon Resonance assay revealed that 3–5 present a good affinity for tankyrase-2, and, in particular, 3 showed an antiproliferative activity on A549 cells higher than the well-known tankyrase-2 inhibitor XAV939 used as reference compound.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of nitric oxide releasing
           derivatives of dapagliflozin as potential anti-diabetic and
           anti-thrombotic agents
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Zheng Li, Xue Xu, Liming Deng, Ruoxian Liao, Ruiying Liang, Bo Zhang, Luyong ZhangThe cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.Graphical abstractGraphical abstract for this article
       
  • Rational design of novel irreversible inhibitors for human arginase
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Xuefeng Guo, Yiming Chen, Christopher T. SetoParasites have developed a variety of strategies for invading hosts and escaping their immune response. A common mechanism by which parasites escape nitric oxide (NO) toxicity is the activation of host arginase. This activation leads to a depletion of l-arginine, which is the substrate for NO synthase, resulting in lower levels of NO and increased production of polyamines that are necessary for parasite growth and differentiation. For this reason, small molecule inhibitors for arginase show promise as new anti-parasitic chemotherapeutics. However, few arginase inhibitors have been reported. Here, we describe the discovery of novel irreversible arginase inhibitors, and their characterization using biochemical, kinetic, and structural studies. Importantly, we determined the site on human arginase that is labeled by one of the small molecule inhibitors. The tandem mass spectra data show that the inhibitor occupies the enzyme active site and forms a covalent bond with Thr135 of arginase. These findings pave the way for the development of more potent and selective irreversible arginase inhibitors.Graphical abstractGraphical abstract for this article
       
  • Senolytic activity of piperlongumine analogues: Synthesis and biological
           evaluation
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Xingui Liu, Yingying Wang, Xuan Zhang, Zhengya Gao, Suping Zhang, Peizhong Shi, Xin Zhang, Lin Song, Howard Hendrickson, Daohong Zhou, Guangrong ZhengSelective clearance of senescent cells (SCs) has emerged as a potential therapeutic approach for age-related diseases, as well as chemotherapy- and radiotherapy-induced adverse effects. Through a cell-based phenotypic screening approach, we recently identified piperlongumine (PL), a dietary natural product, as a novel senolytic agent, referring to small molecules that can selectively kill SCs over normal or non-senescent cells. In an effort to establish the structure-senolytic activity relationships of PL analogues, we performed a series of structural modifications on the trimethoxyphenyl and the α,β-unsaturated δ-valerolactam rings of PL. We show that modifications on the trimethoxyphenyl ring are well tolerated, while the Michael acceptor on the lactam ring is critical for the senolytic activity. Replacing the endocyclic C2–C3 olefin with an exocyclic methylene at C2 render PL analogues 47–49 with increased senolytic activity. These α-methylene containing analogues are also more potent than PL in inducing ROS production in WI-38 SCs. Similar to PL, 47–49 reduce the protein levels of oxidation resistance 1 (OXR1), an important oxidative stress response protein that regulates the expression of a variety of antioxidant enzymes, in cells. This study represents a useful starting point toward the discovery of senolytic agents for therapeutic uses.Graphical abstractGraphical abstract for this article
       
  • Optimization and in vivo evaluation of pyrazolopyridines as a potent and
           selective PI3Kδ inhibitor
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Toshihiro Hamajima, Fumie Takahashi, Koji Kato, Yukihito Sugano, Susumu Yamaki, Ayako Moritomo, Satoshi Kubo, Koji Nakamura, Kaoru Yamagami, Nozomu Hamakawa, Koji Yokoo, Hidehiko FukahoriChemical optimization of pyrazolopyridine 1, focused on cellular potency, isoform selectivity and microsomal stability, led to the discovery of the potent, selective and orally available PI3Kδ inhibitor 5d. On the basis of its desirable potency, selectivity and pharmacokinetic profiles, 5d was tested in the trinitrophenylated aminoethylcarboxymethyl-Ficoll (TNP-Ficoll)-induced antibody production model, and showed higher antibody inhibition than a 4-fold oral dose of the starting compound 1. These excellent results suggest that 5d is a potential candidate for further studies in the treatment of autoimmune diseases and leukocyte malignancies.Graphical abstractGraphical abstract for this article
       
  • Synthesis and antitumor activity of bis(hydroxymethyl)propionate analogs
           of pterostilbene in cisplatin-resistant human oral cancer cells
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Min-Tsang Hsieh, Li-Jiau Huang, Tian-Shung Wu, Hui-Yi Lin, Susan L. Morris-Natschke, Kuo-Hsiung Lee, Sheng-Chu KuoThe aim of this study was to develop a new drug substance with low toxicity and effective inhibitory activity against cisplatin-resistant oral cancer. The naturally produced pterostilbene was selected as the lead compound for design and synthesis of a series of bis(hydroxymethyl)propionate-based prodrugs. All derivatives were screened for antiproliferative effects against the cisplatin-resistant oral squamous (CAR) cell line and the results indicated that several compounds demonstrated superior inhibitory activity compared with pterostilbene and resveratrol. Among them, the most promising compound, 12, was evaluated for in vivo antitumor activity in a CAR xenograft nude mouse model. Obvious antitumor activity was observed at the lowest oral dose (25 mg/kg/day). Increasing the dose of 12 to 100 mg/kg/day reduced the tumor size to 22% of the control group. Based on these findings as well as the extremely low toxicity seen in the in vivo studies, we believe that compound 12 could serve as a new lead for further development.Graphical abstractGraphical abstract for this article
       
  • Facile construction of fused benzimidazole-isoquinolinones that induce
           cell-cycle arrest and apoptosis in colorectal cancer cells
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Liu-Jun He, Dong-Lin Yang, Shi-Qiang Li, Ya-Jun Zhang, Yan Tang, Jie Lei, Brendan Frett, Hui-kuan Lin, Hong-yu Li, Zhong-Zhu Chen, Zhi-Gang XuColorectal cancer (CRC) is one of the most frequent, malignant gastrointestinal tumors, and strategies and effectiveness of current therapy are limited. A series of benzimidazole-isoquinolinone derivatives (BIDs) was synthesized and screened to identify novel scaffolds for CRC. Of the compounds evaluated, 7g exhibited the most promising anti-cancer properties. Employing two CRC cell lines, SW620 and HT29, 7g was found to suppress growth and proliferation of the cell lines at a concentration of ∼20 µM. Treatment followed an increase in G2/M cell cycle arrest, which was attributed to cyclin B1 and cyclin-dependent kinase 1 (CDK1) signaling deficiencies with simultaneous enhancement in p21 and p53 activity. In addition, mitochondrial-mediated apoptosis was induced in CRC cells. Interestingly, 7g decreased phosphorylated AKT, mTOR and 4E-BP1 levels, while promoting the expression/stability of PTEN. Since PTEN controls input into the PI3K/AKT/mTOR pathway, antiproliferative effects can be attributed to PTEN-mediated tumor suppression. Collectively, these results suggest that BIDs exert antitumor activity in CRC by impairing PI3K/AKT/mTOR signaling. Against a small kinase panel, 7g exhibited low affinity at 5 µM suggesting anticancer properties likely stem through a non-kinase mechanism. Because of the novelty of BIDs, the structure can serve as a lead scaffold to design new CRC therapies.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of piperazino-enaminones as
           novel suppressants of pro-Inflammatory cytokines
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Ola M. Ghoneim, Ashley Bill, Jyothi Dhuguru, Doreen E. Szollosi, Ivan O. EdafioghoInfection triggers the release of pro-inflammatory cytokines (TNF-alpha and IL-6). Over-production, however, cause tissue injury seen in severe asthma. The ability of enaminone E121 to reduce pro-inflammatory cytokines in our laboratory encouraged further examination of its structural scaffold. Piperazino-enaminones were designed by incorporating n-arylpiperazine motif into the aromatic enaminone. Four possible modifications were explored systematically. Synthesis was accomplished by amination of the corresponding methyl/ethyl 2,4-dioxo-6-(substituted)cyclohexane-carboxylate.. Sixteen novel compounds were synthesized. Biological activity was tested in J774 macrophages stimulated with lipopolysaccharides. The release of cytokines was measured via ELISA. Four compounds significantly suppressed TNF-alpha and IL-6 release in dose-dependent manner.Graphical abstractGraphical abstract for this article
       
  • The tyrosinase inhibitory effects of isoxazolone derivatives with a
           (Z)-β-phenyl-α, β-unsaturated carbonyl scaffold
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Su Jeong Kim, Jungho Yang, Sanggwon Lee, Chaeun Park, Dongwan Kang, Jinia Akter, Sultan Ullah, Yeon-Jeong Kim, Pusoon Chun, Hyung Ryong MoonThirteen (Z)-4-(substituted benzylidene)-3-phenylisoxazol-5(4H)-ones were designed to confirm the geometric effect of the double bond of the β-phenyl-α, β-unsaturated carbonyl scaffold on tyrosinase inhibitory activity. Compounds 1a–1m, which all possessed the (Z)-β-phenyl-α, β-unsaturated carbonyl scaffold, were synthesized using a tandem reaction consisting of an isoxazolone ring formation and a Knoevenagel condensation, and three starting materials, ethyl benzoylacetate, hydroxylamine and benzaldehydes. Some of the compounds showed inhibitory activity against mushroom tyrosinase as potent as compounds containing the “(E)”-β-phenyl-α, β-unsaturated carbonyl scaffold. Compounds 1c and 1m showed greater inhibitory activity than kojic acid: IC50 = 32.08 ± 2.25 μM for 1c; IC50 = 14.62 ± 1.38 μM for 1m; and IC50 = 37.86 ± 2.21 μM for kojic acid. A kinetic study indicated that 1m inhibited tyrosinase in a competitive manner and that it probably binds to the enzyme’s active site. In silico docking simulation supported binding of 1m (−7.6 kcal/mol) to the active site of tyrosinase with stronger affinity than kojic acid (−5.7 kcal/mol). Similar results were obtained using cell-based assays, and in B16F10 cells, compound 1m dose-dependently inhibited tyrosinase activity and melanogenesis. These results indicate the anti-melanogenic effect of compound 1m is due to the inhibition of tyrosinase and (Z)-isomer of the β-phenyl-α, β-unsaturated carbonyl scaffold can, like its congener the (E)-isomer, act as an excellent scaffold for tyrosinase inhibition.Graphical abstractGraphical abstract for this article
       
  • Synthesis and hybridizing properties of isoDNAs including
           3′-O,4′-C-ethyleneoxy-bridged 5-methyluridine derivatives
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Takashi Osawa, Yuka Hitomi, Sawako Wakita, Han Kim, Yuta Ito, Yoshiyuki Hari3′,4′-Ethyleneoxy-bridged 5-methyluridine derivatives with methyl groups in the bridge, (R)-Me-3′,4′-EoNA-T and (S)-Me-3′,4′-EoNA-T, were synthesized, and these two analogs and unsubstituted 3′,4′-EoNA-T were successfully incorporated into a 2′,5′-linked oligonucleotide (isoDNA). Their duplex-forming ability with complementary DNA and complementary RNA, and triplex-forming ability with double-stranded DNA, were evaluated by UV-melting experiments. The results indicated that isoDNAs, including these 3′,4′-EoNA analogs, could hybridize exclusively with complementary RNA. In particular, 3′,4′-EoNA-T and (R)-Me-3′,4′-EoNA-T modifications within isoDNA could stabilize the duplexes with complementary RNA compared with unmodified or 3′,4′-BNA-modified isoDNAs.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel spiro-pentacylamides
           as acetyl-CoA carboxylase inhibitors
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Qiangqiang Wei, Liankuo Mei, Yifei Yang, Hui Ma, Hongyi Chen, Huibin Zhang, Jinpei ZhouAcetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays an important role in the regulation of fatty acid oxidation. Therefore, ACC inhibition offers a promising option for intervention in nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2DM) and cancer. In this paper, a series of spiropentacylamide derivatives were synthesized and evaluated for their ACC1/2 inhibitory activities and anti-proliferation effects on A549, H1975, HCT116, SW620 and Caco-2 cell lines in vitro. Compound 6o displayed potent ACC1/2 inhibitory activity (ACC1 IC50 = 0.527 μM, ACC2 IC50 = 0.397 μM) and the most potent anti-proliferation activities against A549, H1975, HCT116, SW620 and Caco-2 cell lines, with IC50 values of 1.92 μM, 0.38 μM, 1.22 μM, 2.05 μM and 5.42 μM respectively. Further molecular docking studies revealed that compound 6o maintained hydrogen bonds between the two carbonyls and protein backbone NHs (Glu-B2026 and Gly-B1958). These results indicate that compound 6o is a promising ACC1/2 inhibitor for the potent treatment of cancer.Graphical abstractGraphical abstract for this article
       
  • SIRT4 is the last puzzle of mitochondrial sirtuins
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Yan Li, Yefang Zhou, Fang Wang, Xiaoxue Chen, Chun Wang, Jie Wang, Ting Liu, Yongjun Li, Bin HeSirtuins are recently redefined as a family of nicotinamide adenine dinucleotide (NAD)-dependent deacylases. Sirtuins in mammals including human have seven members, which are SIRT1-7. Compared to other sirtuin members, not much study is focused on mitochondrial sirtuins (SIRT3-5). In mitochondrial sirtuins, SIRT4 was the last of less well-understood mitochondrial sirtuins especially for its robust enzymatic activity. This makes SIRT4 become the last puzzle of mitochondrial sirtuins, and thus brings some obstacles for studying SIRT4 biological functions or developing SIRT4 modulators. In this review, we will summarize and discuss the current findings for substrates, biological functions and possible enzymatic activities of SIRT4. The purpose of this review is to facilitate in discovering the robust enzymatic activity of SIRT4 and eventually finish this last puzzle of mitochondrial sirtuins.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s):
       
  • Graphical abstract TOC
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s):
       
  • Corrigendum to “Exploration of multi-target potential of chromen-4-one
           based compounds in Alzheimer’s disease: Design, synthesis and biological
           evaluations” [Bioorg. Med. Chem. 25 (2017) 6273–6285]
    • Abstract: Publication date: 7 August 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 14Author(s): Manjinder Singh, Maninder Kaur, Nirmal Singh, Om Silakari
       
  • Synthesis, molecular docking, and biological activity of 2-vinyl
           chromones: toward selective butyrylcholinesterase inhibitors for potential
           Alzheimer's disease therapeutics
    • Abstract: Publication date: Available online 6 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Galina F. Makhaeva, Natalia P. Boltneva, Sofya V. Lushchekina, Elena V. Rudakova, Olga G. Serebryakova, Larisa N. Kulikova, Andrei A. Beloglazkin, Roman S. Borisov, Rudy J. RichardsonWe investigated the biological activity of a series of substituted chromeno[3,2-c]pyridines, including compounds previously synthesized by our group and novel compounds whose syntheses are reported here. Tandem transformation of their tetrahydropyridine ring under the action of activated alkynes yielding 2-vinylsubstituted chromones was used to prepare nitrogen-containing derivatives of a biologically active chromone system. The inhibitory activity of these chromone derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) was investigated using the methods of enzyme kinetics and molecular docking. Antioxidant (antiradical) activity of the compounds was assessed in the ABTS assay. The results demonstrated that a subset of the studied chromone derivatives selectively inhibit BChE but do not exhibit antiradical activity. In addition, the results of molecular docking effectively explained the observed features in the efficacy, selectivity, and mechanism of BChE inhibition by the chromone derivatives.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 InoueJanus 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
       
  • A series of camptothecin prodrugs exhibit HDAC inhibition activity
    • Abstract: Publication date: Available online 4 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Qiwen Zhu, Xumeng Yu, Qianqian Shen, Qiumeng Zhang, Mingbo Su, Yubo Zhou, Jia Li, Yi Chen, Wei LuCamptothecin plays an important role in clinical cancer treatment, and its derivatives are a favorite of pharmaceutical chemists. Herein, we have designed a series of camptothecin prodrugs that exhibit histone deacetylase (HDAC) inhibition activity based on the synergy effect between HDAC inhibitors and camptothecin derivatives. With the evaluation of stability in buffers or plasma from human or mouse model, an appropriate linker was found, so the active drug can be released efficiently and compound 21a exhibited strong antiproliferative activity in A549 and HCT-116 cell lines. These results indicated that the well-designed prodrug can be promising in cancer treatment.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of 1,2,3,4-tetrahydro-1-acridone analogues as
           potential dual inhibitors for amyloid-beta and tau aggregation
    • Abstract: Publication date: Available online 4 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Peng Lv, Chun-Li Xia, Ning Wang, Zhen-Quan Liu, Zhi-Shu Huang, Shi-Liang HuangAmyloid-β (Aβ) and tau protein are two crucial hallmarks in Alzheimer’s disease (AD). Their aggregation forms are thought to be toxic to the neurons in the brain. A series of new 1,2,3,4-tetrahydro-1-acridone analogues were designed, synthesized, and evaluated as potential dual inhibitors for Aβ and tau aggregation. In vitro studies showed that compounds 25-30 (20 μM) with N-methylation of the quinolone ring effectively inhibited Aβ1-42 aggregation by 84.7% to 99.5% and tau aggregation by 71.2% to 101.8%. Their structure-activity relationships are discussed. In particular, 30 could permeate the blood-brain barrier, bind to Aβ1-42 and tau, inhibit Aβ1-42 β-sheets formation, and prevent tau aggregation in living cells.Graphical abstractGraphical abstract for this article
       
  • In vitro and in vivo pharmacokinetic and pharmacodynamic study of
           MBRI-001, a deuterium-substituted plinabulin derivative as a potent
           anti-cancer agent
    • Abstract: Publication date: Available online 4 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Mingxu Ma, Jianchun Zhao, Hejuan Cheng, Mengyan Deng, Zhongpeng Ding, Yingwei Hou, Feng Li, Guifang Dou, Wenbao LiMBRI-001 was demonstrated preliminary better pharmacokinetics and antitumor effects than that of plinabulin in vivo. In this approach, we further carried out systematic pharmacokinetic and pharmacodynamic study of MBRI-001 in vitro and in vivo. MBRI-001 was tested stable in rat plasma and more stable in liver microsomes than plinabulin in vitro. In vivo, MBRI-001 could be distributed rapidly and widely in various tissues, especially the concentration of MBRI-001 in lung was remarkably higher than other tissues. Excretion study indicated that MBRI-001 might been decomposed and excreted as metabolites. Additionally, the combination treatment of MBRI-001 and gefitinib revealed better antitumor inhibition rate than monotherapy in vivo. Therefore, we suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.Graphical abstractGraphical abstract for this article
       
  • Dual-targeting for brain-specific liposomes drug delivery system:
           synthesis and preliminary evaluation
    • Abstract: Publication date: Available online 4 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Yao Peng, Yi Zhao, Yang Chen, Zhongzhen Yang, Li Zhang, Wenjiao Xiao, Jincheng Yang, Li Guo, Yong WuThe treatment of glioma has become a great challenge because of the existence of brain barrier (BB). In order to develop an efficient brain targeting drug delivery system to greatly improve the brain permeability of anti-cancer drugs, a novel brain-targeted glucose-vitamin C (Glu-Vc) derivative was designed and synthesized as liposome ligand for preparing liposome to effectively deliver paclitaxel (PTX). The liposome was prepared and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis and cytotoxicity were also characterized. What’s more, the cellular uptake of CFPE-labeled Glu-Vc-Lip on GLUT1- and SVCT2-overexpressed C6 cells was 4.79-, 1.95-, 4.00- and 1.53-fold higher than that of Lip, Glu-Lip, Vc-Lip and Glu+Vc-Lip. Also, the Glu-Vc modified liposomes showed superior targeting ability in vivo evaluation compared with naked paclitaxel, non-coated, singly-modified and co-modified by physical blending liposomes. The relative uptake efficiency was enhanced by 7.53 fold to that of naked paclitaxel, while the concentration efficiency was up to 7.89 times. What’s more, the Glu-Vc modified liposomes also displayed the maximum accumulation of DiD-loaded liposomes at tumor sites with the strongest fluorescence in the brain in vivo imaging. Our results suggest that chemical modification of liposomes with warheads of glucose and vitamin C represents a promising and efficient strategy for the development of brain-specific liposomes drug delivery system by utilizing the endogenous transportation mechanism of the warheads.Graphical abstractGraphical abstract for this article
       
  • 5-Adamantan thiadiazole-based thiazolidinones as antimicrobial agents.
           Design, synthesis, molecular docking and evaluation
    • Abstract: Publication date: Available online 3 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Maria Fesatidou, Panagiotis Zagaliotis, Charalampos Camoutsis, Anthi Petrou, Phaedra Eleftheriou, Christophe Tratrat, Micheline Haroun, Athina Geronikaki, Ana Ciric, Marina SokovicIn continuation of our efforts to develop new compounds with antimicrobial properties we describe design, synthesis, molecular docking study and evaluation of antimicrobial activity of seventeen novel 2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-arylidene-1,3-thiazolidin-4-ones. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. Twelve out of seventeen compounds were more potent than streptomycin and all compounds exhibited higher potency than ampicillin. Compounds were also tested against three resistant bacterial strains: MRSA, P. aeruginosa and E. coli. The best antibacterial potential against ATCC and resistant strains was observed for compound 8 (2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-(4-nitrobenzylidene)-1,3thiazolidin-4-one). The most sensitive bacterium appeared to be S. typhimirium, followed by B. cereus while L. monocitogenes and M. flavus were the most resistant. Compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited antifungal activity better than the reference drugs bifonazole and ketokonazole (3-115 times). It was found that compound 8 appeared again to be the most potent. Molecular docking studies on E.coli MurB, MurA as well as C. albicans CYP 51 and dihydrofolate reductase were used for the prediction of mechanism of antibacterial and antifungal activities confirming the experimental results.Graphical abstractSeventeen novel 2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-arylidene-1,3-thiazolidin-4-ones were designed, synthesized and evaluated for antimicrobial activity. All compounds were potent antimicrobial agents. According to molecular docking studies, inhibition of MurB and CYP 51 may be involved in the mechanism of antibacterial and antifungal activities of most of the compounds.Graphical 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, Xiaoy Ma, Chandrashekhar Honrao, JodiAnne T. Wood, Othman Benchama, Han Zhou, Srikrishnan Mallipeddi, Alexandros MakriyannisNew oximes short-acting CB1 agonists were explored by the introduction of an internal oxime and polar groups at the C3 alkyl tail of 8-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 of 8-THC-DMH), and found to function as either agonists (trans-oximes) or neutral (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 8-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
       
  • Synthesis and properties of 4'-C-aminoalkyl-2'-fluoro-modified
           RNA oligomers
    • Abstract: Publication date: Available online 2 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Toshifumi Kano, Yui Katsuragi, Yusuke Maeda, Yoshihito UenoSynthesis and properties of double-stranded RNAs (dsRNAs) and small interfering RNAs (siRNAs) containing 4'-C-aminoethyl-2'-deoxy-2'-fluorouridine are described. Thermal denaturation studies showed that incorporation of 4'-C-aminoethyl-2'-fluoro analog improved the thermal stabilities of dsRNAs and siRNAs compared to the corresponding 4'-C-aminoethyl-2'-O-methyl analog. siRNA incorporating eight 4'-aminoethyl-2'-fluoro analogs in the passenger strand showed sufficient RNAi activity at 1 nM concentration, which was similar to that of the unmodified siRNA. Furthermore, the siRNA containing the 4'-C-aminoethyl-2'-fluoro analog exhibited high stability in a buffer containing 20% bovine serum. Forty-eight percent of the siRNA remained intact after 48 h of incubation. Thus, modification of siRNAs by the 4'-C-aminoethyl-2'-fluoro analog would be useful for the development of therapeutic siRNA molecules.Graphical abstractGraphical abstract for this article
       
  • A novel synthesis of 2-arylbenzimidazoles in molecular sieves-MeOH system
           and their antitubercular activity
    • Abstract: Publication date: Available online 1 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Amit K. Chaturvedi, Amit Kumar Verma, J.P. Thakur, Sudeep Roy, Shashi Bhushan Tripathi, Balagani Sathish Kumar, Sadiya Khwaja, Naresh K. Sachan, Ashok Sharma, Debabrata Chanda, Karuna Shanker, Dharmendra Saikia, Arvind S. NegiArylbenzimidazoles have been synthesized as antimycobacterial agents. An efficient synthesis has been developed for 2-arylbenzimidazoles from o-phenylenediamines and aromatic aldehydes in molecular sieves-methanol system. The methodology is straightforward to get 2-arylbenzimidazoles (3a-3z) in excellent yields with high chemoselectivity over 2-aryl-1-benzylbenzimidazoles (4a-4z). All these benzimidazole analogues were evaluated against M. tuberculosis in BACTEC radiometric assay compounds 4y and 4z exhibited potential antitubercular activity against M. tuberculosis H37RV, MIC at 16 µM and 24 µM respectively. The best compound of the series i.e. compound 4y was well tolerated by Swiss-albino mice in acute oral toxicity. Compound 4y possessing a diarylbenzimidazole core, can further be optimized for better activity.Graphical abstractGraphical abstract for this article
       
  • Novel Benzodiazepines Derivatives as analgesic Modulating for Transient
           receptor potential vanilloid 1
    • Abstract: Publication date: Available online 1 August 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Yan Liu, Chen Liao, Jiaqi Zhou, Chunxia Liu, Qifei Li, Yue Jiang, Hai QianA new series of derivatives of 3-(7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1], [4]diazepin-3-yl)propanoic acid were designed and synthesized as analgesic modulating for Transient receptor potential vanilloid 1. They were investigated for TRPV1 antagonistic activity in vitro, analgesic activity and sedative activity in vivo and aqueous solubility. Preliminary studies identified 3-(7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1], [4]diazepin-3-yl)-N,N-dimethylpropanamide(Compound 11), as a potent analgesic modulating for TRPV1 with potent activity and good aqueous solubility.Graphical abstractGraphical abstract for this article
       
  • Nitric Oxide Donor-based FFA1 Agonists: Design, Synthesis and Biological
           Evaluation as Potential Anti-diabetic and Anti-thrombotic Agents
    • Abstract: Publication date: Available online 31 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Zheng Li, Xue Xu, Roujia Liu, Fengjian Deng, Xiaohua Zeng, Luyong ZhangThe cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Thus, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of FFA1 agonist and NO donor were design to obtain dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the induced-fit docking study suggested that it is feasible for our design strategy to hybrid NO donor with compound 1. These hybrids exhibited moderate FFA1 agonistic activities and anti-platelet aggregation activities, and their anti-platelet effects mediated by NO were also confirmed in the presence of NO scavenger. Moreover, compound 3 revealed significantly hypoglycemic effect and even stronger than that of TAK-875 during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 3, is expected as a potential candidate with additional cardiovascular benefits for the treatment of T2DM.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as
           anti-leukemia agents by inhibiting Btk and PI3Kδ
    • Abstract: Publication date: Available online 29 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Linyi Liu, Bingyu Shi, Xinyu Li, Xiangqian Wang, Xiang Lu, Xuerong Cai, Ali Huang, Guoshun Luo, Qidong You, Hua XiangBtk inhibitors and PI3Kδ inhibitors play crucial roles in the treatment of leukemia, and studies confirmed that the synergetic inhibition against Btk and PI3Kδ could gain an optimal response. Herein, a series of novel benzofuro[3,2-b]pyridin-2(1H)-one derivatives were designed and synthesized as dual Btk/PI3Kδ kinases inhibitors for the treatment of leukemia. Studies indicated that most compounds could suppress the proliferation of multiple leukemia or lymphoma cells (Raji, HL60 and K562 cells) at low micromolar concentrations in vitro. Further kinase assays identified several compounds could simultaneously inhibit Btk kinase and PI3Kδ kinase. Thereinto, compound 16b exhibited the best inhibitory activity (Btk: IC50 =139 nM; PI3Kδ: IC50 = 275 nM) and showed some selectivity against PI3Kδ compared to PI3Kβ/γ. Finally, the SAR of target compounds was preliminarily discussed combined with docking results. In brief, 16b possessed of the potency for the further optimization as anti-leukemia drugs by inhibiting simultaneously Btk kinase and PI3Kδ kinase.Graphical abstractGraphical abstract for this article
       
  • Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine
           based radioligand for PET imaging of the adenosine A2B receptor
    • Abstract: Publication date: Available online 29 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Marcel Lindemann, Sonja Hinz, Winnie Deuther-Conrad, Vigneshwaran Namasivayam, Sladjana Dukic-Stefanovic, Rodrigo Teodoro, Magali Toussaint, Mathias Kranz, Cathleen Juhl, Jörg Steinbach, Peter Brust, Christa E. Müller, Barbara WenzelOn the basis of a pyrazine core structure, three new adenosine A2B receptor ligands (7a – c) were synthesized containing a 2-fluoropyridine moiety suitable for 18F-labeling. Compound 7a was docked into a homology model of the A2B receptor based on X-ray structures of the related A2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were determined at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A1 receptor, 7a was radiolabeled as the most suitable candidate (Ki(A2B) = 4.24 nM) in order to perform in vivo studies in mice with the aim to estimate fundamental pharmacokinetic characteristics of the compound class. Organ distribution studies and a single PET study demonstrated brain uptake of [18F]7a with a standardized uptake value (SUV) of ≈1 at 5 min post injection followed by a fast wash out. Metabolism studies of [18F]7a in mice revealed the formation of a blood-brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivatives with improved binding properties and metabolic stability in vivo.Graphical abstractGraphical abstract for this article
       
  • Gymnotic delivery and gene silencing activity of reduction-responsive
           siRNAs bearing lipophilic disulfide-containing modifications at
           2’-position
    • Abstract: Publication date: Available online 27 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Florian Gauthier, Sandra Claveau, Jean-Rémi Bertrand, Jean-Jacques Vasseur, Christelle Dupouy, Françoise DebartModified oligoribonucleotides used as siRNAs bearing biolabile disulfide-containing groups at some 2’-positions were synthesized following a post-synthesis transformation of solid-supported 2’-O-acetylthiomethyl RNA, previously described. Thus, the reduction-responsive and lipophilic benzyldithiomethyl (BnSSM) modification was introduced at different locations into siRNAs targeting the Ewing sarcoma EWS-Fli1 protein. Thermal stability, serum stability and response to glutathione treatment of modified siRNAs were thoroughly investigated. Among 17 modified siRNAs, significant gene silencing activities were demonstrated for the 8 most stable siRNAs in serum (half-life> 1 h) when using a transfection reagent. Of special interest, two naked 2’-O-BnSSM siRNAs transfection exhibited a remarkable gene silencing activity after 24 h incubation. These inhibitions are consistent with an efficient gymnotic delivery demonstrated by the presence of the corresponding fluorescent siRNAs within cells.Graphical abstractGraphical abstract for this article
       
  • Synthesis and pharmacological characterization of functionalized
           
    • Abstract: Publication date: Available online 27 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): George S. Amato, Amruta Manke, Vineetha Vasukuttan, Robert W. Wiethe, Rodney W. Snyder, Scott P. Runyon, Rangan MaitraAntagonists of peripheral type 1 cannabinoid receptors (CB1) may have utility in the treatment of obesity, liver disease, metabolic syndrome and dyslipidemias. We have targeted the purine otenabant (1) analogues for this purpose. The non-tissue selective CB1 antagonist rimonabant (2) was approved as a weight-loss agent in Europe but produced centrally mediated adverse effects in some patients including dysphoria and suicidal ideation leading to its withdrawal. Efforts are now underway to produce compounds with limited brain exposure. While many structure-activity relationship (SAR) studies of 2 have been reported, along with peripheralized compounds, 1 remains relatively less studied. In this report, we pursued analogues of 1 in which the 4-aminopiperidine group was switched to piperazine group to enable a better understanding of SAR to eventually produce compounds with limited brain penetration. To access a binding pocket and modulate physical properties, the piperazine was functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a variety of connectors, including amides, sulfonamides, carbamates and ureas. These studies resulted in compounds that are potent antagonists of hCB1 with high selectivity for hCB1 over hCB2. The SAR obtained led to the discovery of 65 (Ki = 4 nM,>10,000-fold selective for hCB1 over hCB2), an orally bioavailable aryl urea with reduced brain penetration, and provides direction for discovering peripherally restricted compounds with good in vitro and in vivo properties.Graphical abstractGraphical abstract for this article
       
  • 7β-Methyl substituent is a structural locus associated with activity
           cliff for nepenthone analogues
    • Abstract: Publication date: Available online 24 July 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Hui-jiao Sun, Yu-hua Wang, Cong-min Yuan, Ling-hui Kong, Xue-jun Xu, Yu-jun Wang, Hai-hao Wu, Cheng Lin, Yuan-yuan Qian, Huo-ming Huang, Li Xiao, Xiao Liu, Qian He, Sheng-yang Fang, Deng-qi Xue, Xi-cheng Yang, Hao Chen, Yi-lin Zheng, Lan Zheng, Lin-qian YuWith the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7β-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7β-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7β-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7β-methyl orvinol analogues. Surprisingly, SLL-603, a 7β-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7β-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of novel bivalent β-carboline
           derivatives as multifunctional agents for the treatment of Alzheimer's
           disease
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Yifan Zhao, Feng Ye, Jian Xu, Qinghong Liao, Lei Chen, Weijia Zhang, Haopeng Sun, Wenyuan Liu, Feng Feng, Wei QuTo develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent β-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC50 = 1.7 and 2.7 μM, respectively), Aβ1-42 disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aβ1-42 aggregation, with inhibitory rate 82.7% and 85.7% at 25 μM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by H2O2, okadaic acid (OA) and Aβ1-42 without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s):
       
  • Corrigendum to “Synthesis, structure-activity relationship and molecular
           docking studies of 3-O-flavonol glycosides as cholinesterase inhibitors”
           [Bioorg. Med. Chem. 26 (12) (2018) 3696–3706]
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Ehsan Ullah Mughal, Asif Javid, Amina Sadiq, Shahzad Murtaza, Muhammad Naveed Zafar, Bilal Ahmad Khan, Sajjad Hussain Sumrra, Muhammad Nawaz Tahir, Kanwal, Khalid Mohammed KhanGraphical abstractGraphical abstract for this article
       
  • Corrigendum to “2-Arylthio-5-iodo pyrimidine derivatives as
           non-nucleoside HBV polymerase inhibitors” [Bioorg. Med. Chem. 26 (2018)
           1573–1578]
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Jie Wang, Liang Zhang, Jianxiong Zhao, Yu Zhang, Qingchuan Liu, Chao Tian, Zhili Zhang, Junyi Liu, Xiaowei Wang
       
  • Corrigendum to “Nrf2 activators from Glycyrrhiza inflata and their
           hepatoprotective activities against CCl4-induced liver injury in mice”
           [Bioorg. Med. Chem. 25 (20) (2017) 5522–5530]
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Yan Lin, Yi Kuang, Kai Li, Shuang Wang, Shuai Ji, Kuan Chen, Wei Song, Xue Qiao, Min Ye
       
  • Sameuramide A, a new cyclic depsipeptide isolated from an ascidian of the
           family Didemnidae
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Koshi Machida, Daisuke Arai, Ryosuke Katsumata, Satoshi Otsuka, Jun K. Yamashita, Tao Ye, Shoubin Tang, Nobuhiro Fusetani, Yoichi NakaoSameuramide A (1), a new cyclic depsipeptide encompassing one each of alanine, N-methyl alanine, N-methyl dehydroalanine, N,O-dimethyl threonine, phenyllactic acid, three β-hydroxy leucines, and two propionates, was isolated from a didemnid ascidian collected at the northern part of Japan. The planar structure was established based on the interpretation of MS and NMR data. The absolute configuration of the subunits was determined by the advanced Marfey’s method and the chiral LC-MS analysis. Compound 1 exhibited the activity of maintaining colony formation of murine embryonic stem (mES) cells without leukemia inhibitory factor (LIF). Down regulation of the gene expression of Krüppel-like transcription factor 4 (Klf4) indicated that 1 itself was not able to maintain the undifferentiated state of the mES cells. However, the expression levels of the marker genes (Nestin, T, Sox17) for three germ layers were upregulated in embryoid bodies (EBs) after treatment of 1 together with LIF, suggesting that 1 plays a supportive role for LIF in maintaining the multipotency of mES cells.Graphical abstractGraphical abstract for this article
       
  • Polysaccharide deacetylases serve as new targets for the design of
           inhibitors against Bacillus anthracis and Bacillus cereus
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Stavroula Balomenou, Dimitris Koutsioulis, Anastasia Tomatsidou, Mary Tzanodaskalaki, Kyriacos Petratos, Vassilis BouriotisPeptidoglycan N-acetylglucosamine (GlcNAc) deacetylases (PGNGdacs) from bacterial pathogens are validated targets for the development of novel antimicrobial agents. In this study we examined the in vitro inhibition of hydroxamate ligand N-hydroxy-4-(naphthalene-1-yl)benzamide (NHNB), a selective inhibitor of histone deacetylases-8 (HDAC8), against two PGNGdacs namely BC1974 and BC1960 from B. cereus, highly homologous to BA1977 and BA1961 of B. anthracis, respectively. Kinetic analysis showed that this compound functions as a competitive inhibitor of both enzymes with apparent Ki’s of 8.7 μM (for BC1974) and 66 μM (for BC1960), providing thus the most potent CE4 inhibitor reported to date. NHNB was tested in antibacterial assays and showed bactericidal activity against both examined pathogens acting as a multi-target drug. This compound can serve as lead for the development of inhibitors targeting the conserved active sites of the multiple polysaccharide deacetylases (PDAs) of both pathogens.Graphical abstractGraphical abstract for this article
       
  • Antiplasmodial activity of hydroxyethylamine analogs: Synthesis,
           biological activity and structure activity relationship of plasmepsin
           inhibitors
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Amit Kumar Singh, Vinoth Rajendran, Snigdha Singh, Prashant Kumar, Yogesh Kumar, Archana Singh, Whelton Miller, Vladimir Potemkin, Poonam, Maria Grishina, Nikesh Gupta, Prakasha Kempaiah, Ravi Durvasula, Brajendra K. Singh, Ben M. Dunn, Brijesh RathiMalaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (Ki, 1.93 ± 0.29 µM for Plm II; Ki, 1.99 ± 0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (Ki, 0.84 ± 0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC50, 2.27 ± 0.95 µM for 10f; IC50, 3.11 ± 0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC50 value of 1.35 ± 0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.Graphical abstractGraphical abstract for this article
       
  • New somatostatin-drug conjugates for effective targeting pancreatic cancer
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): E. Ragozin, A. Hesin, A. Bazylevich, H. Tuchinsky, A. Bovina, T. Shekhter Zahavi, M. Oron-Herman, G. Kostenich, M.A. Firer, T. Rubinek, I. Wolf, G. Luboshits, M.Y. Sherman, G. GellermanPancreatic cancer poorly responds to available drugs, and finding novel approaches to target this cancer type is of high significance. Here, based on a common property of pancreatic cancer cells to express somatostatin receptors (SSTR), we designed drug conjugates with novel somatostatin-derived cyclic peptides (SSTp) with broad selectivity towards SSTR types to facilitate drug targeting of the pancreatic cancer cells specifically. Uptake of our newly designed SSTps was facilitated by SSTRs expressed in the pancreatic cancers, including SSTR2, SSTR3, SSTR4 and SSTR5. Three major drugs were conjugated to our best SSTps that served as delivery vehicles, including Camptothecin (CPT), Combretastatin-4A (COMB) and Azatoxin (AZA). All designed drug conjugates demonstrated penetration to pancreatic cancer cell lines, and significant toxicity towards them. Furthermore, the drug conjugates specifically accumulated in tumors in the animal xenograft model, though some accumulation was also seen in kidney. Overall these findings lay the basis for development of novel drug series that could target the fatal pancreatic cancer.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s):
       
  • Novel androgen receptor full antagonists: Design, synthesis, and a docking
           study of glycerol and aminoglycerol derivatives that contain p-carborane
           cages
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Asako Kaise, Kiminori Ohta, Shinya Fujii, Akifumi Oda, Tokuhito Goto, Yasuyuki EndoBased on the co-crystal structure of bicalutamide with a T877A-mutated androgen receptor (AR), glycerol and aminoglycerol derivatives were designed and synthesized as a novel type of carborane-containing AR modulators. The (R)-isomer of 6c, whose chirality is derived from the glycerol group, showed 20 times more potent cell inhibitory activity against LNCaP cell lines expressing T877A-mutated AR than the corresponding (S)-isomer. Docking studies of both isomers with AR suggested that (R)-6c is in closer spatial proximity to helix-12 of the AR than (S)-6c, which is the most important common motif in the secondary structure of AR for the expression of antagonistic activity.Graphical abstractGraphical abstract for this article
       
  • Synthesis, in vitro and in silico studies of novel potent urease
           inhibitors:
           
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Muhammad Athar Abbasi, Mubashir Hassan, Aziz-ur-Rehman, Sabahat Zahra Siddiqui, Hussain Raza, Syed Adnan Ali Shah, Sung-Yum SeoThe present article describes the synthesis, in vitro urease inhibition and in silico molecular docking studies of a novel series of bi-heterocyclic bi-amides. The synthesis of title compounds was initiated by benzoylation, with benzoyl chloride (1), of the key starter ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (2) in weak basic aqueous medium followed by hydrazide formation, 4, and cyclization with CS2 to reach the parent bi-heterocyclic nucleophile, N-{4-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-thiazol-2-yl}benzamide (5). Various electrophiles, 8a–l, were synthesized by a two-step process and these were finally coupled with 5 to yield the targeted bi-heterocyclic bi-amide molecules, 9a–l. The structures of the newly synthesized products were corroborated by IR, 1H NMR, 13C NMR, EI-MS and elemental analysis. The in vitro screening of these molecules against urease explored that most of the compounds exhibit potent inhibitory potential against this enzyme. The compound 9j, with IC50 value of 2.58 ± 0.02 µM, exhibited most promising inhibitory activity among the series, relative to standard thiourea having IC50 value of 21.11 ± 0.12 µM. In silico studies fully augmented the experimental enzyme inhibition results. Chemo-informatics analysis showed that synthesized compounds (9a–l) mostly obeyed the Lipinski's rule. Molecular docking study suggested that ligand 9j exhibited good binding energy value (−7.10 kcal/mol) and binds within the active region of target protein. So, on the basis of present investigation, it was inferred that 9j may serve as a novel scaffold for designing more potent urease inhibitors.Graphical abstractGraphical abstract for this article
       
  • Synthesis of and triplex formation in oligonucleotides containing
           2′-deoxy-6-thioxanthosine
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Takeshi Inde, Shuhei Nishizawa, Yuusaku Hattori, Takashi Kanamori, Hideya Yuasa, Kohji Seio, Mitsuo Sekine, Akihiro OhkuboThis study aimed to synthesize triplex-forming oligonucleotides (TFOs) containing 2′-deoxy-6-thioxanthosine (s6X) and 2′-deoxy-6-thioguanosine (s6Gs) residues and examined their triplex-forming ability. Consecutive arrangement of s6X and s6Gs residues increased the triplex-forming ability of the oligonucleotides more than 50 times, compared with the unmodified TFOs. Moreover, the stability of triplex containing a mismatched pair was much lower than that of the full-matched triplex, though s6X could form a s6X-GC mismatched pair via tautomerization of s6X. The present results reveal excellent properties of modified TFOs containing s6Xs and s6Gs residues, which may be harnessed in gene therapy and DNA nanotechnology.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and cardiovascular evaluation of some
           aminoisopropanoloxy derivatives of xanthone
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): M. Kubacka, N. Szkaradek, S. Mogilski, K. Pańczyk, A. Siwek, A. Gryboś, B. Filipek, P. Żmudzki, H. Marona, A.M. WaszkielewiczA series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α1-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α1/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.Graphical abstractGraphical abstract for this article
       
  • d-fructose+derivatives+and+evaluation+of+their+inflammasome+inhibitors&rft.title=Bioorganic+&+Medicinal+Chemistry&rft.issn=0968-0896&rft.date=&rft.volume=">Synthesis of 1,5-Anhydro-d-fructose derivatives and evaluation of their
           inflammasome inhibitors
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Kohtaro Goto, Hiroko Ideo, Akiko Tsuchida, Yuriko Hirose, Ikuro Maruyama, Satoshi Noma, Takashi Shirai, Junko Amano, Mamoru Mizuno, Akio MatsudaSynthesis of several 1,5-Anhydro-d-fructose (1,5-AF) derivatives to evaluate inhibitory activities of the inflammasome was carried out. Recently, 1,5-AF reported to suppress the inflammasome, although with only low activity. We focused on the hydration of 2-keto form of 1,5-AF and speculated that this hydration was the cause of low activity. Therefore, we synthesized some 1,5-AF derivatives that would not be able to form the dimer conformation and can be expected to have high activity against inflammasome, and then evaluated their inhibitory activities with respect to the NLRP3 inflammasome by using mouse bone marrow-derived macrophages and human THP-1 cells. As a result, some synthesized 2-keto form compounds had much higher inhibitory activities with respect to the NLRP3 inflammasome than did 1,5-AF.Graphical abstractGraphical abstract for this article
       
  • Developing hybrid molecule therapeutics for diverse enzyme inhibitory
           action: Active role of coumarin-based structural leads in drug discovery
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s): Aliya Ibrar, Syeda Aaliya Shehzadi, Faiq Saeed, Imtiaz KhanHybrid drugs featuring two or more potentially bioactive pharmacophores have been recognized as advanced and superior chemical entities to simultaneously modulate multiple drug targets of multifactorial diseases, thus overcoming the severe side effects associated with a single drug molecule. The selection of these chemical moieties to produce hybrid structures with druggable properties is generally facilitated by the observed and/or anticipated synergistic pharmacological activities of the individual molecules. In this perspective, coumarin template has extensively been studied in pursuit of structurally diverse leads for drug development due to high affinity and specificity to different molecular targets. This review highlights the most commonly exploited approaches conceptualizing the design and construction of hybrid molecules by coupling two or more individual fragments with or without an appropriate linker. In addition to the design strategies, this review also summarizes and reflects on the therapeutic potential of these hybrid molecules for diverse enzyme inhibitory action as well as their observed structure-activity relationship (SAR). Several key features of the synthesized hybrid structures that assert a profound impact on the inhibitory function have also been discussed alongside computational investigations, inhibitor molecular diversity and selectivity toward multiple drug targets. Finally, these drug discovery and development efforts should serve as a handy reference aiming to provide a useful platform for the exploration of new coumarin-based compounds with enhanced enzyme inhibitory profile.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 30 July 2018Source: Bioorganic & Medicinal Chemistry, Volume 26, Issue 13Author(s):
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-