Bioorganic & Medicinal Chemistry Letters

Editorial Board ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8
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Enantiomeric neolignans from Picrasma quassioides exhibit distinctive cytotoxicity on hepatic carcinoma cells through ROS generation and apoptosis induction ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Li-Li Lou, Guo-Dong Yao, Jie Wang, Wen-Yu Zhao, Xiao-Bo Wang, Xiao-Xiao Huang, Shao-Jiang Song Three pairs of enantiomeric neolignans 1a/1b–3a/3b were isolated from the stems of Picrasma quassioides, and separated successfully by chiral-phase HPLC. Their structures were established by comprehensive spectroscopic analyses as well as ECD spectroscopy. The in vitro cytotoxicity of the isolates was evaluated against human hepatocellular carcinoma HepG2 and Hep3B cells. Among them, 1 and its enantiomers 1a/1b, 3 and 3a/3b displayed similar cytotoxicity in pair-wise comparison against HepG2 and Hep3B cells, and the similar effects of 2 and 2a/2b were found in Hep3B cells. Interestingly, 2a and 2b had different cytotoxic activities on HepG2 cells with IC50 values of 35.6 μM and 104.4 μM, respectively. In addition, 2 exerted middle cytotoxicity against HepG2 cells with an IC50 value of 78.6 μM. The different cytotoxicity between enantiomers 2a and 2b attracted our interest. To investigate the underlying mechanisms responsible for the distinct cytotoxicity, we further assessed the effects of 2a and 2b on cell cycle distribution, cell apoptosis and reactive oxygen species (ROS) generation. The results indicated that 2a had more significant effect than 2b on apoptosis induction and ROS generation, but both had no obvious effect on cell cycle of HepG2 cells. It is concluded that the different configurations of 2a/2b determined the enantioselective cytotoxicity on HepG2 cells through apoptosis induction and ROS generation. Graphical abstract image
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Sulfoximines as potent RORγ inverse agonists ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Gilles Ouvry, Franck Bihl, Claire Bouix-Peter, Olivier Christin, Claire Defoin-Platel, Sophie Deret, Christophe Feret, David Froude, Feriel Hacini-Rachinel, Craig S. Harris, Catherine Hervouet, Guillaume Lafitte, Anne-Pascale Luzy, Branislav Musicki, Danielle Orfila, Veronique Parnet, Coralie Pascau, Jonathan Pascau, Romain Pierre, Catherine Raffin, Patricia Rossio, Delphine Spiesse, Nathalie Taquet, Etienne Thoreau, Rodolphe Vatinel, Emmanuel Vial, Laurent F. Hennequin Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model. Graphical abstract image
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Probing cytochrome P450 bioactivation and fluorescent properties with morpholinyl-tethered anthraquinones ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Rachel J. Errington, Maria Sadiq, Laura Cosentino, Marie Wiltshire, Omair Sadiq, Marcella Sini, Enric Lizano, Maria D. Pujol, Goreti R. Morais, Klaus Pors Structural features from the anticancer prodrug nemorubicin (MMDX) and the DNA-binding molecule DRAQ5™ were used to prepare anthraquinone-based compounds, which were assessed for their potential to interrogate cytochrome P450 (CYP) functional activity and localisation. 1,4-disubstituted anthraquinone 8 was shown to be 5-fold more potent in EJ138 bladder cancer cells after CYP1A2 bioactivation. In contrast, 1,5-bis((2-morpholinoethyl)amino) substituted anthraquinone 10 was not CYP-bioactivated but was shown to be fluorescent and subsequently photo-activated by a light pulse (at a bandwidth 532–587 nm), resulting in punctuated foci accumulation in the cytoplasm. It also showed low toxicity in human osteosarcoma cells. These combined properties provide an interesting prospective approach for opto-tagging single or a sub-population of cells and seeking their location without the need for continuous monitoring. Graphical abstract image
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Synthesis and investigations into the anticancer and antibacterial activity studies of β-carboline chalcones and their bromide salts ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): P.O. Venkataramana Reddy, M. Hridhay, Kumar Nikhil, Shahid Khan, P.N. Jha, Kavita Shah, Dalip Kumar A series of sixteen β-carbolines, bearing chalcone moiety at C-1 position, were prepared from easily accessible 1-acetyl-β-carboline and various aldehydes under basic conditions followed by N 2-alkylation using different alkyl bromides. The prepared compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. N 2-Alkylated-β-carboline chalcones 13a-i represented the interesting anticancer activities compared to N 2-unsubstituted β-carboline chalcones 12a-g. Off the prepared β-carbolines, 13g exhibited broad spectrum of activity with IC50 values lower than 22.5 µM against all the tested cancer cell lines. Further, the N 2-alkylated-β-carboline chalcone 13g markedly induced cell death in MDA-MB-231 cells by AO/EB staining assay. The most cytotoxic compound 13g possessed a relatively high drug score of 0.48. Additionally, the prepared β-carboline chalcones displayed moderate antibacterial activities against tested bacterial strains. Graphical abstract image
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Head-to-tail macrocyclization of cysteine-free peptides using an o-aminoanilide linker ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Takumi Ohara, Masato Kaneda, Tomo Saito, Nobutaka Fujii, Hiroaki Ohno, Shinya Oishi A head-to-tail macrocyclization protocol for the preparation of cysteine-free cyclic peptides was investigated. The o-aminoanilide linker constructed in the peptide sequence by a standard Fmoc-based peptide synthesis procedure was subjected to nitrite-mediated activation under acidic conditions toward N-acyl benzotriazole as the active ester species. The subsequent cyclization smoothly proceeded by neutralization in the presence of additives such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) to afford the expected cyclic pentapeptide, a CXCR4 antagonist. The cyclization efficiencies were dependent on the precursor open-chain sequence. The application of this step-wise activation-cyclization protocol to microflow reaction systems is also described. Graphical abstract image
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Adamantane amine-linked chloroquinoline derivatives as chloroquine resistance modulating agents in Plasmodium falciparum ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Opute M. Yvette, Sarel F. Malan, Dale Taylor, Erika Kapp, Jacques Joubert Previously we have shown that pentacycloundecylamine-chloroquinoline (PCU-CQ) conjugates possess significant chemosensitizing abilities and can circumvent the resistance associated with chloroquine (CQ) resistant plasmodia. In order to further explore structurally related polycyclic compounds as reversed CQ agents we synthesized a series of eight aza-adamantanol (1–4) and adamantane-imine (5–8) CQ conjugates. All conjugates showed limited cytotoxicity against CHO cells (IC50 > 37 µM). Compounds 1, 2 and 5 were highly active (K1 IC50 < 100 nM) exhibiting a 3–4-fold increase in antiplasmodial activity against CQ resistant strain K1 compared to CQ. Reduced cross-resistance (resistance index, RI: 2–4.3) relative to CQ (RI = 38) was also observed for these compounds. Compound 1 which showed an 18-fold enhancement at retaining its activity against the K1 strain compared to CQ is a promising candidate to substitute CQ in P. falciparum resistant malaria. Graphical abstract image
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Evaluation of analogues of furan-amidines as inhibitors of NQO2 ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Soraya Alnabulsi, Buthaina Hussein, Elham Santina, Izzeddin Alsalahat, Manikandan Kadirvel, Rachael N. Magwaza, Richard A. Bryce, Carl H. Schwalbe, Alex G. Baldwin, Ilaria Russo, Ian J. Stratford, Sally Freeman Inhibitors of the enzyme NQO2 (NRH: quinone oxidoreductase 2) are of potential use in cancer chemotherapy and malaria. We have previously reported that non-symmetrical furan amidines are potent inhibitors of NQO2 and here novel analogues are evaluated. The furan ring has been changed to other heterocycles (imidazole, N-methylimidazole, oxazole, thiophene) and the amidine group has been replaced with imidate, reversed amidine, N-arylamide and amidoxime to probe NQO2 activity, improve solubility and decrease basicity of the lead furan amidine. All compounds were fully characterised spectroscopically and the structure of the unexpected product N-hydroxy-4-(5-methyl-4-phenylfuran-2-yl)benzamidine was established by X-ray crystallography. The analogues were evaluated for inhibition of NQO2, which showed lower activity than the lead furan amidine. The observed structure-activity relationship for the furan-amidine series with NQO2 was rationalized by preliminary molecular docking and binding mode analysis. In addition, the oxazole-amidine analogue inhibited the growth of Plasmodium falciparum with an IC50 value of 0.3 μM. Graphical abstract image
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Disulfiram-based disulfides as narrow-spectrum antibacterial agents ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Jordan G. Sheppard, Keely R. Frazier, Pushkar Saralkar, Mohammad F. Hossain, Werner J. Geldenhuys, Timothy E. Long Sixteen disulfides derived from disulfiram (Antabuse™) were evaluated as antibacterial agents. Derivatives with hydrocarbon chains of seven and eight carbons in length exhibited antibacterial activity against Gram-positive Staphylococcus, Streptococcus, Enterococcus, Bacillus, and Listeria spp. A comparison of the cytotoxicity and microsomal stability with disulfiram further revealed that the eight carbon chain analog was of lower toxicity to human hepatocytes and has a longer metabolic half-life. In the final analysis, this investigation concluded that the S-octylthio derivative is a more effective growth inhibitor of Gram-positive bacteria than disulfiram and exhibits more favorable cytotoxic and metabolic parameters over disulfiram. Graphical abstract image
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Design, synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Yanhui Yang, Haifa Albanyan, Sumi Lee, Herve Aloysius, Jian-Jie Liang, Vladyslav Kholodovych, Amrik Sahota, Longqin Hu To overcome the chemical and metabolic stability issues of l-cystine dimethyl ester (CDME) and l-cystine methyl ester (CME), a series of l-cystine diamides with or without N α-methylation was designed, synthesized, and evaluated for their inhibitory activity of l-cystine crystallization. l-Cystine diamides 2a–i without N α-methylation were found to be potent inhibitors of l-cystine crystallization while N α-methylation of l-cystine diamides resulted in derivatives 3b–i devoid of any inhibitory activity of l-cystine crystallization. Computational modeling indicates that N α-methylation leads to significant decrease in binding of the l-cystine diamides to l-cystine crystal surface. Among the l-cystine diamides 2a–i, l-cystine bismorpholide (CDMOR, LH707, 2g) and l-cystine bis(N′-methylpiperazide) (CDNMP, LH708, 2h) are the most potent inhibitors of l-cystine crystallization. Graphical abstract image
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Alkylated/aminated nitroimidazoles and nitroimidazole-7-chloroquinoline conjugates: Synthesis and anti-mycobacterial evaluation ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Shalini, Albertus Viljoen, Laurent Kremer, Vipan Kumar The success in exploring anti-tubercular potency of nitroimidazole and quinoline, the core moieties of recently approved anti-tubercular drugs instigated us to synthesize a series of alkylated/aminated 2-methyl-5-nitroimidazoles and nitroimidazole-7-chloroquinoline conjugates and to evaluate them for their activities against Mycobacterium tuberculosis as well as for their cytotoxicity towards the J774 murine macrophage cell line. Although the synthesized compounds did not surpass the activity of the standard drug Isoniazid, they have appreciable activities with minimal cytotoxicity. The synthesized nitroimidazole-7-chloroquinoline conjugate, 11c, having butyl chain as linker, proved to be the most potent among the series with an MIC50 value of 2.2 μg/mL. Graphical abstract image
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Design, synthesis, and evaluation of simple phenol amides as ERRγ agonists ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Hua Lin, Christelle Doebelin, Rémi Patouret, Ruben D. Garcia-Ordonez, Mi Ra Chang, Venkatasubramanian Dharmarajan, Claudia Ruiz Bayona, Michael D. Cameron, Patrick R. Griffin, Theodore M. Kamenecka Herein we report the design and synthesis of a series of simple phenol amide ERRγ agonists based on a hydrazone lead molecule. Our structure activity relationship studies in this series revealed the phenol portion of the molecule to be required for activity. Attempts to replace the hydrazone with more suitable chemotypes led to a simple amide as a viable alternative. Differential hydrogen-deuterium exchange experiments were used to help understand the structural basis for binding to ERRγ and aid in the development of more potent ligands. Graphical abstract image
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Synthesis and biological evaluation of novel carbazole-rhodanine conjugates as topoisomerase II inhibitors ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Hong Jiang, Wen-Jin Zhang, Peng-Hui Li, Jian Wang, Chang-Zhi Dong, Kun Zhang, Hui-Xiong Chen, Zhi-Yun Du In this study, a series of carbazole-rhodanine conjugates was synthesized and evaluated for their Topoisomerase II inhibition potency as well as cytotoxicity against a panel of four human cancer cell lines. Among these thirteen compounds, 3a, 3b, 3g, and 3h possessed Topoisomerase II inhibition potency at 20 μM. Mechanism study revealed that these compounds may function as Topo II catalytic inhibitors. It was found that the electron-withdrawing groups on the phenyl ring of compounds played an important role on enhancing both enzyme inhibition and cytotoxicity. Graphical abstract image
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Design, synthesis, biological evaluation, homology modeling and docking studies of (E)-3-(benzo[d][1,3]dioxol-5-ylmethylene) pyrrolidin-2-one derivatives as potent anticonvulsant agents ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Tiantian Wang, Shiyang Dong, Xiaodong Chen, Kun Qian, Huayu Wang, Hexiu Quan, Zhongli Zhang, Yueming Zuo, Liping Huang, Dongxun Li, Ming Yang, Shilin Yang, Yi Jin, Zengtao Wang A series of (E)-3-(benzo[d][1,3]dioxol-5-ylmethylene)pyrrolidin-2-one derivatives were designed, synthesized, and evaluated for their anticonvulsant activities. In the preliminary screening, compounds 5, 6a–6f and 6h–6i showed promising anticonvulsant activities in MES model, while 6f and 6g represented protection against seizures at doses of 100 mg/kg and 0.5 h in scPTZ model. The most active compound 6d had a high-degree protection against the MES-induced seizures with ED50 value of 4.3 mg/kg and TD50 value of 160.9 mg/kg after intraperitoneal (i.p.) injection in mice, which provided 6d in a high protective index (TD50/ED50) of 37.4 comparable to the reference drugs. Beyond that, 6d has been selected and evaluated in vitro experiment to estimate the activation impact. Apparently, 6d clearly inhibits the Nav1.1 channel. Our preliminary results provide new insights for the development of small-molecule activators targeting specifically Nav1.1 channels to design potential drugs for treating epilepsy. The computational parameters, such as homology modeling, docking study, and ADME prediction, were made to exploit the results. Graphical abstract image
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Synthesis of new 4-aryloxy-N-arylanilines and their inhibitory activities against succinate-cytochrome c reductase ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Hua Cheng, Wei Song, Ren Nie, Yu-Xia Wang, Hui-Lian Li, Xiang-Sheng Jiang, Jun-Jun Wu, Cheng Chen, Qiong-You Wu Succinate-cytochrome c reductase (SCR) is composed of a mixture of mitochondrial complex II (succinate-ubiquinone oxidoreductase) and complex III (cytochrome bc 1 complex). Meanwhile, complexes II and III are two promising targets of numerous antibiotics and fungicides. With an aim to identify new lead structures for SCR, complex II or III, a new series of 4-aryloxy-N-arylanilines were synthesized by introducing a 4-aryloxy phenyl group as one of the aryl groups in diaryl amines. With the economic Cu(OAc)2·H2O as the optimal copper promoter, a simple and facile protocol was utilized to afford 24 target products in 56–93% yields. Furthermore, extensive screening results suggested variable inhibitory activities of these compounds against SCR. Exceptionally, compounds 7k–7n showed excellent inhibition potency with their IC50 values in the nanomolar range, demonstrating higher potency than the commercial controls (penthiopyrad and azoxystrobin) by over one order of magnitude. Graphical abstract image
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Discovery of 2,6-disubstituted pyrazine derivatives as inhibitors of CK2 and PIM kinases ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Lakshmaiah Gingipalli, Michael H. Block, Larry Bao, Emma Cooke, Les A. Dakin, Christopher R. Denz, Andrew D. Ferguson, Jeffrey W. Johannes, Nicholas A. Larsen, Paul D. Lyne, Timothy W. Pontz, Tao Wang, Xiaoyun Wu, Allan Wu, Hai-Jun Zhang, Xiaolan Zheng, James E. Dowling, Michelle L. Lamb The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinase inhibitors is described. Structure-guided optimization of a 5-substituted-3-thiophene carboxylic acid screening hit (3a) led to the development of a lead compound (12b), which shows inhibition in both enzymatic and cellular assays. Subsequent design and hybridization efforts also led to the unexpected identification of analogs with potent PIM kinase activity (14f). Graphical abstract image
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Design, synthesis, nuclear localization, and biological activity of a fluorescent duocarmycin analog, HxTfA ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Kostantinos Kiakos, Bernhard Englinger, Stephanie K. Yanow, Debora Wernitznig, Michael A. Jakupec, Walter Berger, Bernhard K. Keppler, John A. Hartley, Moses Lee, Pravin C. Patil HxTfA 4 is a fluorescent analog of a potent cytotoxic and antimalarial agent, TfA 3, which is currently being investigated for the development of an antimalarial vaccine, PlasProtect®. HxTfA contains a p-anisylbenzimidazole or Hx moiety, which is endowed with a blue emission upon excitation at 318 nm; thus enabling it to be used as a surrogate for probing the cellular fate of TfA using confocal microscopy, and addressing the question of nuclear localization. HxTfA exhibits similar selectivity to TfA for A-tract sequences of DNA, alkylating adenine-N3, albeit at 10-fold higher concentrations. It also possesses in vitro cytotoxicity against A549 human lung carcinoma cells and Plasmodium falciparum. Confocal microscopy studies showed for the first time that HxTfA, and by inference TfA, entered A549 cells and localized in the nucleus to exert its biological activity. At biologically relevant concentrations, HxTfA elicits DNA damage response as evidenced by a marked increase in the levels of γH2AX observed by confocal microscopy and immunoblotting studies, and ultimately induces apoptosis. Graphical abstract image
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First discovery of a potential carbonate prodrug of NNRTI drug candidate RDEA427 with submicromolar inhibitory activity against HIV-1 K103N/Y181C double mutant strain ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Boshi Huang, Xinhao Liu, Ye Tian, Dongwei Kang, Zhongxia Zhou, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu In the present work, we described the synthesis, antiviral profiles and metabolic stability in human plasma of compound 6, a potential carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound 6 was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at nano- and submicromolar concentrations, respectively. Moreover, it displayed potent HIV-1 reverse transcriptase inhibitory activity (IC50 = 0.264 μM). Further stability test in human plasma showed that 6 could release its active form RDEA427 in a linearly time-independent manner, possibly acting as a potential prodrug. Graphical abstract image
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A multi-gram-scale stereoselective synthesis of Z-endoxifen ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Lech-Gustav Milroy, Bartjan Koning, Daphne S.V. Scheppingen, Nynke G.L. Jager, Jos H. Beijnen, Jan Koek, Luc Brunsveld Z-Endoxifen is widely regarded as the most active metabolite of tamoxifen, and has recently demonstrated a 26.3% clinical benefit in a phase I clinical trial to treat metastatic breast cancer after the failure of standard endocrine therapy. Future pharmacological and pre-clinical studies of Z-endoxifen would benefit from reliable and efficient synthetic access to the drug. Here, we describe a short and efficient, stereoselective synthesis of Z-endoxifen capable of delivering multi-gram (37 g) quantities of the drug in >97% purity with a Z/E ratio >99% after trituration. Graphical abstract image
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Design and synthesis of triple inhibitors of janus kinase (JAK), histone deacetylase (HDAC) and Heat Shock Protein 90 (HSP90) ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Lianbin Yao, Sten Ohlson, Brian W. Dymock Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90). Although these enzymes have totally different functions they are related through inter-dependent pathways in the developing cancer cell. Synthesis of several complex multi-inhibiting ligands are presented along with initial enzyme inhibition data against 3 biological target classes of interest. A lead compound, 47, was discovered which had low micromolar activity for all 3 targets. Further development of these complex trispecific designed multiple ligands could result in a ‘transient drug’, an alternative combination therapy for treating cancer mediated via a single molecule. Graphical abstract image
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Site-specific and hydrophilic ADCs through disulfide-bridged linker and branched PEG ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Shuai Shao, Mei-Hsuan Tsai, Jiawei Lu, Tao Yu, Jin Jin, Di Xiao, Huanhuan Jiang, Mo Han, Min Wang, Jun Wang Kadcyla® (T-DM1), an antibody–drug conjugates (ADCs) for HER2+ breast cancer treatment, has been approved by the Food and Drug Administration (FDA) in 2013. An ADC of random lysine conjugation, it has difficulties in DAR control and unsatisfactory PK due to uneven DAR distribution. It also gives rise to aggregation during conjugation because of the hydrophobicity nature of the cytotoxin, DM1. The linker-drug in T-DM1, SMCC-DM1 is hydrophobic and requires certain percentage of organic solvent such as DMA in the conjugation solution, limiting the manufacturing process in an organic-solvent-compatible device and adding extra costs. To address these problems, a site-specific conjugation method was developed involving full reduction of antibody and full conjugation with the bridge-like conjugator-drug, based on the work of Caddick and co-workers, to obtain a site-directed antibody-drug conjugate with DAR 4. The bridge-like conjugator was assembled with SMCC-DM1 and different lengths of hydrophilic polyethylene glycol (PEG) moiety. By applying PEG moiety in the side chain of the linker-drug, the organic solvent used in the conjugation can be reduced. When the PEG length is about 26 units, organic solvent is no longer needed in the conjugation. Reducing the amount of organic solvent in conjugation could also diminish the aggregation occurrence during the conjugation. Moreover, the conjugation configuration with the designed conjugator was also discussed in the article. The binding affinity of the resulting ADCs did not show significant decrease and the cell based assay and animal study have shown the comparable results with T-DM1. Graphical abstract image
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Structure-based drug design of 1,3,6-trisubstituted 1,4-diazepan-7-ones as selective human kallikrein 7 inhibitors ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Hidenobu Murafuji, Hiroki Sakai, Megumi Goto, Yoshiaki Oyama, Seiichi Imajo, Hajime Sugawara, Toshiyuki Tomoo, Tsuyoshi Muto A novel series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were investigated as human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Based on the X-ray co-crystal structure of compound 1 bound to human KLK7, the derivatives of this scaffold were designed, synthesized, and evaluated. Through structure-activity relationship studies focused on the side chain located in the prime site region of the enzyme, representative compounds 15, 33a, and 35a were identified as highly potent and selective inhibitors of human KLK7. Graphical abstract image
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The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Travis R. Helgren, Elif S. Seven, Congling Chen, Thomas E. Edwards, Bart L. Staker, Jan Abendroth, Peter J. Myler, James R. Horn, Timothy J. Hagen Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a concentration of 10 µM and potential hits were determined to be those exhibiting greater than 50% inhibition of enzymatic activity. These hit compounds were then rescreened against the target in 8-point dose–response curves and 11 compounds were found to inhibit enzymatic activity with IC50 values of less than 10 µM. Finally, compounds (1–5) were docked against RpMetAP with AutoDock to determine potential binding mechanisms and the results were compared with crystal structures deposited within the PDB. Graphical abstract image
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Synthesis and activity of functionalizable derivatives of the serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist M100907 ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Scott R. Gilbertson, Ying-Chu Chen, Claudia A. Soto, Yaxing Yang, Kenner C. Rice, Kathryn A. Cunningham, Noelle C. Anastasio The approach of tethering together two known receptor ligands, to be used as molecular probes for the study of G protein-coupled receptor (GPCR) systems, has proven to be a valuable approach. Selective ligands that possess functionality that can be used to link to other ligands, are useful in the development of novel antagonists and agonists. Such molecules can also be attached to reporter molecules, such as fluorophores, for the study of GPCR dimerization and its role in signaling. The highly selective serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist M100907 (volinanserin) is of clinical interest in the treatment of neurological and mental health disorders. Here, we synthesized the most active (+)-M100907 enantiomer as well as a series of derivatives that possessed either an alkyne or an azide. The triazole resulting from the dipolar cycloaddition of these groups did not interfere with the ability of the bivalent ligand to act as an antagonist. Thus, we have synthesized a number of compounds which will prove useful in elucidating the role of the 5-HT2AR in the central nervous system. Graphical abstract image
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Discovery of novel CDK inhibitors via scaffold hopping from CAN508 ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Liandong Jing, Yanbo Tang, Zhiyan Xiao Cyclin-dependent kinases (CDKs) are promising drug targets for various human diseases, especially for cancers. Scaffold hopping strategy was applied on CAN508, a known selective CDK9 inhibitor, and a series of pyrazolo[3,4-b]pyridine compounds were synthesized and evaluated in vitro as CDK2 and CDK9 inhibitors. Most compounds exhibited moderate to potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems. Among them, compound 2e showed IC50 values of 0.36 μM for CDK2 and 1.8 μM for CDK9, respectively. Notably, the scaffold alteration seems to cause a shift in the selectivity profile of the inhibitors. In contrast to CAN508, compound 2k demonstrated remarkable selectivity toward CDK2 (265-fold over CDK9). Docking studies on compound 2k provided hints for further design of more potent and selective CDK2/CDK9 inhibitors. Graphical abstract image
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Identification of second-generation P2X3 antagonists for treatment of pain ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Anthony T. Ginnetti, Daniel V. Paone, Shaun R. Stauffer, Craig M. Potteiger, Anthony W. Shaw, James Deng, James J. Mulhearn, Diem N. Nguyen, Carolyn Segerdell, Juliana Anquandah, Amy Calamari, Gong Cheng, Michael D. Leitl, Annie Liang, Eric Moore, Jacqueline Panigel, Mark Urban, Jixin Wang, Kerry Fillgrove, Cuyue Tang, Sean Cook, Stefanie Kane, Christopher A. Salvatore, Samuel L. Graham, Christopher S. Burgey A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead. Graphical abstract image
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Discovery of a highly potent orally bioavailable imidazo-[1, 2-a]pyrazine Aurora inhibitor ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Tao Yu, Yonglian Zhang, Angela D. Kerekes, Jayaram R. Tagat, Ronald J. Doll, Yushi Xiao, Sara Esposite, Alan Hruza, David B. Belanger, Matthew Voss, Matthew P. Rainka, Andrea Basso, Ming Liu, Lianzhu Liang, Ning Sui, Daniel Prelusky, Diane Rindgen, Likang Zhang Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally. Graphical abstract image
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Multipurpose isothiocyanyl alanine/lysine: Use as solvatochromic IR probes and in site specific labeling/ligation of short peptides ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Subhendu Sekhar Bag, Suranjan De The solvatochromic IR responsivity of small side chain –NCS in two unexplored unnatural amino acids, isothiocyanyl alanine ( NCSAla = Ita) and lysine ( NCSLys = Itl), without perturbing the conformation is demonstrated in two designed short tripeptide (BocAla- NCSAla-Ala-OMe) and hexapeptide (BocLeu-Val-Phe-Phe- NCSLys-Gly-OMe). Demonstration of site specific fluorescent labeling in both the peptides and ligation type reaction in NCSLys indicates the novelty of these two amino acids as alternative to the available canonical amino acids. Graphical abstract image
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Synthesis of novel isoxazoline-containing podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives and their insecticidal/acaricidal activities ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Ruige Yang, Yuanyuan Zhang, Hui Xu In continuation of our program aimed at the development of natural product-based pesticidal agents, a series of isoxazoline-containing podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives were prepared, and their structures were well characterized by 1H NMR, IR, optical rotation, HRMS and mp. Especially the structure of compound Ia was further confirmed by 1H–1H COSY and NOESY spectrum. Among them, two compounds showed good insecticidal and acaricidal activities against Mythimna separata and Tetranychus cinnabarinus. Their structure–activity relationships were also observed. Graphical abstract image
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Discovery and validation of 2-styryl substituted benzoxazin-4-ones as a novel scaffold for rhomboid protease inhibitors ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Parul Goel, Thorsten Jumpertz, Anežka Tichá, Isabella Ogorek, David C. Mikles, Martin Hubalek, Claus U. Pietrzik, Kvido Strisovsky, Boris Schmidt, Sascha Weggen Rhomboids are intramembrane serine proteases with diverse physiological functions in organisms ranging from archaea to humans. Crystal structure analysis has provided a detailed understanding of the catalytic mechanism, and rhomboids have been implicated in various disease contexts. Unfortunately, the design of specific rhomboid inhibitors has lagged behind, and previously described small molecule inhibitors displayed insufficient potency and/or selectivity. Using a computer-aided approach, we focused on the discovery of novel scaffolds with reduced liabilities and the possibility for broad structural variations. Docking studies with the E. coli rhomboid GlpG indicated that 2-styryl substituted benzoxazinones might comprise novel rhomboid inhibitors. Protease in vitro assays confirmed activity of 2-styryl substituted benzoxazinones against GlpG but not against the soluble serine protease α-chymotrypsin. Furthermore, mass spectrometry analysis demonstrated covalent modification of the catalytic residue Ser201, corroborating the predicted mechanism of inhibition and the formation of an acyl enzyme intermediate. In conclusion, 2-styryl substituted benzoxazinones are a novel rhomboid inhibitor scaffold with ample opportunity for optimization. Graphical abstract image
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Benzoxazin-4-ones as novel, easily accessible inhibitors for rhomboid proteases ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8 Author(s): Jian Yang, Marta Barniol-Xicota, Minh T.N. Nguyen, Anezka Ticha, Kvido Strisovsky, Steven H.L. Verhelst Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms. Graphical abstract image
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Graphical abstract TOC ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8
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Graphical abstract TOC ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8
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Graphical abstract TOC ()
Publication date: 1 May 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8
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Editorial Board ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7
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Small molecule modulators of PCSK9 – A literature and patent overview ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Daniel Pettersen, Ola Fjellström Proprotein convertase subtilisin kexin like type 9 (PCSK9) has since its discovery been a key protein target for the modulation of LDL cholesterol. The interest in PCSK9 has grown even more with the positive clinical trial outcomes in cardiovascular disease recently reported for two PCSK9 antibodies. Currently, there are no PCSK9 small molecule programs active in clinical development. However, there has been a steady increase in publications and patent applications within the PCSK9 small molecule field. This digest will provide a summary of small molecule and peptide PCSK9 modulators reported both in scientific journals and in patent applications, most of them originating from the last 3–4 years. As such, this digest will serve as an introduction to the field and assist further identification and discovery of small molecule PCSK9 modulators. Graphical abstract image
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Nano-chemotherapy using cationic liposome that strategically targets the cell membrane potential of pancreatic cancer cells with negative charge ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Muneaki Motomura, Hideaki Ichihara, Yoko Matsumoto Negatively charged phosphatidylserine (PS) and sialic acid-containing glycosphingolipids (GM1) were observed to be over represented on the cell membranes of pancreatic cancer cells (BxPC-3) as opposed to normal pancreatic cells. Cationic liposomes (CL) were also found to selectively accumulate into the negatively charged cell membranes of BxPC-3 cells and inhibited their growth but have no effect on the viability of normal pancreatic cells. CL induced apoptosis in BxPC-3 cells via activation of caspase-3, -8, and -9 and mitochondrial events and inhibited tumor enlargement in xenograft mouse models of pancreatic cancer. Graphical abstract image
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A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-microbial evaluation and molecular docking studies ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Saleha Banu, Rajitha Bollu, Mohammad Naseema, P. Mary Gomedhika, Lingaiah Nagarapu, K. Sirisha, C. Ganesh Kumar, Shravan Kumar Gundasw A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by 1H NMR, 13C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9b and 10c were identified as promising antimicrobial lead molecules. This study might provide insights to identify new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase. Graphical abstract image
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Enantiomeric trans β-aryl-δ-iodo-γ-lactones derived from 2,5-dimethylbenzaldehyde induce apoptosis in canine lymphoma cell lines by downregulation of anti-apoptotic Bcl-2 family members Bcl-xL and Bcl-2 ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Aleksandra Pawlak, Witold Gładkowski, Justyna Kutkowska, Marcelina Mazur, Bożena Obmińska-Mrukowicz, Andrzej Rapak For many years, studies focused on developing new natural or synthetic compounds with antineoplastic activity have attracted the attention of researchers. An interesting group of such compounds seem to be those with both lactone moiety and an aromatic ring which, in addition to antimicrobial or antiviral activity, also exhibit antitumor properties. The study shows antitumor activity of two enantiomeric trans isomers of 5-(1-iodoethyl)-4-(2′,5′-dimethylphenyl)dihydrofuran-2-one. Our aim was to determine their antitumor activity manifested as an ability to induce apoptosis in selected canine cancer cell lines as well as to evaluate differences in their strength depending on the configuration of their stereogenic centers. The enantiomers (+)-(4R,5S,6R)-1 and (−)-(4S,5R,6S)-2 were found to induce classical caspase-dependent apoptosis through downregulation of the expression of anti-apoptotic proteins Bcl-xL and Bcl-2. Although the mechanism of apoptosis induction was the same for both enantiomers, they differed in their strength, as stronger antineoplastic activity in vitro was exhibited by isomer (+)-(4R,5S,6R)-1. Graphical abstract image
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Identification of an aminothiazole series of RORβ modulators ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Rémi Patouret, Christelle Doebelin, Ruben D. Garcia-Ordonez, Mi Ra Chang, Claudia Ruiz, Michael D. Cameron, Patrick R. Griffin, Theodore M. Kamenecka Crystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORβ, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORβ and RORγ inverse agonist with no activity towards RORα (Fig. 1). To our knowledge, this is one of only two small molecule RORβ inverse agonists identified in the primary literature from a tractable chemical series and represents an ideal starting point from which to design RORβ-selective modulators. Herein we describe our SAR optimization efforts that led to a series of potent neutral antagonists of RORβ. Graphical abstract image
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Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Gee-Hong Kuo, Micheal D. Gaul, Yin Liang, June Z. Xu, Fuyong Du, Pamela Hornby, Guozhang Xu, Jenson Qi, Nathaniel Wallace, Seunghun Lee, Eugene Grant, William V. Murray, Keith Demarest Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50 = 45 nM), and excellent potency at SGLT2 (IC50 = 1 nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F = 78–107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24 h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome. Graphical abstract image
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Structure-based design and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Yixian Liao, Yiming Guo, Sumei Li, Lei Wang, Yongmei Tang, Tianmiao Li, Weihao Chen, Guohua Zhong, Gaopeng Song This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC50 of 0.88 µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH3O group or CF3O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation. Graphical abstract image
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Identification of caffeoylquinic acid derivatives as natural protein tyrosine phosphatase 1B inhibitors from Artemisia princeps ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Jie Zhang, Tatsunori Sasaki, Wei Li, Kazuya Nagata, Koji Higai, Feng Feng, Jian Wang, Maosheng Cheng, Kazuo Koike Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes, obesity, and cancer. Ten caffeoylquinic acid derivatives (1–10) from leaves of Artemisia princeps Pamp. (Asteraceae) were identified as natural PTP1B inhibitors. Among them, chlorogenic acid (3) showed the most potent inhibitory activity (IC50 11.1 μM). Compound 3 was demonstrated to be a noncompetitive inhibitor by a kinetic analysis. Molecular docking simulation suggested that compound 3 bound to the allosteric site of PTP1B. Furthermore, compound 3 showed remarkable selectivity against four homologous PTPs. According to these findings, compound 3 might be potentially valuable for further drug development. Graphical abstract image
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Design, synthesis and biological evaluation of spiropyrimidinetriones oxazolidinone derivatives as antibacterial agents ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Asher M. Siddiqui, Jitendra A. Sattigeri, Kalim Javed, Syed Shafi, M. Shamim, Smita Singhal, Zubbair M. Malik Gram-positive bacteria are among the most common human pathogens associated with clinical infections which range from mild skin infections to sepsis. Resistance towards existing class of drugs by Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE) is a growing concern. There is an urgent need to discover new antibiotics which are active against resistant strains of Gram positive bacteria. We report herein a novel class of spiropyrimidinetrione oxazolidinone derivatives as novel antibacterial agents. Key step towards the synthesis of title compounds involved the use of tert-amino reaction with [1,5]-hydride shift leading to the new CC bond formation. Compound 30n has demonstrated potent antibacterial activity against a panel of Gram-positive microbial strains including MRSA, MRSE, and LNZ and vancomycin resistant strains of E. faecalis. Further, molecular docking studies suggest that 30n has binding mode similar to that of LNZ in 50S RNA ribosome. Graphical abstract image
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Two new lathyrane-type diterpenoid glycosides with IL-6 production inhibitory activity from the roots of Euphorbia kansui ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Young-Mi Kim, Jongmin Ahn, Hee-Sung Chae, Young Hee Choi, Jinwoong Kim, Young-Won Chin As part of our ongoing search for anti-inflammatory compounds from higher plants, we isolated and elucidated two new diterpenoid glycosides, kansuingol A (1) and kansuingol B (2), from the roots of Euphorbia kansui. These structures were elucidated by extensive spectroscopic methods such as NMR and MS. Compounds were assessed for their IL-6 production inhibitory activity in PMA + A23187-stimulated HMC-1 cells. As a result, compounds 1 and 2 exerted inhibitory activities in the production of IL-6 with IC50 values of 2.96, and 1.94 μM, respectively. Further, kansuingol A (1) decreased mRNA expressions of TNF-α and IL-6. Graphical abstract image
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Alleviating CYP and hERG liabilities by structure optimization of dihydrofuran-fused tricyclic benzo[d]imidazole series – Potent, selective and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-2 ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Nagarajan Muthukaman, Sanjay Deshmukh, Macchindra Tambe, Dnyandeo Pisal, Shital Tondlekar, Mahamadhanif Shaikh, Neelam Sarode, Vidya G. Kattige, Pooja Sawant, Monali Pisat, Vikas Karande, Srinivasa Honnegowda, Abhay Kulkarni, Dayanidhi Behera, Satyawan B. Jadhav, Ramchandra R. Sangana, Girish S. Gudi, Neelima Khairatkar-Joshi, Laxmikant A. Gharat In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160–950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106 mg/kg). Graphical abstract image
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The synthesis and evaluation of thymoquinone analogues as anti-ovarian cancer and antimalarial agents ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Okiemute Rosa Johnson-Ajinwo, Imran Ullah, Haddijatou Mbye, Alan Richardson, Paul Horrocks, Wen-Wu Li Thymoquinone (TQ), 2-isopropyl-5-methyl-1,4-benzoquinone, a natural product isolated from Nigella sativa L., has previously been demonstrated to exhibit antiproliferative activity in vitro against a range of cancers as well as the human malarial parasite Plasmodium falciparum. We describe here the synthesis of a series of analogues of TQ that explore the potential for nitrogen-substitution to this scaffold, or reduction to a hydroquinone scaffold, in increasing the potency of this antiproliferative activity against ovarian cancer cell lines and P. falciparum. In addition, alkyl or halogen-substituted analogues were commercially sourced and tested in parallel. Several TQ analogues with improved potency against ovarian cancer cells and P. falciparum were found, although this increase is suggested to be moderate. Key aspects of the structure activity relationship that could be further explored are highlighted. Graphical abstract image
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Synthesis of new analogs of tetraiodothyroacetic acid (tetrac) as novel angiogenesis inhibitors for treatment of cancer ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Mehdi Rajabi, Murat Yalcin, Shaker A. Mousa In the angiogenesis process, integrins, which are members of a family of cell surface transmembrane receptors, play a critical role particularly in blood vessel formation and the local release of vascular growth factors. Thyroid hormones such as l-thyroxine (T4) and 3,5,3′-triiodo-l-thyronine (T3) promote angiogenesis and tumor cell proliferation via integrin αvβ3 receptor. At or near an arginine-glycine-aspartate (RGD) recognition site on the binding pocket of integrin αvβ3, tetraiodothyroacetic acid (tetrac, a deaminated derivative of T4) is a thyrointegrin receptor antagonist and blocks the actions of T3 and T4 as well as different growth factors-mediated angiogenesis. In this study, we synthesized novel tetrac analogs by modifying the phenolic moiety of tetrac and tested them for their anti-angiogenesis activity using a Matrigel plug model for angiogenesis in mice. Pharmacological activity results showed that tetrac can accommodate numerous modifications and maintain its anti-angiogenesis activity. Graphical abstract image
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Design and synthesis of novel and potent GPR119 agonists with a spirocyclic structure ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Kazuhito Harada, Jun Mizukami, Sho Kadowaki, Isamu Matsuda, Takashi Watanabe, Yasuhiro Oe, Yoshitoshi Kodama, Kenta Aoki, Katsunori Suwa, Sumiaki Fukuda, Shinji Yata, Takashi Inaba Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50 = 4 nM) with no CYP inhibitory activity (IC50 >10 μM). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats. Graphical abstract image
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Inhibition of histone lysine methyltransferases G9a and GLP by ejection of structural Zn(II) ()
Publication date: 15 April 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7 Author(s): Danny C. Lenstra, Abbas H.K. Al Temimi, Jasmin Mecinović Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site. Our work demonstrates that targeting these labile zinc fingers with electrophilic small molecules results in ejection of structural zinc ions, and consequently inhibition of the methyltransferase activity. Very effective Zn(II) ejection and inhibition of G9a and GLP was observed with clinically used ebselen, disulfiram and cisplatin. Graphical abstract image
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