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Bioorganic & Medicinal Chemistry
Journal Prestige (SJR): 0.871
Citation Impact (citeScore): 3
Number of Followers: 184  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0968-0896
Published by Elsevier Homepage  [3181 journals]
  • Preparation and Biological Evaluation of BACE1 Inhibitors: Leveraging
    • Abstract: Publication date: Available online 15 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Leonard L. Winneroski, Jon A. Erickson, Steven J. Green, Jose E. Lopez, Stephanie L. Stout, Warren J. Porter, David E. Timm, James E. Audia, Mario Barberis, James P. Beck, Leonard N. Boggs, Anthony R. Borders, Robert D. Boyer, Richard A. Brier, Erik J. Hembre, Jörg Hendle, Pablo Garcia-Losada, Jose Miguel Minguez, Brian M. Mathes, Patrick C. May Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer’s disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.Graphical abstractGraphical abstract for this article
  • The architecture of hydrogen and sulfur σ-hole interactions explain
           differences in the inhibitory potency of C-β-D-glucopyranosyl thiazoles,
           imidazoles and an N-β-D glucopyranosyl tetrazole for human liver glycogen
           phosphorylase and offer new insights to structure-based design
    • Abstract: Publication date: Available online 14 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Efthimios Kyriakis, Aikaterini G. Karra, Olga Papaioannou, Theodora Solovou, Vassiliki T. Skamnaki, Panagiota G.V. Liggri, Spyros E. Zographos, Eszter Szennyes, Éva Bokor, Sándor Kun, Anna-Maria G. Psarra, László Somsák, Demetres D. Leonidas C-Glucopyranosyl imidazoles, thiazoles, and an N-glucopyranosyl tetrazole were assessed in vitro and ex vivo for their inhibitory efficiency against isoforms of glycogen phosphorylase (GP; a validated pharmacological target for the development of anti-hyperglycaemic agents). Imidazoles proved to be more potent inhibitors than the corresponding thiazoles or the tetrazole. The most potent derivative has a 2-naphthyl substituent, a Ki value of 3.2 µM for hepatic glycogen phosphorylase, displaying also 60% inhibition of GP activity in HepG2 cells, compared to control vehicle treated cells, at 100 μM. X-Ray crystallography studies of the protein - inhibitor complexes revealed the importance of the architecture of inhibitor associated hydrogen bonds or sulfur σ-hole bond interactions to Asn284 OD1, offering new insights to structure-based design efforts. Moreover, while the 2-glucopyranosyl-tetrazole seems to bind differently from the corresponding 1,2,3-triazole compound, the two inhibitors are equipotent.Graphical abstractGraphical abstract for this article
  • Structure-activity relationship study of the pyridine moiety of
           isothiazolo[4,3-b]pyridines as antiviral agents targeting cyclin
           G-associated kinase
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Belén Martinez-Gualda, Szu-Yuan Pu, Mathy Froeyen, Piet Herdewijn, Shirit Einav, Steven De Jonghe Previously, we reported the discovery of 3,6-disubstituted isothiazolo[4,3-b]pyridines as potent and selective cyclin G-associated kinase (GAK) inhibitors with promising antiviral activity. In this manuscript, the structure-activity relationship study was expanded to synthesis of isothiazolo[4,3-b]pyridines with modifications of the pyridine moiety. This effort led to the discovery of an isothiazolo[4,3-b]pyridine derivative with a 3,4-dimethoxyphenyl residue at position 5 that displayed low nanomolar GAK binding affinity and antiviral activity against dengue virus.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of
           8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives
           as potent β2-adrenoceptor agonists
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Ce Yi, Gang Xing, Siqi Wang, Xiaoran Li, Yichuang Liu, Jinyan Li, Bin Lin, Anthony Yiu-Ho Woo, Yuyang Zhang, Li Pan, Maosheng Cheng A series of β2-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β2-adrenoceptor and β1-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β2-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β2-adrenoceptor agonistic effect with an EC50 value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β2-AR agonists.Graphical abstractGraphical abstract for this article
  • Development of novel phenoxy-diketopiperazine-type plinabulin derivatives
           as potent antimicrotubule agents based on the co-crystal structure
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Zhongpeng Ding, Mingxu Ma, Changjiang Zhong, Shixiao Wang, Zhangyu Fu, Yingwei Hou, Yuqian Liu, Lili Zhong, Yanyan Chu, Feng Li, Cai Song, Yuxi Wang, Jinliang Yang, Wenbao Li The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC50 = 4.0 nM) through SAR study of three series derivatives, which was more potent than plinabulin (IC50 = 26.2 nM) and similar to Compound 6b (IC50 = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.Graphical abstractTo create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.Graphical abstract for this article
  • Discovery of Novel Small Molecule Induced Selective Degradation of the
           Bromodomain and Extra-Terminal (BET) Bromodomain Protein BRD4 and BRD2
           with Cellular Potencies
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Fei Jiang, Qingyun Wei, Huili Li, Hongmei Li, Yong Cui, Yu Ma, Haifang Chen, Peng Cao, Tao Lu, Yadong Chen The BET proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation and can be degraded by proteolysis-targeting chimeras (PROTACs) for BET proteins. However, the lack of intra-BET proteins selectivity limits the scope of current degraders as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We describe herein the design, synthesis, and evaluation of PROTAC BET degraders, based on the BET inhibitor with selectivity for the first Bromodomain benzo[cd]indole-2-one, alkylamide linker and cereblon ligand thalidomide. Compound 15 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 and BRD2 over BRD3, which not only effectively inhibits cell growth in human acute leukemia cell lines, but also very effective in inhibiting solid tumors with low cytotoxic effect in the cell profiles of NCI 60 cell lines. Remarkable dependency on linker length was observed for BRD4-degrading and c-Myc-driven antiproliferative activities in acute myeloid leukemia cell line MV4-11. The small-molecular 15 represents a novel, potent, and selective class of BRD4 and BRD2 degraders for the development of therapeutics to treat cancers.Graphical abstractGraphical abstract for this article
  • Discovery of novel nonpeptide small-molecule NRP1 antagonists: virtual
           screening, molecular simulation and structural modification
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Kewen Peng, Yu Li, Ying Bai, Teng Jiang, Huiyong Sun, Qihua Zhu, Yungen Xu Multifaceted roles of vascular endothelial growth factor (VEGF)-neuropilin-1 (NRP1) interaction have been implicated in cancer, but reports on small-molecule inhibitors of VEGF-NRP1 interaction are scarce. Herein, we describe the identification of 1, a novel nonpeptide small-molecule NRP1 antagonist with moderate activity via structure-based virtual screening. Ensemble docking and molecular dynamics (MD) simulations of 1 were carried out and an interesting binding model was obtained. We found that the “aromatic box” enclosed by Tyr297, Trp301 and Tyr353 of NRP1 is critical for NRP1-1 binding. Further structure modification of 1 based on the binding model derived from MD simulations resulted in the identification of 12a with significantly improved activity.Graphical abstractGraphical abstract for this article
  • Generation of Highly Potent DYRK1A-Dependent Inducers of Human β-Cell
           Replication via Multi-Dimensional Compound Optimization
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Paul A. Allegretti, Timothy M. Horton, Yassan Abdolazimi, Hannah P. Moeller, Benjamin Yeh, Matthew Caffet, Guillermina Michel, Mark Smith, Justin P. Annes Small molecule stimulation of β-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance β-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human β-cell replication. Unfortunately, OTS167’s target promiscuity and cytotoxicity curtails utility. To tailor kinase selectivity towards DYRK1A and reduce cytotoxicity we designed a library of fifty-one OTS167 derivatives based upon a modeled structure of the DYRK1A-OTS167 complex. Indeed, derivative characterization yielded several leads with exceptional DYRK1A inhibition and human β-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human β-cell replication-promoting compounds yet described and exemplify the potential to purposefully leverage off-target activities of advanced stage compounds for a desired application.Graphical abstractGraphical abstract for this article
  • Synthesis and antileishmanial activity of fluorinated rhodacyanine
           analogues: the ‘fluorine-walk’ analysis
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Thitiya Lasing, Atchara Phumee, Padet Siriyasatien, Kantima Chitchak, Parichatr Vanalabhpatana, Kit-Kay Mak, Chew Hee Ng, Tirayut Vilaivan, Tanatorn Khotavivattana In a search for potent antileishmanial drug candidates, eighteen rhodacyanine analogues bearing fluorine or perfluoroalkyl substituents at various positions were synthesized. These compounds were tested for their inhibitory activities against Leishmania martiniquensis and L. orientalis. This ‘fluorine-walk’ analysis revealed that the introduction of fluorine atom at C-5, 6, 5’, or 6’ on the benzothiazole units led to significant enhancement of the activity, correlating with the less negative reduction potentials of the fluorinated analogues confirmed by the electrochemical study. On the other hand, -CF3 and –OCF3 groups were found to have detrimental effects, which agreed with the poor aqueous solubility predicted by the in silico ADMET analysis. In addition, some of the analogues including the difluorinated species showed exceptional potency against the promastigote and axenic amastigote stages (IC50 = 40-85 nM), with the activities surpassing both amphotericin B and miltefosine.Graphical abstractTo create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.Graphical abstract for this article
  • Synthesis and Evaluation of 2’-Dihalo Ribonucleotide Prodrugs with
           Activity against Hepatitis C Virus
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): A. Chris Krueger, Hui-Ju Chen, John T. Randolph, Brian S. Brown, Geoff T. Halvorsen, Howard R. Heyman, Tongmei Li, Christopher C. Marvin, Jason P. Shanley, Eric A. Voight, Daniel A.J. Bow, Cecilia Van Handel, Vincent Peterkin, Robert A. Carr, DeAnne Stolarik, Tatyana Dekhtyar, Michelle L. Irvin, Preethi Krishnan, Rodger F. Henry, Rolf Wagner Graphical abstract for this articleHepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2’-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2’-deoxy-2’-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 hours post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.Graphical abstractGraphical abstract for this article
  • Design and synthesis of cyanamides as potent and selective
           N-acylethanolamine acid amidase inhibitors
    • Abstract: Publication date: Available online 11 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Michael S. Malamas, Shrouq I. Farah, Lamani Manjunath, Dimitrios N. Pelekoudas, Nicholas Thomas Perry, Girija Rajarshi, Christina Yume Miyabe, Honrao Chandrashekhar, Jay West, Spiro Pavlopoulos, Alexandros Makriyannis N-acylethanolamine acid amidase (NAAA) inhibition represents an exciting novel approach to treat inflammation and pain. NAAA is a cysteine amidase which preferentially hydrolyzes the endogenous biolipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA is an endogenous agonist of the nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is a key regulator of inflammation and pain. Thus, blocking the degradation of PEA with NAAA inhibitors results in augmentation of the PEA/PPAR-α signaling pathway and regulation of inflammatory and pain processes. We have prepared a new series of NAAA inhibitors exploring the azetidine-nitrile (cyanamide) pharmacophore that led to the discovery of highly potent and selective compounds. Key analogs demonstrated single-digit nanomolar potency for hNAAA and showed>100-fold selectivity against serine hydrolases FAAH, MGL and ABHD6, and cysteine protease cathepsin K. Additionally, we have identified potent and selective dual NAAA-FAAH inhibitors to investigate a potential synergism between two distinct anti-inflammatory molecular pathways, the PEA/PPAR-α anti-inflammatory signaling pathway1, 2, 3, 4, and the cannabinoid receptors CB1 and CB2 pathways which are known for their antiinflammatory and antinociceptive properties5, 6, 7, 8. Our ligand design strategy followed a traditional structure-activity relationship (SAR) approach and was supported by molecular modeling studies of reported X-ray structures of hNAAA. Several inhibitors were evaluated in stability assays and demonstrated very good plasma stability (t1/2> 2 hours; human and rodents). The disclosed cyanamides represent promising new pharmacological tools to investigate the potential role of NAAA inhibitors and dual NAAA-FAAH inhibitors as therapeutic agents for the treatment of inflammation and pain.Graphical abstractGraphical abstract for this article
  • Identification of small molecule inhibitors of human COQ7
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Keiko Tsuganezawa, Katsuhiko Sekimata, Yukari Nakagawa, Rei Utata, Kana Nakamura, Naoko Ogawa, Hiroo Koyama, Mikako Shirouzu, Takehiro Fukami, Kiyoshi Kita, Akiko Tanaka Given that the associated clinical manifestations of ubiquinone (UQ, or coenzyme Q) deficiency diseases are highly heterogeneous and complicated, effective new research tools for UQ homeostasis studies are awaited. We set out to develop human COQ7 inhibitors that interfere with UQ synthesis. Systematic structure-activity relationship development starting from a screening hit compound led to the identification of highly potent COQ7 inhibitors that did not disturb physiological cell growth of human normal culture cells. These new COQ7 inhibitors may serve as useful tools for studying the balance between UQ supplementation pathways: de novo UQ synthesis and extracellular UQ uptake.Graphical abstractGraphical abstract for this article
  • Design, synthesis, and evaluation of indeno[2,1-c]pyrazolones for use as
           inhibitors against hypoxia-inducible factor (HIF)-1 transcriptional
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Shinichiro Fuse, Kensuke Suzuki, Takahiro Kuchimaru, Tetsuya Kadonosono, Hiroki Ueda, Shinichi Sato, Shinae Kizaka-Kondo, Hiroyuki Nakamura HIF-1 is regarded as a promising target for the drugs used in cancer chemotherapy, and creating readily accessible templates for the development of synthetic drug candidates that could inhibit HIF-1 transcriptional activity is an important pursuit. In this study, indeno[2,1-c]pyrazolones were designed as readily available synthetic inhibitors of HIF-1 transcriptional activity. Nine compounds were synthesized in 4-5 steps from commercially available starting materials. In evaluations of the ability to inhibit the hypoxia-induced transcriptional activity of HIF-1, compound 3c showed a higher level compared with that of known inhibitor, YC-1. The compound 3c suppressed HIF-1α protein accumulation without affecting the levels of HIF-1α mRNA.Graphical abstractGraphical abstract for this article
  • Synthesis, in-vitro antiprotozoal activity and molecular docking study of
           isothiocyanate derivatives
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Kosar Babanezhad Harikandei, Peyman Salehi, Samad Nejad Ebrahimi, Morteza Bararjanian, Marcel Kaiser, Ahmed Al-Harrasi Novel isothiocyanate derivatives were synthesized starting from noscapine, bile acids, amino acids, and some aromatic compounds. Antiparasitic activities of the synthesized derivatives were tested against four unicellular protozoa, i.e., Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. Interestingly, seven isothiocyanate analogues displayed promising antiparasitic activity against Leishmania donovani with IC50 values between 0.4 -1.0 µM and selectivity index (SI) ranged from 7.8 to 18.4, comparable to the standard drug miltefosine (IC50 = 0.7 μM). Compound 7h demonstrated the best antileishmanial activity with an IC50 value of 0.4 µM. Seven products exhibited inhibition activity against T. brucei rhodesiense with IC50s below 2.0 μM and SI between 2.7 - 29.3. Four primary amine derivatives of noscapine and five isothiocyanate derivatives exhibited antiplasmodial activity with IC50s in the range of 1.1 - 2.7 µM and SI values between 1.1 to 14.5. The isothiocyanate derivative 7c showed against T. cruzi with an IC50 value of 1.9 µM and SI 4. Molecular docking and ADMET studies were performed to investigate the interaction between active ligands and T. brucei trypanothione reductase active site. The docking studies showed significant binding affinity of noscapine derivatives to enzyme active site and good compatibility with experimental data.Graphical abstractGraphical abstract for this article
  • Development and characterization of a 68Ga-labeled A20FMDV2 peptide probe
           for the PET imaging of αvβ6 integrin-positive pancreatic ductal
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Takashi Ui, Masashi Ueda, Yusuke Higaki, Shinichiro Kamino, Kohei Sano, Hiroyuki Kimura, Hideo Saji, Shuichi Enomoto Pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal cancers. Since the majority of patients are diagnosed at an advanced stage, development of a detection method for PDAC at an earlier stage of disease progression is strongly desirable. Integrin αVβ6 is a promising target for early PDAC detection because its expression increases during precancerous changes. The present study aimed to develop an imaging probe for positron emission tomography (PET) which targets αVβ6 integrin-positive PDAC. We selected A20FMDV2 peptide, which binds specifically to αvβ6 integrin, as a probe scaffold, and 68Ga as a radioisotope. A20FMDV2 peptide has not been previously labeled with 68Ga. A cysteine residue was introduced to the N-terminus of the probe at a site-specific conjugation of maleimide-NOTA (mal-NOTA) chelate. Different numbers of glycine residues were also introduced between cysteine and the A20FMDV2 sequence as a spacer in order to reduce the steric hindrance of the mal-NOTA on the binding probe to αVβ6 integrin. In vitro, the competitive binding assay revealed that probes containing a 6-glycine linker ([natGa]CG6 and [natGa]Ac-CG6) showed high affinity to αVβ6 integrin. Both probes could be labeled by 67/68Ga with high radiochemical yield (>50%) and purity (>98%). On biodistribution analysis, [67Ga]Ac-CG6 showed higher tumor accumulation, faster blood clearance, and lower accumulation in the surrounding organs of pancreas than did [67Ga]CG6. The αVβ6 integrin-positive xenografts were clearly visualized by PET imaging with [68Ga]Ac-CG6. The intratumoral distribution of [68Ga]Ac-CG6 coincided with the αVβ6 integrin-positive regions detected by immunohistochemistry. Thus, [68Ga]Ac-CG6 is a useful peptide probe for the imaging of αVβ6 integrin in PDAC.Graphical abstractGraphical abstract for this article
  • Pan-specific and partially selective dye-labeled peptidic inhibitors of
           the polycomb paralog proteins
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Natalia Milosevich, James McFarlane, Michael C. Gignac, Janessa Li, Tyler M. Brown, Chelsea R. Wilson, Lindsey Devorkin, Caitlin S. Croft, Rebecca Hof, Irina Paci, Julian J. Lum, Fraser Hof Epigenetic regulation of gene expression is in part controlled by post-translational modifications on histone proteins. Histone methylation is a key epigenetic mark that controls gene transcription and repression. There are five human polycomb paralog proteins (Cbx2/4/6/7/8) that use their chromodomains to recognize trimethylated lysine 27 on histone 3 (H3K27me3). Recognition of the methyllysine side chain is achieved through multiple cation-pi interactions within an ‘aromatic cage’ motif. Despite high structural similarity within the chromodomains of this protein family, they each have unique functional roles and are linked to different cancers. Selective inhibition of different CBX proteins is highly desirable for both fundamental studies and potential therapeutic applications. We report here on a series of peptidic inhibitors that target certain polycomb paralogs. We have identified peptidic scaffolds with sub-micromolar potency, and will report examples that are pan-specific and that are partially selective for individual members within the family. These results highlight important structure-activity relationships that allow for differential binding to be achieved through interactions outside of the methyllysine-binding aromatic cage motif.Graphical abstractGraphical abstract for this article
  • Discovery of metyltetraprole: Identification of tetrazolinone
           pharmacophore to overcome QoI resistance
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yuichi Matsuzaki, Yuya Yoshimoto, Sadayuki Arimori, So Kiguchi, Toshiyuki Harada, Fukumatsu Iwahashi Quinone outside inhibitors (QoIs) are one of the major agricultural fungicide groups used worldwide. However, the development of resistance by different pathogenic species associated with specific mutation at the target gene site is becoming a critical issue for the sustainable use of QoIs. The authors aimed to design a novel QoI molecule to overcome the aforementioned issue. A rational approach to avoid steric hindrance between the QoI molecule and the mutated target site was successfully employed. The resulting compound, metyltetraprole, is characterized by 3-substituted central ring with a tetrazolinone moiety, the key structure to retain potent activity against QoI-resistant mutants. Metyltetraprole is a promising new fungicide under commercial development, and its development in this study has paved the way to overcoming resistance to QoI fungicides.Graphical abstractGraphical abstract for this article
  • Basil polysaccharides: A Rewiew on Extraction,Bioactivities and
           Pharmacological Applications
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yanfei Zhan, Xinin An, Shuang Wang, Mengjia Sun, Honglei Zhou Traditional Chinese Medicine has been widely used in China and is regarded as the most commonly used treatment. As a natural plant used in traditional Chinese Medicine, Basil has various functions associated with a number of its components. There are many compositions in basil including polysaccharides, naphtha, steroids, flavone, coumarins, vitamins, and so on. Among these, polysaccharides play a significant role in based therapeutics. The article summarizes that basil polysaccharides have a lot of biological activities and pharmacological applications, such as their antitumor activity, antioxidant activity, anti-aging activity, immunity enhancement effect, hypolipidemic and anti-atherosclerotic effects, antibacterial effect, treatment of diabetes mellitus, and so on. This review summarized the extraction method, purification method, compositions, pharmacological applications, molecular weight, biological activities, and prospects of basil polysaccharides, providing a basis for further study of basil and basil polysaccharides.
  • Synthesis and characterization of 64Cu- and Cy5.5-labeled
           tetraiodothyroacetic acid derivatives for tumor angiogenesis imaging
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Hyunjung Kim, Hyun-Jung Koo, Jinhee Ahn, Jung Young Kim, Joon Young Choi, Kyung-Han Lee, Byung-Tae Kim, Yearn Seong Choe It was previously reported that tetraiodothyroacetic acid (tetrac) inhibits angiogenesis by binding to the cell surface receptor for thyroid hormone on integrin αVβ3. Therefore, we synthesized and evaluated two 64Cu-labeled tetrac derivatives and a Cy5.5-labeled tetrac derivative for tumor angiogenesis imaging. Tetrac was structurally modified to conjugate with 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid (DOTA) via its hydroxy or carboxylic acid end, and the resulting DOTA-conjugated tetrac derivatives were then labeled with 64Cu. Tetrac was also conjugated with Cy5.5 via its carboxylic acid end. All three tetrac derivatives (1-3) exhibited greater inhibitory activity than tetrac against endothelial cell tube formation. The U87MG cell binding of [64Cu]2 showed a time-dependent increase over 24 h and it was inhibited by 38% at 4 h in the presence of tetrac, indicating specificity of [64Cu]2 to the thyroid hormone receptor site on integrin αVβ3. Positron emission tomography (PET) images of U87MG tumor-bearing mice injected with [64Cu]1 and [64Cu]2 revealed that high radioactivity accumulated in the tumors, and the tumor uptake and tumor-to-nontarget uptake ratio were higher in small tumors than in large tumors. In addition, the Cy5.5-labeled tetrac derivative (3) displayed a strong near-infrared (NIR) signal in the tumors. Taken together, these results suggest that these ligands hold promise as imaging agents for tumor angiogenesis.Graphical abstractPET and NIR images of U87MG tumor xenograft models obtained 24 h after injection of [64Cu]1 and 3Graphical abstract for this article
  • Design, Synthesis and Biological Evaluation of Substituted Flavones and
           Aurones as Potential Anti-Influenza Agents
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Anand S. Chintakrindi, Devanshi J. Gohil, Abhay S. Chowdhary, Meena A. Kanyalkar We designed a series of substituted flavones and aurones as non-competitive H1N1 neuraminidase (NA) inhibitors and anti-influenza agents. The molecular docking studies showed that the designed flavones and aurones occupied 150-cavity and 430-cavity of H1N1-NA. We then synthesized these compounds and evaluated these for cytotoxicity, reduction in H1N1 virus yield, H1N1-NA inhibition and kinetics of inhibition. The virus yield reduction assay and H1N1-NA inhibition assay demonstrated that the compound 1f (4-methoxyflavone) had the lowest EC50 of 9.36 nM and IC50 of 8.74 μM respectively. Moreover, kinetic studies illustrated that compounds 1f and 2f had non-competitive inhibition mechanism.Graphical abstractGraphical abstract for this article
  • Synthesis, in vitro and in vivo biological evaluation of novel
           graveolinine derivatives as potential anti-Alzheimer agents
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Wen Luo, Jian-Wu Lv, Ting Wang, Zhi-Yang Zhang, Hui-Yan Guo, Zhi-Yi Song, Chao-Jie Wang, Jing Ma, Yi-ping Chen A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC50 values of 0.72 μM and 0.16 μM, respectively. The results from Lineweaver–Burk plot and molecular modeling study indicated non-competitive inhibition of AChE by compound 5f. In addition, these derivatives showed potent self-induced β-amyloid (Aβ) aggregation inhibition. Moreover, 5f didn’t show obvious toxicity against PC12 and HepG2 cells at 50 μM. Finally, in vivo studies confirmed that 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, these graveolinine derivatives should be thoroughly and systematically studied for the treatment of Alzheimer’s disease.Graphical abstractA novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer’s agents.Compound 5f showed moderate inhibitory activities for AChE, BuChE and Aβ self-aggregation.Compound 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice.Graphical abstract for this article
  • Identification of antimalarial leads with dual falcipain-2 and falcipain-3
           inhibitory activity
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Devika Rana, Md. Kalamuddin, Sandeep Sundriyal, Varun Jaiswal, Gaurav Sharma, Koushik Das Sarma, Puran Singh Sijwali, Asif Mohmmed, Pawan Malhotra, Neeraj Mahindroo Falcipains (FPs), cysteine proteases in the malarial parasite, are emerging as the promising antimalarial drug targets. In order to identify novel FP inhibitors, we generated a pharmacophore derived from the reported co-crystal structures of inhibitors of Plasmodium falciparum Falcipain-3 to screen the ZINC library. Further, the filters were applied for dock score, drug-like characters, and clustering of similar structures. Sixteen molecules were purchased and subject to in vitro enzyme (FP-2 and FP-3) inhibition assays. Two compounds showed in vitro inhibition of FP-2 and FP-3 at low µM concentration. The selectivity of the inhibitors can be explained based on the predicted interactions of the molecule in the active site. Further, the inhibitors were evaluated in a functional assay and were found to induce morphological changes in line with their mode of action arresting Plasmodium development. Compound 15 was most potent inhibitor identified in this study.Graphical abstractGraphical abstract for this article
  • High Content Phenotypic Screening Identifies Serotonin Receptor Modulators
           with Selective Activity upon Breast Cancer Cell Cycle and Cytokine
           Signaling Pathways
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Scott J. Warchal, John C. Dawson, Emelie Shepherd, Alison F. Munro, Rebecca E. Hughes Ashraff Makda, Neil O. Carragher Heterogeneity in disease mechanisms between genetically distinct patients contributes to high attrition rates in late stage clinical drug development. New personalized medicine strategies aim to identify predictive biomarkers which stratify patients most likely to respond to a particular therapy. However, for complex multifactorial diseases not characterized by a single genetic driver, empirical approaches to identifying predictive biomarkers and the most promising therapies for personalized medicine are required. In vitro pharmacogenomics seeks to correlate in vitro drug sensitivity testing across panels of genetically distinct cell models with genomic, gene expression or proteomic data to identify predictive biomarkers of drug response. However, the vast majority of in vitro pharmacogenomic studies performed to date are limited to dose-response screening upon a single viability assay endpoint. In this article we describe the application of multiparametric high content phenotypic screening and the theta comparative cell scoring method to quantify and rank compound hits, screened at single concentration, which induce a broad variety of divergent phenotypic responses between distinct breast cancer cell lines. High content screening followed by transcriptomic pathway analysis identified serotonin receptor modulators which display selective activity upon breast cancer cell cycle and cytokine signaling pathways correlating with inhibition of cell growth and survival. These methods describe a new evidence-led approach to rapidly identify compounds which display distinct response between different cell types. The results presented also warrant further investigation of the selective activity of serotonin receptor modulators upon breast cancer cell growth and survival as a potential drug repurposing opportunity.Graphical abstractGraphical abstract for this article
  • Design of enkephalin modifications protected from brain extracellular
           peptidases providing long-term analgesia
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Ekaterina S. Kropotova, Irina S. Ivleva, Marina N. Karpenko, Mark I. Mosevitsky The main obstacle to the use of many therapeutic peptides in practice is their rapid destruction by extracellular peptidases. Earlier we have found that active in the extracellular medium of mammalian brain exopeptidases are unable to break the bonds formed by β-alanine. We have designed several modified forms of opioid peptide enkephalin (Tyr-Gly-Gly-Phe-Met; Enk) with end βAla: ModEnk1 (βAla-Tyr-Gly-Gly-Phe-Met-βAla), ModEnk2 (βAla-Tyr-Gly-Gly-Phe-NH2), ModEnk3 (βAla-Tyr-Gly-Phe-NH2). These modifications are much more stable than Enk in the suspension of isolated axonal endings (synaptosomes) that mimics the brain extracellular medium. ModEnk1-3 have been tested in standard “pain” experiment “tail flick” on rats using intranasal peptide administration. ModEnk1 and ModEnk2 (but not ModEnk3) have fully preserved pain-relieving properties of Enk, but their efficiency was maintained for much longer. Compared to ModEnk1, ModEnk2 is more stable and provides longer analgesia because it is less accessible for endopeptidases. They are potent non-toxic analgesics.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of imidazole and oxazole
           fragments as HIV-1 integrase-LEDGF/p75 disruptors and inhibitors of
           microbial pathogens
    • Abstract: Publication date: Available online 9 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Thompho J. Rashamuse, Angela T. Harrison, Salerwe Mosebi, Sandy van Vuuren, E. Mabel Coyanis, Moira L. Bode We describe here the synthesis of libraries of novel 1-subtituted-5-aryl-1H-imidazole, 5-aryl-4-tosyl-4,5-dihydro-1,3-oxazole and 5-aryl-1,3-oxazole fragments via microwave (MW)-assisted cycloaddition of para-toluenesulfonylmethyl isocyanide (TosMIC) to imines and aldehydes. The compounds obtained were biologically evaluated in an AlphaScreen HIV-1 IN-LEDGF/p75 inhibition assay with six imidazole-based compounds (16c, 16f, 17c, 17f, 20a and 20d) displaying more than 50% inhibition at 10 µM, with IC50 values ranging from 7.0 to 30.4 µM. Additionally the hypothesis model developed predicts all active scaffolds except 20d to occupy similar areas as the N-heterocyclic (A) moiety and two aromatic rings (B and C) of previously identified inhibitor 5. These results indicate that the identified compounds represent a viable starting points for their use as templates in the design of a next generation of inhibitors targeting the HIV-1 IN and LEDGF/p75 protein-protein interaction. In addition, the in vitro antimicrobial properties of these fragments were tested by minimum inhibitory concentration (MIC) assays showing that compound 16f exhibited a MIC value of 15.6 μg/ml against S. aureus, while 17f displayed a similar MIC value against B. cereus, suggesting that these compounds could be further developed to specifically target those microbial pathogens.Graphical abstractGraphical abstract for this article
  • Rational design, synthesis and biological profiling of new KDM4C
    • Abstract: Publication date: Available online 8 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Vatroslav Letfus, Dubravko Jelić, Ana Bokulić, Adriana Petrinić Grba, Sanja Koštrun The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge.Graphical abstractGraphical abstract for this article
  • Synthesis of natural product-like polyprenylated phenols and quinones:
           evaluation of their neuroprotective activities
    • Abstract: Publication date: Available online 8 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Hitoshi Kamauchi, Takumi Oda, Kanayo Horiuchi, Koichi Takao, Yoshiaki Sugita Twenty-seven natural product-like polyprenylated phenols and quinones were synthesized and their neuroprotective activity was tested using human monoamine oxidase B (MAO-B) and SH-SY5Y cells. Eight compounds inhibited MAO-B (IC50 values
  • Kolavenic acid analog restores growth in HSET-overproducing fission yeast
           cells and multipolar mitosis in MDA-MB-231 human cells
    • Abstract: Publication date: Available online 8 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Naoaki Kurisawa, Masashi Yukawa, Hiroyuki Koshino, Takumu Onodera, Takashi Toda, Ken-ichi Kimura Although cancer cells often harbor supernumerary centrosomes, they form pseudo-bipolar spindles via centrosome clustering, instead of lethal multipolar spindles, and thus avoid cell death. Kinesin-14 HSET/KIFC1 is a crucial protein involved in centrosome clustering. Accordingly, a compound that targets HSET could potentially inhibit cancer cell proliferation in a targeted manner. Here, we report three natural compounds derived from Solidago altissima that restored the growth of fission yeast cells exhibiting lethal HSET overproduction (positive screening), namely solidagonic acid (SA) (1), kolavenic acid analog (KAA: a stereo isomer at C-9 and C-10 of 6β-tigloyloxykolavenic acid) (2), and kolavenic acid (KA) (3). All three compounds suppressed fission yeast cell death and enabled reversion of the mitotic spindles from a monopolar to bipolar morphology. Compound 2, which exerted the strongest activity against HSET-overproducing yeast cells, also inhibited centrosome clustering in MDA-MB-231 human breast adenocarcinoma cells, which contained large numbers of supernumerary centrosomes. These natural compounds may be useful as bioprobes in studies of HSET function. Moreover, compound 2 is a prime contender in the development of novel agents for cancer treatment.Graphical abstractGraphical abstract for this article
  • Superior inhibition of influenza virus hemagglutinin-mediated fusion by
           indole-substituted spirothiazolidinones
    • Abstract: Publication date: Available online 8 November 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Gökçe Cihan-Üstündağ, Muhammet Zopun, Evelien Vanderlinden, Elif Ozkirimli, Leentje Persoons, Gültaze Çapan, Lieve Naesens The influenza virus hemagglutinin (HA) mediates membrane fusion after viral entry by endocytosis. The fusion process requires drastic low pH-induced HA refolding and is prevented by arbidol and tert-butylhydroquinone (TBHQ). We here report a class of superior inhibitors with indole-substituted spirothiazolidinone structure. The most active analogue 5f has an EC50 value against influenza A/H3N2 virus of 1 nM and selectivity index of almost 2000. Resistance data and in silico modeling indicate that 5f combines optimized fitting in the TBHQ/arbidol HA binding pocket with a capability for endosomal accumulation. Both criteria appear relevant to achieve superior inhibitors of HA-mediated fusion.Graphical abstractGraphical abstract for this article
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    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 23Author(s):
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    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 23Author(s):
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    • Abstract: Publication date: 1 December 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 23Author(s):
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    • Abstract: Publication date: 15 November 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 22Author(s):
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    • Abstract: Publication date: 15 November 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 22Author(s):
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    • Abstract: Publication date: 15 November 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 22Author(s):
  • Design, synthesis, and bioactivity of dihydropyrimidine derivatives as
           kinesin spindle protein inhibitors
    • Abstract: Publication date: Available online 18 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Haytham O. Tawfik, Mervat H. El-Hamamsy, Nabaweya A. Sharafeldin, Tarek F. El-Moselhy A series of twenty-one 3,4-dihydropyrimidine derivatives bearing the heterocyclic 1,3-benzodioxole at position 4 in addition to different substituents at positions 2, 3 and 5 were designed and synthesized as monastrol analogs. The novel synthesized compounds were screened for their cytotoxic activity towards 60 cancer cell lines according to NCI (USA) protocol. Compounds 10b and 15 showed the best antitumor activity against most cell lines. Compound 15 was subsequently tested in 5-doses mode and displayed high selectivity towards CNS, prostate and leukemia subpanel with selectivity ratios of 22.30, 15.38 and 12.56, respectively at GI50 level. The IC50 of compounds 9d, 10b, 12, 15 and 16 against kinesin enzyme were 3.86 ± 0.12, 10.70 ± 0.35, 3.95 ± 0.12, 4.36 ± 0.14, and 14.07 ± 0.45 μM respectively, while the prototype compound, monastrol, reported IC50 value of 20 ± 0.42 μM. The safest compound among test compounds against normal cell line (HEK 293) is 10b with IC50 value of 62.02 ± 2.42 µM/ml in comparison to doxorubicin (IC50 = 11.34 ± 0.44 µM/ml). Cell cycle analysis of SNB-75 cells treated with compound 15 showed cell cycle arrest at G2/M phase. Further, the assay of levels of active caspase-3 and caspase-9 was investigated. Moreover, Molecular docking of compounds, 9d, 10b, 12, 15, 16, monastrol and mon-97 was performed to study the interaction between inhibitors and the kinesin spindle protein allosteric binding site.Graphical abstractCompound 15 possessed potent activity against most cell lines in NCI (USA) protocol at the single concentration of 10 μM. It proved to have promising inhibitory influence against kinesin enzyme assay. Cell cycle analysis of SNB-75 cell treated with 15 showed cell cycle arrest at G2/M phase.Graphical abstract for this article
  • Discovery of amide-bridged pyrrolo[2,3-d]pyrimidines as tumor targeted
           classical antifolates with selective uptake by folate receptor α and
           inhibition of de novo purine nucleotide biosynthesis
    • Abstract: Publication date: Available online 17 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Weiguo Xiang, Aamod Dekhne, Arpit Doshi, Carrie O'Connor, Zhanjun Hou, Larry H. Matherly, Aleem Gangjee We previously showed that classical 6-substituted pyrrolo[2,3-d]pyrimidine antifolates bind to folate receptor (FR) α and the target purine biosynthetic enzyme glycinamide ribonucleotide formyltransferase (GARFTase) with different cis and trans conformations. In this study, we designed novel analogs of this series with an amide moiety in the bridge region that can adopt both the cis and trans lowest energy conformations. This provides entropic benefit, by restricting the number of side-chain conformations of the unbound ligand to those most likely to promote binding to FRα and the target enzyme required for antitumor activity. NMR of the most active compound 7 showed both cis and trans amide bridge conformations in ∼1:1 ratio. The bridge amide group in the best docked poses of 7 in the crystal structures of FRα and GARFTase adopted both cis and trans conformations, with the lowest energy conformations predicted by Maestro and evidenced by NMR within 1 kcal/mol. Compound 7 showed ∼3-fold increased inhibition of FRα-expressing cells over its non-restricted parent analog 1 and was selectively internalized by FRα over the reduced folate carrier (RFC), resulting in significant in vitro antitumor activity toward FRα-expressing KB human tumor cells. Antitumor activity of 7 was abolished by treating cells with adenosine but was incompletely protected by 5-aminoimidazole-4-carboxamide (AICA) at higher drug concentrations, suggesting GARFTase and AICA ribonucleotide formyltransferase (AICARFTase) in de novo purine biosynthesis as the likely intracellular targets. GARFTase inhibition by compound 7 was confirmed by an in situ cell-based activity assay. Our results identify a “first-in-class” classical antifolate with a novel amide linkage between the scaffold and the side chain aryl L-glutamate that affords exclusive selectivity for transport via FRα over RFC and antitumor activity resulting from inhibition of GARFTase and likely AICARFTase. Compound 7 offers significant advantages over clinically used inhibitors of this class that are transported by the ubiquitous RFC, resulting in dose-limiting toxicities.Graphical abstractGraphical abstract for this article
  • Effect of self-assembly on antimicrobial activity of double-chain short
           cationic lipopeptides
    • Abstract: Publication date: Available online 17 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Oktawian Stachurski, Damian Neubauer, Izabela Małuch, Dariusz Wyrzykowski, Marta Bauer, Sylwia Bartoszewska, Wojciech Kamysz, Emilia Sikorska Short cationic antimicrobial lipopeptides with surfactant-like structure are promising antibiotic candidates that preferentially target microbial membranes. Therefore, we focused our study on double-chain lipopeptides, (C10-16)2Dab-KKK-NH2 and (C10-16)2Dap-KKK-NH2, where Dab and Dap are 2,4-diaminobutyric and 2,3-diaminopropionic acids, respectively. We tried to answer a question how the self-assembly behaviour affects biological activities of the tested compounds. The subject compounds were synthesized manually by solid-phase method and screened for their antimicrobial and haemolytic activities. Cytotoxicity tests on human keratinocytes were carried out for the most promising lipopeptides. Self-assembly properties were evaluated by both experimental and theoretical methods. Interactions with membrane models were examined using the ITC and FTIR techniques. All the lipopeptides studied showed the tendency to self-assembly in solution, and this behaviour was affected by the length of the hydrocarbon chains. Acyl chain elongation supported the formation of the bilayer structure and deprived the lipopeptides of antimicrobial activity. A multi-step mechanism of interaction with a negatively charged membrane was observed for the short-chain lipopeptides, indicating other processes accompanying the binding process. Short-chain lipopeptides were able to penetrate into the liposome’s interior and/or cause the rupture of the liposome, this being compatible with their high antimicrobial activity.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of benzoylacrylic acid
           shikonin ester derivatives as irreversible dual inhibitors of tubulin and
    • Abstract: Publication date: Available online 15 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Wen-Xue Sun, Hong-Wei Han, Min-Kai Yang, Zhong-Ling Wen, Yin-Song Wang, Jiang-Yan Fu, Yun-Ting Lu, Ming-Yue Wang, Jia-Xin Bao, Gui-Hua Lu, Jin-Liang Qi, Xiao-Ming Wang, Hong-Yan Lin, Yong-Hua Yang In this study, a series of shikonin derivatives combined with benzoylacrylic had been designed and synthesized, which showed an inhibitory effect on both tubulin and the epidermal growth factor receptor (EGFR). In vitro EGFR and cell growth inhibition assay demonstrated that compound PMMB-317 exhibited the most potent anti-EGFR (IC50 = 22.7 nM) and anti-proliferation activity (IC50 = 4.37 μM) against A549 cell line, which was comparable to that of Afatinib (EGFR, IC50 = 15.4 nM; A549, IC50 = 6.32 μM). Our results on mechanism research suggested that, PMMB-317 could induce the apoptosis of A549 cells in a dose- and time-dependent manner, along with decrease in mitochondrial membrane potential (MMP), production of ROS and alterations in apoptosis-related protein levels. Also, PMMB-317 could arrest cell cycle at G2/M phase to induce cell apoptosis, and inhibit the EGFR activity through blocking the signal transduction downstream of the mitogen-activated protein MAPK pathway and the anti-apoptotic kinase AKT pathway; typically, such results were comparable to those of afatinib. In addition, PMMB-317 could suppress A549 cell migration through the Wnt/β-catenin signaling pathway in a dose-dependent manner. Additionally, molecular docking simulation revealed that, PMMB-317 could simultaneously combine with EGFR protein (5HG8) and tubulin (1SA0) through various forces. Moreover, 3D-QSAR study was also carried out, which could optimize our compound through the structure-activity relationship analysis. Furthermore, the in vitro and in vivo results had collectively confirmed that PMMB-317 might serve as a promising lead compound to further develop the potential therapeutic anticancer agents.Chemical compounds studies in this article:Shikonin (PubChem CID: 479503); Maleic anhydride (PubChem CID: 7923); Colchicine (PubChem CID: 6167); Paclitaxel (PubChem CID: 36314); Afatinib (PubChem CID: 10184653); Benzene (PubChem CID: 241); Methylbenzene (PubChem CID: 1140); Fluorobenzene (PubChem CID: 10008); Chlorobenzene (PubChem CID: 7964); Bromobenzene (PubChem CID: 7961).Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of amino acids-oleanolic acid
           conjugates as influenza virus inhibitors
    • Abstract: Publication date: Available online 15 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Lingkuan Meng, Yangqing Su, Fan Yang, Sulong Xiao, Zhili Yin, Jiaxin Liu, Jindong Zhong, Demin Zhou, Fei Yu Viral entry inhibitors are of great importance in current efforts to develop a new generation of anti-influenza drugs. Inspired by the discovery of a series of pentacyclic triterpene derivatives as entry inhibitors targeting the HA protein of influenza virus, we designed and synthesized 32 oleanolic acid (OA) analogues in this study by conjugating different amino acids to the 28-COOH of OA. The antiviral activity of these compounds was evaluated in vitro. Some of these compounds revealed impressive anti-influenza potencies against influenza A/WSN/33 (H1N1) virus. Among them, compound 15a exhibited robust potency and broad antiviral spectrum with IC50 values at the low-micromolar level against four different influenza strains. Hemagglutination inhibition (HI) assay and docking experiment indicated that these OA analogues may act in the same way as their parent compound by interrupting the interaction between HA protein of influenza virus and the host cell sialic acid receptor via binding to HA, thus blocking viral entry.Graphical abstractGraphical abstract for this article
  • The plant-derived chalcone Xanthoangelol targets the membrane of
           Gram-positive bacteria
    • Abstract: Publication date: Available online 15 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Dieter Meier, Melissa Vázquez Hernández, Lasse van Geelen, Rini Muharini, Peter Proksch, Julia E. Bandow, Rainer Kalscheuer Xanthoangelol is a geranylated chalcone isolated from fruits of Amorpha fructicosa that exhibits antibacterial effects at low micromolar concentration against Gram-positive bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium and Enterococcus faecalis. We demonstrate that Xanthoangelol treatment of Gram-positive bacteria affects bacterial membrane integrity and leads to a leakage of intracellular metabolites. This correlates with a rapid collapse of the membrane potential and results in a fast and strong bactericidal effect. Proteomic profiling of Xanthoangelol-treated cells revealed signatures of cell wall and/or membrane damage and oxidative stress. Xanthoangelol specifically disturbs the membrane of Gram-positive bacteria potentially by forming pores resulting in cell lysis. In contrast, Xanthoangelol treatment of human cells showed only mildly hemolytic and cytotoxic effects at higher concentrations. Therefore, geranylated chalcones such as Xanthoangelol are promising lead structures for new antimicrobials against drug-resistant gram-positive pathogens.Graphical abstractGraphical abstract for this article
  • Design, synthesis, in vitro, and in silico studies of novel
           diarylimidazole-1,2,3-triazole hybrids as potent α-glucosidase inhibitors
    • Abstract: Publication date: Available online 15 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Mina Saeedi, Maryam Mohammadi-Khanaposhtani, Mohammad Sadegh Asgari, Nafiseh Eghbalnejad, Somaye Imanparast, Mohammad Ali Faramarzi, Bagher Larijani, Mohammad Mahdavi, Tahmineh Akbarzadeh In this work, new derivatives of diarylimidazole-1,2,3-triazole 7a-p were designed, synthesized, and evaluated for their in vitro α-glucosidase inhibitory activity. All compounds showed potent inhibitory activity in the range of IC50 = 90.4-246.7 µM comparing with acarbose as the standard drug (IC50 = 750.0 µM). Among the synthesized compounds, compounds 7b, 7c, and 7e were approximately 8 times more potent than acarbose. The kinetic study of those compounds indicated that they acted as the competitive inhibitors of α-glucosidase. Molecular docking studies were also carried out for compounds 7b, 7c, and 7e using modeled α-glucosidase to find the interaction modes responsible for the desired inhibitory activity.Graphical abstractGraphical abstract for this article
  • Pyrenocine A induces monopolar spindle formation and suppresses
           proliferation of cancer cells
    • Abstract: Publication date: Available online 15 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yusuke Myobatake, Shinji Kamisuki, Senko Tsukuda, Tsunehito Higashi, Takumi Chinen, Kenji Takemoto, Masami Hachisuka, Yuka Suzuki, Maya Takei, Yukine Tsurukawa, Hiroaki Maekawa, Toshifumi Takeuchi, Tomoko M. Matsunaga, Hiroeki Sahara, Takeo Usui, Sachihiro Matsunaga, Fumio Sugawara Pyrenocine A, a phytotoxin, was found to exhibit cytotoxicity against cancer cells with an IC50 value of 2.6-12.9 μM. Live cell imaging analysis revealed that pyrenocine A arrested HeLa cells at the M phase with characteristic ring-shaped chromosomes. Furthermore, as a result of immunofluorescence staining analysis, we found that pyrenocine A resulted in the formation of monopolar spindles in HeLa cells. Monopolar spindles are known to be induced by inhibitors of the kinesin motor protein Eg5 such as monastrol and STLC. Monastrol and STLC induce monopolar spindle formation and M phase arrest via inhibition of the ATPase activity of Eg5. Interestingly, our data revealed that pyrenocine A had no effect on the ATPase activity of Eg5 in vitro, which suggested the compound induces a monopolar spindle by an unknown mechanism. Structure-activity relationship analysis indicates that the enone structure of pyrenocine A is likely to be important for its cytotoxicity. An alkyne-tagged analog of pyrenocine A was synthesized and suppressed proliferation of HeLa cells with an IC50 value of 2.3 μM. We concluded that pyrenocine A induced monopolar spindle formation by a novel mechanism other than direct inhibition of Eg5 motor activity, and the activity of pyrenocine A may suggest a new anticancer mechanism.Graphical abstractGraphical abstract for this article
  • A mouse model-based screening platform for the identification of immune
           activating compounds such as natural products for novel cancer
    • Abstract: Publication date: Available online 9 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Lisa Richter, Sonja Kropp, Peter Proksch, Stefanie Scheu The therapy of cancer continues to be a challenge aggravated by the evolution of resistance against current medications. As an alternative for the traditional tripartite treatment options of surgery, radiation and chemotherapy, immunotherapy is gaining increasing attention due to the opportunity of more targeted approaches. Promising targets are antigen-presenting cells which drive innate and adaptive immune responses. The discovery and emergence of new drugs and lead structures can be inspired by natural products which comprise many highly bioactive molecules. The development of new drugs based on natural products is hampered by the current lack of guidelines for screening these structures for immune activating compounds. In this work, we describe a phenotypic pre-clinical screening pipeline for first-line identification of promising natural products using the mouse as a model system. Favorable compounds are defined to be non-toxic to immune target cells, to show direct anti-tumor effects and to be immunostimulatory at the same time. The presented screening pipeline constitutes a useful tool and aims to integrate immune activation in experimental approaches early on in drug discovery. It supports the selection of natural products for later chemical optimization, direct application in in vivo mouse models and clinical trials and promotes the emergence of new innovative drugs for cancer treatment.Graphical abstractGraphical abstract for this article
  • Impact of hydroxy moieties at the benzo[7]annulene ring system of GluN2B
           ligands: design, synthesis and biological evaluation
    • Abstract: Publication date: Available online 8 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Louisa Temme, Frederik Börgel, Dirk Schepmann, Dina Robaa, Wolfgang Sippl, Constantin Daniliuc, Bernhard Wünsch In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc)2, HCO2H, phosphane ligand) or the 6-hydroxyketone 10 (H2, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc)3 afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of Ki = 49 nM and a cytoprotective activity of IC50 = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH2OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.Graphical abstractGraphical abstract for this article
  • Synthesis, biological evaluation and molecular docking studies of new
           amides of 4-bromothiocolchicine as anticancer agents
    • Abstract: Publication date: Available online 8 October 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Greta Klejborowska, Alicja Urbaniak, Jordane Preto, Ewa Maj, Mahshad Moshari, Joanna Wietrzyk, Jack A. Tuszynski, Timothy C. Chambers, Adam Huczyński Colchicine is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute lymphoblastic leukemia cells, specifically compounds: 5 – 9 against primary ALL-5 (IC50 = 5.3 – 14 nM), 5, 7– 9 against A549 (IC50 = 10 nM), 5, 7 – 9 against MCF-7 (IC50 = 11 nM), 5 – 9 against LoVo (IC50 = 7 – 12 nM), and 5, 7 – 9 against LoVo/DX (IC50 = 48 – 87 nM). These IC50 values were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies revealed that colchicine and selected analogues induced characteristics of apoptotic cell death but manifested their effects in different phases of the cell cycle in MCF-7 versus ALL-5 cells. Specifically, while colchicine and the studied derivatives arrested MCF-7 cells in mitosis, very little mitotically arrested ALL-5 cells were observed, suggesting effects were manifest instead in interphase. We also developed an in silico model of the mode of binding of these compounds to their primary target, β-tubulin. We conducted a correlation analysis (linear regression) between the calculated binding energies of colchicine derivatives and their anti-proliferative activity, and determined that the obtained correlation coefficients strongly depend on the type of cells used.Graphical abstractGraphical abstract for this article
  • Design, synthesis and evaluation of structurally diverse
           chrysin-chromene-spirooxindole hybrids as anticancer agents
    • Abstract: Publication date: Available online 16 September 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Wen-Hui Zhang, Shuang Chen, Xiong-Li Liu, Ting-Ting Feng, Wu-De Yang, Ying Zhou A series of structurally diverse chrysin-chromene-spirooxindole hybrids were designed, synthesized via a Knoevenagel/Michael/cyclization of chrysin and isatylidene malononitrile derivatives through utilizing a hybrid pharmacophore approach. The newly synthesized compounds were evaluated for their in vitro anticancer activity, and most of the compounds showed stronger anti-proliferative activity than parent compound chrysin. In particular, compound 3e had the highest cytotoxicity towards A549 cells (IC50 = 3.15 ± 0.51 μM), and had better selectivity in A549 cells and normal MRC-5 cells. Furthermore, compound 3e could significantly inhibit the proliferation and migration of A549 cells in a dose-dependent manner, as well as induce the apoptosis possibly through mitochondria-mediated caspase-3/8/9 activation and multi-target co-regulation of the p53 signaling pathway. Thus, our results provide in vitro evidence that compound 3e may be a potential candidate for the development of new anti-tumour drugs.Graphical abstractUnlabelled Image
  • Developing new hybrid scaffold for urease inhibition based on
           carbazole-chalcone conjugates: Synthesis, assessment of therapeutic
           potential and computational docking analysis
    • Abstract: Publication date: Available online 16 September 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Madiha Kazmi, Imtiaz Khan, Ajmal Khan, Sobia Ahsan Halim, Aamer Saeed, Saifullah Mehsud, Ahmed Al-Harrasi, Aliya Ibrar Although a diverse range of chemical entities offering striking therapeutic potential against urease enzyme has been reported, the key challenges (toxicity and safety) associated with these inhibitors create a large unmet medical need to unveil new, potent and safe inhibitors of urease enzyme. In this pursuit, the present study demonstrates the successful synthesis of carbazole-chalcone hybrids (4a-n) in good yields. The evaluation of the preliminary in vitro biological results showed that selected members of the investigated library of hybrid compounds possess excellent urease inhibitory efficacy. In particular, compounds 4c and 4k were the most potent inhibitors with lowest IC50 values of 8.93 ± 0.21 and 6.88 ± 0.42 μM, respectively. Molecular docking analysis of the most potent inhibitor 4k suggests that the compound is fitted neatly at the active site interface and mediates interaction with both nickel atoms present in the active site. Several other obvious interactions including metal-carbonyl contact, hydrogen bonding and hydrophobic interactions were also observed, playing a crucial part in the stabilization of 4k in the active site of urease.Graphical abstractUnlabelled Image
  • Development of a novel class of peroxisome proliferator-activated receptor
           (PPAR) gamma ligands as an anticancer agent with a unique binding mode
           based on a non-thiazolidinedione scaffold
    • Abstract: Publication date: Available online 16 September 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Keisuke Yamamoto, Tomohiro Tamura, Rina Nakamura, Shintaro Hosoe, Masahiro Matsubara, Keiko Nagata, Hiroshi Kodaira, Takeshi Uemori, Yuichi Takahashi, Michihiko Suzuki, Jun-ichi Saito, Kimihisa Ueno, Satoshi Shuto We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPARγ ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.Graphical abstractUnlabelled Image
  • Reaction of ribulose biphosphate carboxylase/oxygenase assembled on a DNA
    • Abstract: Publication date: Available online 14 September 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Huyen Dinh, Eiji Nakata, Peng Lin, Masayuki Saimura, Hiroki Ashida, Takashi Morii Ribulose-1,5-biphosphate carboxylase/oxygenase (RuBisCO), an enzyme in the Calvin-Bensen-Bassham cycle of photosynthesis, catalyzes the first step of CO2 fixation in plants, algae, and photosynthetic bacteria. Despite of the important function in the global carbon cycle, RuBisCO suffers from a slow reaction rate and a competing reaction with O2 which draw attentions to improve the enzyme efficiency. In this study, a RuBisCO dimer from Rhodospirillum rubrum was assembled on a DNA scaffold using a dimeric DNA binding protein as an adaptor. The enzyme assembly was characterized by atomic force microscopy and RuBisCO assembled on the DNA scaffold showed avid enzymatic activity with retaining its parent carboxylase function. To mimic the environment of the natural microcompartment in cyanobacterial carboxysome that encapsulate the second enzyme carbonic anhydrase (CA) with RuBisCO, RuBisCO was next co-assembled with CA on the DNA scaffold. Although the natural carboxysome assembly is believed to enhance the RuBisCO activity, the co-assembly of RuBisCO and CA reduced the RuBisCO activity, suggesting that the preferential CO2 dehydration by CA reduced the RuBisCO reaction rate. In line with the recent study, our results suggest that the proximity in the interenzyme distance of RuBisCO and CA is not the crucial determinant for the enhanced RuBisCO activity in carboxysome. The assembly of RuBisCO and CA on DNA scaffold provides a platform for further study on the spatial control of RuBisCO and associating enzymes.Graphical abstractUnlabelled Image
  • Use of a fluorescence assay to determine relative affinities of
           semisynthetic aminoglycosides to small RNAs representing bacterial and
           mitochondrial A sites
    • Abstract: Publication date: Available online 13 September 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Prabuddha Waduge, Girish C. Sati, David Crich, Christine S. Chow The off-target binding of aminoglycosides (AGs) to the A site of human mitochondrial ribosomes in addition to bacterial ribosomes causes ototoxicity and limits their potential as antibiotics. A fluorescence assay was employed to determine relative binding affinities of classical and improved AG compounds to synthetic RNA constructs representing the bacterial and mitochondrial A sites. Results compared well with previously reported in vitro translation assays with engineered ribosomes. Therefore, the minimal RNA motifs and fluorescence assay are shown here to be useful for assessing the selectivity of new compounds.Graphical abstractUnlabelled Image
  • Piperidine and piperazine inhibitors of fatty acid amide hydrolase
           targeting excitotoxic pathology
    • Abstract: Publication date: Available online 10 September 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Manjunath Lamani, Michael S. Malamas, Shrouq I. Farah, Vidyanand G. Shukla, Michael F. Almeida, Catherine M. Weerts, Joseph Anderson, JodiAnne T. Wood, Karen L.G. Farizatto, Ben A. Bahr, Alexandros Makriyannis FAAH inhibitors offer safety advantages by augmenting the anandamide levels “on demand” to promote neuroprotective mechanisms without the adverse psychotropic effects usually seen with direct and chronic activation of the CB1 receptor. FAAH is an enzyme implicated in the hydrolysis of the endocannabinoid N-arachidonoylethanolamine (AEA), which is a partial agonist of the CB1 receptor. Herein, we report the discovery of a new series of highly potent and selective carbamate FAAH inhibitors and the evaluation for neuroprotection. The new inhibitors showed potent nanomolar inhibitory activity against human recombinant and purified rat FAAH, were selective (>1000-fold) against serine hydrolases MGL and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Evaluation of FAAH inhibitors 9 and 31 using the in vitro competitive activity-based protein profiling (ABPP) assay confirmed that both inhibitors were highly selective for FAAH in the brain, since none of the other FP-reactive serine hydrolases in this tissue were inhibited by these agents. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on known FAAH cocrystal structures. To rationally design new molecules that are irreversibly bound to FAAH, we have constructed “precovalent” FAAH-ligand complexes to identify good binding geometries of the ligands within the binding pocket of FAAH and then calculated covalent docking poses to select compounds for synthesis. FAAH inhibitors 9 and 31 were evaluated for neuroprotection in rat hippocampal slice cultures. In the brain tissue, both inhibitors displayed protection against synaptic deterioration produced by kainic acid-induced excitotoxicity. Thus, the resultant compounds produced through rational design are providing early leads for developing therapeutics against seizure-related damage associated with a variety of disorders.Graphical abstractGraphical abstract for this article
  • Recent advances in class IIa histone deacetylases research
    • Abstract: Publication date: Available online 6 September 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yodita Asfaha, Christian Schrenk, Leandro A. Alves Avelar, Alexandra Hamacher, Marc Pflieger, Matthias U. Kassack, Thomas Kurz Epigenetic control plays an important role in gene regulation through chemical modifications of DNA and post-translational modifications of histones. An essential post-translational modification is the histone acetylation/deacetylation-process which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The mammalian zinc dependent HDAC family is subdivided into three classes: class I (HDACs 1-3, 8), class II (IIa: HDACs 4, 5, 7, 9; IIb: HDACs 6, 10) and class IV (HDAC 11). In this review, recent studies on the biological role and regulation of class IIa HDACs as well as their contribution in neurodegenerative diseases, immune disorders and cancer will be presented. Furthermore, the development, synthesis, and future perspectives of selective class IIa inhibitors will be highlighted.Graphical abstractGraphical abstract for this article
  • Synthesis and structure-activity relationship of nitrile-based cruzain
    • Abstract: Publication date: Available online 28 August 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Juliana C. Gomes, Lorenzo Cianni, Jean Ribeiro, Fernanda dos Reis Rocho, Samelyn da Costa Martins Silva, Pedro Henrique Jatai Batista, Carolina Borsoi Moraes, Caio Haddad Franco, Lucio H.G. Freitas-Junior, Peter W. Kenny, Andrei Leitão, Antonio C.B. Burtoloso, Daniela de Vita, Carlos A. Montanari The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly non-additive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the non-additivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.Graphical abstractGraphical abstract for this article
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