Bioorganic & Medicinal Chemistry Letters

Editorial board ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20
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Lead discovery and chemical biology approaches targeting the ubiquitin proteasome system ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Favour A. Akinjiyan, Seth Carbonneau, Nathan T. Ross Protein degradation is critical for proteostasis, and the addition of polyubiquitin chains to a substrate is necessary for its recognition by the 26S proteasome. Therapeutic intervention in the ubiquitin proteasome system has implications ranging from cancer to neurodegeneration. Novel screening methods and chemical biology tools for targeting E1-activating, E2-conjugating and deubiquitinating enzymes will be discussed in this review. Approaches for targeting E3 ligase-substrate interactions as well as the proteasome will also be covered, with a focus on recently described approaches. Graphical abstract image
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Synthesis, characterization, and cellular localization of a fluorescent probe of the antimalarial 8-aminoquinoline primaquine ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Adonis McQueen, Lynn D. Blake, Ala Azhari, M. Trent Kemp, Tommy W. McGaha, Niranjan Namelikonda, Randy W. Larsen, Roman Manetsch, Dennis E. Kyle Primaquine (PQ) is the only commercially available drug that clears dormant liver stages of malaria and blocks transmission to mosquito vectors. Although an old drug, much remains to be known about the mechanism(s) of action. Herein we develop a fluorescent tagged PQ to discover cellular localization in the human malaria parasite, Plasmodium falciparum. Successful synthesis and characterization of a primaquine-coumarin fluorescent probe (PQCP) demonstrated potency equivalent to the parent drug and the probe was not cytotoxic to HepG2 carcinoma cells. Cellular localization was found primarily in the cytosol of the asexual erythrocytic and gametocyte stages of parasite development. Graphical abstract image
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Discovery of potent antiviral (HSV-1) quinazolinones and initial structure-activity relationship studies ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Carla E. Brown, Tiffany Kong, James McNulty, Leonardo D'Aiuto, Kelly Williamson, Lora McClain, Paolo Piazza, Vishwajit L. Nimgaonkar The discovery of antiviral activity of 2,3-disubstituted quinazolinones, prepared by a one-pot, three-component condensation of isatoic anhydride with amines and aldehydes, against Herpes Simplex Virus (HSV)-1 is reported. Sequential iterative synthesis/antiviral assessment allowed structure-activity relationship (SAR) generation revealing synergistic structural features required for potent anti-HSV-1 activity. The most potent derivatives show greater efficacy than acyclovir against acute HSV-1 infections in neurons and minimal toxicity to the host. Graphical abstract image
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Discovery of novel [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Imran Ali, Jooyun Lee, Areum Go, Gildon Choi, Kwangho Lee Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay. The substantial antiproliferative activities in human cancer cell lines, promising drug-like properties, and the selectivity for the BET family make the lead compound (13) as a novel BRD4 inhibitor motif for anti-cancer drug discovery. Graphical abstract image
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Diverse amide analogs of sulindac for cancer treatment and prevention ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development. Graphical abstract image
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Discovery of highly potent, selective, covalent inhibitors of JAK3 ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): James Kempson, Damaso Ovalle, Junqing Guo, Stephen T. Wrobleski, Shuqun Lin, Steven H. Spergel, James J.-W. Duan, Bin Jiang, Zhonghui Lu, Jagabandhu Das, Bingwei V. Yang, John Hynes, Hong Wu, John Tokarski, John S. Sack, Javed Khan, Gary Schieven, Yuval Blatt, Charu Chaudhry, Luisa M. Salter-Cid, Aberra Fura, Joel C. Barrish, Percy H. Carter, William J. Pitts A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads. Graphical abstract image
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A potent neuromedin U receptor 2-selective alkylated peptide ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Naoki Nishizawa, Yoko Kanematsu-Yamaki, Masaaki Funata, Hiroaki Nagai, Ayako Shimizu, Hisashi Fujita, Junichi Sakamoto, Shiro Takekawa, Taiji Asami Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe19, Nle21, and Arg(Me)24] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU. Graphical abstract image
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Heliotropiumides A and B, new phenolamides with N-carbamoyl putrescine moiety from Heliotropium foertherianum collected in Hawaii and their biological activities ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): You-Sheng Cai, Ariel M. Sarotti, Daniela Gündisch, Tamara P. Kondratyuk, John M. Pezzuto, James Turkson, Shugeng Cao Two new compounds heliotropiumides A (1) and B (2), phenolamides each with an uncommon carbamoyl putrescine moiety, were isolated from the seeds of a naturalized Hawaiian higher plant, Heliotropium foertherianum Diane & Hilger in the borage family, which is widely used for the treatment of ciguatera fish poisoning. The structures of compounds 1 and 2 were characterized based on MS spectroscopic and NMR analysis, and DP4+ calculations. The absolute configuration (AC) of compound 1 was determined by comparison of its optical rotation with those reported in literature. Compound 2 showed inhibition against NF-κB with an IC50 value of 36μM. Graphical abstract image
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Design and synthesis of novel PRMT1 inhibitors and investigation of their binding preferences using molecular modelling ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Hao Yang, Yifan Ouyang, Hao Ma, Hui Cong, Chunlin Zhuang, Wun-Taai Lok, Zhe Wang, Xuanli Zhu, Yutong Sun, Wei Hong, Hao Wang Protein arginine methyltransferase 1 (PRMT1) catalyses the methylation of substrate arginine by transferring the methyl group from SAM (S-adenosyl-l-methionine), which leads to the formation of S-adenosyl homocysteine (SAH) and methylated arginine. We have shown previously that the Asp84 on PRMT1 could be a potential inhibitor binding site. In the current study, 28 compounds were designed and synthesized that were predicted to bind the Asp84 and substrate arginine sites together. Among them, 6 compounds were identified as potential PRMT1 inhibitors, and showed strong inhibitory effects on cancer cell lines, especially HepG2. The most potent PRMT1 inhibitor, compound 13d, was selected for molecular dynamic simulations to investigate binding poses. Based on the free energy calculations and structural analysis, we predicted that the ethylenediamine group would tightly bind to Asp84, and the trifluoromethyl group should occupy part of substrate arginine binding site, which is consistent with our original goal. Our results show for the first time that PRMT1 inhibitors can target the Asp84 binding site, which will be helpful for future drug discovery studies. Graphical abstract image
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gem-Dithioacetylated indole derivatives as novel antileishmanial agents ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Sharad Porwal, Suman Gupta, Prem M.S. Chauhan In this communication we report a serendipitously discovered hybrid molecule 1, combining fragment of 3 (an in vivo active antileishmanial molecule) with H2S donor moiety (known for bimodal behavior of cytoprotection and apoptosis), as antileishmanial agent. Compound 1 suppresses 99.82% parasitemia of L. donovani infected macrophages at 12.5μg/ml without even deforming them (CC50 >100μg/ml). This compound appears cytotoxic for intracellular amastigotes while cytoprotective to host macrophages. The concept can be utilized to develop high therapeutic index NCE (New Chemical Entities) for other macrophage mediated diseases like tuberculosis and cancer. Graphical abstract image
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Evaluation of novel 111In-labeled gonadotropin-releasing hormone peptides for human prostate cancer imaging ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Jingli Xu, Changjian Feng, Yubin Miao The purpose of this study was to evaluate the tumor targeting and imaging properties of novel 111In-labeled gonadotropin-releasing hormone (GnRH) peptides for human prostate cancer. Three new 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-linker-d-Phe-(d-Lys6-GnRH) peptides with different hydrocarbon linkers were designed to evaluate their effects on GnRH receptor binding affinities. The Aoc (aminooctanoic acid) linker was better than βAla (3-aminopropanoic acid) and Aun (aminoundecanoic acid) linkers in retaining strong receptor binding affinity. DOTA-Aoc-d-Phe-(d-Lys6-GnRH) exhibited 6.6±0.1nM GnRH receptor binding affinity. 111In-DOTA-Aoc-d-Phe-(d-Lys6-GnRH) exhibited fast tumor uptake and urinary clearance in DU145 human prostate cancer-xenografted nude mice. The DU145 tumor lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using 111In-DOTA-Aoc-d-Phe-(d-Lys6-GnRH) as an imaging probe, providing an insight into the design of new GnRH peptides for prostate cancer in the future. Graphical abstract image
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Discovery and optimization of oxadiazole-based FLAP inhibitors ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Alessandra Bartolozzi, Asitha Abeywardane, Todd Bosanac, John A. Broadwater, Zhidong Chen, J. Matthew Hutzler, John D. Huber, Peter Nemoto, Alan Olague, Doris Riether, Tom Simpson, Hidenori Takahashi, Lifen Wu, Yunlong Zhang, Renee M. Zindell Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling. Graphical abstract image
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Dodecyl sorbitan ethers as antimicrobials against Gram-positive bacteria ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Dorine Belmessieri, Charlotte Gozlan, Marie-Christine Duclos, Oana Dumitrescu, Gérard Lina, Andreas Redl, Nicolas Duguet, Marc Lemaire A range of amphiphilic sorbitan ethers has been synthesized in two steps from sorbitan following an acetalization/hydrogenolysis sequence. These sorbitan ethers and the acetal intermediates have been evaluated as antimicrobials against Gram-negative and Gram-positive bacteria. No antimicrobial activity was observed for Gram-negative bacteria. However, the compounds bearing a linear dodecyl chain exhibit antimicrobial activity (MIC as low as 8μg/mL) against Gram-positive bacteria such as Listeria monocytogenes, Enterococcus faecalis and Staphylococcus aureus. Encouraged by these preliminary results, dodecyl sorbitan was tested against a range of resistant strains and was found to be active against vancomycin-, methicillin- and daptomycin-resistant strains (MIC=32–64μg/mL). Graphical abstract image
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Anticancer efficacy of p-dodecylaminophenol against high-risk and refractory neuroblastoma cells in vitro and in vivo ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Noriko Takahashi, Shunpei Koyama, Shinya Hasegawa, Masahiro Yamasaki, Masahiko Imai Neuroblastoma is an aggressive and drug-resistant refractory cancer. The human high-risk neuroblastoma cell line, SK-N-AS (non-amplified N-myc) is derived from stromal cells and it is resistant to treatment with retinoic acid (1, RA), which is a chemotherapeutic agent used to induce neuronal cellular differentiation of neuroblastomas. We have developed p-dodecylaminophenol (3, p-DDAP), based on N-(4-hydroxyphenyl)retinamide (2, 4-HPR), a synthetic amide of 1, since 1 and 2 are associated with the side-effect of nyctalopia. In order to evaluate the effects of 3 on high-risk neuroblastomas, we employed SK-N-AS cells as well asa second high-risk human neuroblastoma cell line, IMR-32, which is derived from neuronal cells (amplified N-myc, drug sensitive). Compound 3 suppressed cell growth of SK-N-AS and IMR-32 cells more effectively than 1, 2, p-decylaminophenol (4, p-DAP), N-(4-hydroxyphenyl)dodecananamide (5, 4-HPDD) or N-(4-hydroxyphenyl)decananamide (6, 4-HPD). In SK-N-AS cells, 3 induced G0/G1 arrest and apoptosis to a greater extent than 1 and 2. In IMR-32 cells, 3 induced apoptosis to a similar extent as 1 and 2, potentially by inhibiting N-myc expression. In addition, i.p. administration of 3 suppressed tumor growth in SK-N-AS-implanted mice in vivo. Since 3 showed no effects on blood retinol concentrations, in contrast to reductions following the administration of 2, it exhibited excellent anticancer efficacy against high-risk neuroblastoma SK-N-AS and IMR-32 expressing distinct levels of N-myc. Compound 3 may have potential for clinical use in the treatment of refractory neuroblastoma with reduced side effects. Graphical abstract image
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Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Steven M. Sparks, Paul K. Spearing, Caroline J. Diaz, David J. Cowan, Channa Jayawickreme, Grace Chen, Thomas J. Rimele, Claudia Generaux, Lindsey T. Harston, Shane G. Roller Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774). Graphical abstract image
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d-Amino acid mutation of PMI as potent dual peptide inhibitors of p53-MDM2/MDMX interactions ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Xiang Li, Chao Liu, Si Chen, Honggang Hu, Jiacan Su, Yan Zou According to the previously reported potent dual l-peptide PMI of p53-MDM2/MDMX interactions, a series of d-amino acid mutational PMI analogues, PMI-1-4, with enhanced proteolytic resistence and in vitro tumor cell inhibitory activities were reported, of which Liposome-PMI-1 showed a stronger inhibitory activity against the U87 cell lines than Nutlin-3. This d-amino acid mutation strategy may give a hand for enhancing the potential of peptide drugs. Graphical abstract image
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Design and synthesis of pregnenolone/2-cyanoacryloyl conjugates with dual NF-κB inhibitory and anti-proliferative activities ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Jia-Li Song, Juan Zhang, Chang-Liang Liu, Chao Liu, Kong-Kai Zhu, Fei-Fei Yang, Xi-Gong Liu, João Paulo Figueiró Longo, Luis Alexandre Muehlmann, Ricardo Bentes Azevedo, Yu-Ying Zhang, Yue-Wei Guo, Cheng-Shi Jiang, Hua Zhang Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6–30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27–30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC50 =2.5μM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC50 =6.5–36.2μM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server asa novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy. Graphical abstract image
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Novel xanthone-polyamine conjugates as catalytic inhibitors of human topoisomerase IIα ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Elirosa Minniti, Jo Ann W. Byl, Laura Riccardi, Claudia Sissi, Michela Rosini, Marco De Vivo, Anna Minarini, Neil Osheroff It has been proposed that xanthone derivatives with anticancer potential act as topoisomerase II inhibitors because they interfere with the ability of the enzyme to bind its ATP cofactor. In order to further characterize xanthone mechanism and generate compounds with potential as anticancer drugs, we synthesized a series of derivatives in which position 3 was substituted with different polyamine chains. As determined by DNA relaxation and decatenation assays, the resulting compounds are potent topoisomerase IIα inhibitors. Although xanthone derivatives inhibit topoisomerase IIα-catalyzed ATP hydrolysis, mechanistic studies indicate that they do not act at the ATPase site. Rather, they appear to function by blocking the ability of DNA to stimulate ATP hydrolysis. On the basis of activity, competition, and modeling studies, we propose that xanthones interact with the DNA cleavage/ligation active site of topoisomerase IIα and inhibit the catalytic activity of the enzyme by interfering with the DNA strand passage step. Graphical abstract image
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Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Cheng-Jie Yang, Zi-Long Song, Masuo Goto, Pei-Ling Hsu, Xiao-Shuai Zhang, Qian-Ru Yang, Ying-Qian Liu, Mei-Juan Wang, Susan L. Morris-Natschke, Xiao-Fei Shang, Kuo-Hsiung Lee Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC50, 67.0nM) and 19b (IC50, 99.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives. Graphical abstract image
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Design, synthesis and biological evaluation of benzamide and phenyltetrazole derivatives with amide and urea linkers as BCRP inhibitors ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Nehaben A. Gujarati, Leli Zeng, Pranav Gupta, Zhe-Sheng Chen, Vijaya L. Korlipara Breast cancer resistant protein (BCRP/ABCG2), a 72kDa plasma membrane transporter protein is a member of ABC transporter superfamily. Increased expression of BCRP causes increased efflux and therefore, reduced intracellular accumulation of many unrelated chemotherapeutic agents leading to multidrug resistance (MDR). A series of 31 benzamide and phenyltetrazole derivatives with amide and urea linkers has been synthesized to serve as potential BCRP inhibitors in order to overcome BCRP-mediated MDR. The target derivatives were tested for their cytotoxicity and reversal effects in human non-small cell lung cancer cell line H460 and mitoxantrone resistant cell line H460/MX20 using the MTT assay. In the benzamide series, compounds 6 and 7 exhibited a fold resistance of 1.51 and 1.62, respectively at 10µM concentration which is similar to that of FTC, a known BCRP inhibitor. Compounds 27 and 31 were the most potent analogues in the phenyltetrazole series with amide linker with a fold resistance of 1.39 and 1.32, respectively at 10µM concentration. For the phenyltetrazole series with urea linker, 38 exhibited a fold resistance of 1.51 which is similar than that of FTC and is the most potent compound in this series. The target compounds did not exhibit reversal effect in P-gp overexpressing resistant cell line SW620/Ad300 suggesting that they are selective BCRP inhibitors. Graphical abstract image
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A mimetic of the mSin3-binding helix of NRSF/REST ameliorates abnormal pain behavior in chronic pain models ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Hiroshi Ueda, Jun-ichi Kurita, Hiroyuki Neyama, Yuuka Hirao, Hiroyuki Kouji, Tadashi Mishina, Masaji Kasai, Hirofumi Nakano, Atsushi Yoshimori, Yoshifumi Nishimura The neuron-restrictive silencing factor NRSF/REST binds to neuron-restrictive silencing elements in neuronal genes and recruits corepressors such as mSin3 to inhibit epigenetically neuronal gene expression. Because dysregulation of NRSF/REST is related to neuropathic pain, here, we have designed compounds to target neuropathic pain based on the mSin3-binding helix structure of NRSF/REST and examined their ability to bind to mSin3 by NMR. One compound, mS-11, binds strongly to mSin3 with a binding mode similar to that of NRSF/REST. In a mouse model of neuropathic pain, mS-11 was found to ameliorate abnormal pain behavior and to reverse lost peripheral morphine analgesia. Furthermore, even in the less well epigenetically defined case of fibromyalgia, mS-11 ameliorated symptoms in a mouse model, suggesting that fibromyalgia is related to the dysfunction of NRSF/REST. Taken together, these findings show that the chemically optimized mimetic mS-11 can inhibit mSin3-NRSF/REST binding and successfully reverse lost peripheral and central morphine analgesia in mouse models of pain. Graphical abstract image
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Synthesis and biological evaluation of peptide-derived TSLP inhibitors ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Seonghu Park, Yeeun Park, Sang-Hyun Son, Kiho Lee, Yong Woo Jung, Ki Yong Lee, Young Ho Jeon, Youngjoo Byun Thymic stromal lymphopoietin (TSLP) is a type II cytokine which is associated with most inflammatory allergic disorders in humans. It is produced mainly by epithelial cells with important role in the development of chronic inflammatory diseases by activating T-helper cell type-2 (TH2) pathways. In this study, a total of 16 peptides were prepared by solid phase peptide synthesis based on amino acid sequences of the interface between TSLP and TSLP receptor. Their TSLP inhibition activities were determined by ELISA assay. Among them, three peptides (6−8) exhibited >50% inhibition at concentration of 0.3mM. They can be used as hit compounds for developing peptide-based TSLP inhibitors. Graphical abstract image
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Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Jihye Lee, Yijiang Shi, Mario Vega, Yonghui Yang, Joseph Gera, Michael E. Jung, Alan Lichtenstein DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein–protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast. This therapeutic (compound B) also prevented DEPTOR/mTOR binding in MM cells and was selectively cytotoxic to MM cells. We now present a structure–activity relationship (SAR) study around this compound as a follow-up report of this previous work. This study has led to the discovery of five new leads – namely compounds 3g, 3k, 4d, 4e and 4g – all of which have anti-myeloma cytotoxic properties superior to compound B. Due to their targeting of DEPTOR, these compounds activate mTORC1 and selectively induce MM cell apoptosis and cell cycle arrest. Graphical abstract image
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A structural investigation of FISLE-412, a peptidomimetic compound derived from saquinavir that targets lupus autoantibodies ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Mingzhu He, Kai Fan Cheng, Sonya VanPatten, Ona Bloom, Betty Diamond, Yousef Al-Abed FISLE-412 is the first reported small molecule peptidomimetic that neutralizes anti-dsDNA autoantibodies associated with systemic lupus erythematosus (SLE) pathogenesis. FISLE-412 is a complex small molecule that involves a challenging synthesis scheme, but has attractive pharmacological activities as a potential small molecule therapeutic in lupus. Therefore, we initiated a Structure–Activity Relationship study to simplify the complexity of FISLE-412. We synthesized a small library of mimetopes around the FISLE-412 structure and identified several analogues which could neutralize anti-DNA lupus antibodies in vitro and ex vivo. Our strategies reduced the structural complexity of FISLE-412 and provide important information that may guide development of potential autoantibody-targeted lupus therapeutics. Graphical abstract image
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Discovery of N-substituted 7-azaindoles as PIM1 kinase inhibitors – Part I ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Claude Barberis, Neil Moorcroft, Chris Arendt, Mikhail Levit, Sandra Moreno-Mazza, Joseph Batchelor, Ingrid Mechin, Tahir Majid Novel N-substituted azaindoles have been discovered as PIM1 inhibitors. X-ray structures have played a significant role in orienting the chemistry effort in the initial phase of hit confirmation. Disclosure of an unconventional binding mode for 1 and 2, as demonstrated by X-ray crystallography, is presented and was an important factor in selecting and advancing a lead series. Graphical abstract image
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Discovery of N-substituted 7-azaindoles as Pan-PIM kinase inhibitors – Lead series identification – Part II ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Claude Barberis, Neil Moorcroft, James Pribish, Elina Tserlin, Alexandre Gross, Mark Czekaj, Matthieu Barrague, Paul Erdman, Tahir Majid, Joseph Batchelor, Mikhail Levit, Andrew Hebert, Liduo Shen, Sandra Moreno-Mazza, Anlai Wang N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate. Graphical abstract image
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Design, synthesis and biological evaluation of 8-substituted-6-hydrazonoindolo[2,1-b]quinazolin-12(6H)-one scaffolds as potential cytotoxic agents: IDO-1 targeting molecular docking studies ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Ramu Guda, Rajashekar Korra, Siripireddy Balaji, Rambabu Palabindela, Rakesh Eerla, Harikiran Lingabathula, Narsimha Reddy Yellu, Girijesh Kumar, Mamatha Kasula Herein, we have reported the synthesis of 18 novel 8-substituted tryptanthrin analogues based on our earlier work. All these tryptanthrin analogues were well characterized by 1H & 13C NMR, FT-IR, Mass Spectrometry and Elemental Analysis. All these 8-substituted analogues were screened for their anti-oxidant activity by DPPH radical scavenging assay. Out of all the tested compounds, T11 , T12 , T17 and T18 showed potent anti-oxidant activity. The anti-cancer activity have been performed by using MTT assay protocol and their results depicts that compounds having the 4-pyridyl or 4-carboxyphenyl substituents at the 8th position of the tryptanthrin framework are found to be the most promising cytotoxic agent against A549, MCF-7 and HeLa human cancer cell lines compared to others as well as with the standard drug cisplatin. Moreover, the comparative molecular docking studies against the three protein receptors IDO1, EGFR and HER2 strongly suggested that IDO1 is the best target protein, which exhibits lowest binding energies of −11.73 and −11.61kcalmol−1 for T11 and T12 scaffolds, respectively towards the in vitro anti-cancer activity. Graphical abstract image
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Synthesis and evaluation of the NSCLC anti-cancer activity and physical properties of 4-aryl-N-phenylpyrimidin-2-amines ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Borvornwat Toviwek, Praphasri Suphakun, Kiattawee Choowongkomon, Supa Hannongbua, M. Paul Gleeson Reported herein are efforts to profile 4-aryl-N-phenylpyrimidin-2-amines in terms of their anti-cancer activity towards non small-cell lung carcinoma (NSCLC) cells. We have synthesized new 4-aryl-N-phenylpyrimidin-2-amines and assessed them in terms of their cytotoxicity (A549, NCI-H187, MCF7, Vero & KB) and physicochemical properties (logD7.4 and solubility). 13f and 13c demonstrated potent anti-cancer activity in A549 cells (0.2µM), compared to 0.4μM for the NSCLC drug Doxorubicin. 13f also displayed low experimental logD7.4 (2.9) and the best solubility (∼40μM). Compounds 13b and 13d showed the best balance of A549 anti-cancer activity and selectivity. 13g showed good activity and selectivity comparable with the anti-cancer drug Doxorubicin. Graphical abstract image
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Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1 ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Daniel P. Mould, Ulf Bremberg, Allan M. Jordan, Matthis Geitmann, Alison E. McGonagle, Tim C.P. Somervaille, Gary J. Spencer, Donald J. Ogilvie As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a K d value of 22nM and a biochemical IC50 of 57nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping asa method to develop structurally diverse, potent inhibitors of LSD1. Graphical abstract image
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Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis, functional evaluation and molecular modeling study ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Sherihan El-sayed, Kamel Metwally, Abdalla A. El-Shanawani, Lobna M. Abdel-Aziz, Ahmed A. El-Rashedy, Mahmoud E.S. Soliman, Luca Quattrini, Vito Coviello, Concettina la Motta A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors. Graphical abstract image
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Natural neuro-inflammatory inhibitors from Caragana turfanensis ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Yan Song, Lan Pan, Wenjie Li, Yingying Si, Di Zhou, Chengjian Zheng, Xiaofang Hao, Xinyue Jia, Yuemei Jia, Minghui Shi, Xiaoguang Jia, Ning Li, Yue Hou Because of the critical role of over-activated microglia in the progress of neurodegenerative diseases, it has been selected as a potential therapeutic target for drug discovery. In order to find natural neuroinflammatory inhibitors, we carried out a bioactivity-oriented phytochemical research of Caragana turfanensis Kom. (Krassn.), which is a folk medicine widely distributed in Xinjiang. As a result, a new coumarin lactone caraganolide A (1) and 35 known components were characterized from the effective extract of C. turfanensis. Furthermore, their anti-neuroinflammatory effects were evaluated in LPS-induced BV2 microglial cells using Griess assay to determine the release of nitric oxide (NO). Compounds 1, 2, 4–6, 9, 13–15, 20, 29 and 30 exhibited significant inhibitory activities and no obvious cytotoxicities were observed at their effective concentrations. It is noteworthy, the new compound caraganolide A (1) (IC50 1.01±1.57µM) and 3′,7,8-trihydroxy-4′-methoxyisoflavone (5) (IC506.87±2.23µM) exhibited more excellent action than that of positive control minocycline (IC50 9.07±0.86μM). Graphical abstract image
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Structure-activity relationship study of β-oxidation resistant indole-based 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) receptor antagonists ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Qiuji Ye, Shishir Chourey, Rui Wang, Nagendra Reddy Chintam, Sylvie Gravel, William S. Powell, Joshua Rokach 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is formed from 5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) by the 5-lipoxygenase (5-LO) pathway under conditions associated with oxidative stress. 5-Oxo-ETE is an important pro-inflammatory mediator, which stimulates the migration of eosinophils via a selective G-protein coupled receptor, known as the OXE receptor (OXE-R). Previously, we designed and synthesized structural mimics of 5-oxo-ETE such as 1 using an indole scaffold. In the present work, we added various substituents at C-3 of this moiety to block potential β-oxidation of the 5-oxo-valerate side chain, and investigated the structure-activity relationships of the resulting novel β-oxidation-resistant antagonists. Cyclopropyl and cyclobutyl substituents were well tolerated in this position, but were less potent as the highly active 3S-methyl compound. It seems likely that 3-alkyl substituents can affect the conformation of the 5-oxovalerate side chain containing the critical keto and carboxyl groups, thereby affecting interaction with the OXE-receptor. Graphical abstract image
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Anti-fatigue activity of a Lachnum polysaccharide and its carboxymethylated derivative in mice ()
Publication date: 15 October 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 20 Author(s): Maheen Mahwish Surhio, Yufen Wang, Shi Fang, Jinglei Li, Ming Ye The present study was designed to evaluate the anti-fatigue activity of an exopolysaccharide LEP-1b and its carboxymethylated derivative CLEP-1b from a Lachnum sp. Carboxymethylation was confirmed through FT-IR and 13C NMR spectroscopies, which showed that the (–CH2COOH) group was attached to an oxygen (O) atom of the hydroxyl group on (C-3) of LEP-1b. Each treatment group LEP-1b and CLEP-1b at doses (50, 100, 200mg/kg, respectively) ameliorated physical fatigue and extended exhaustive swimming time in mice. Results of the fatigue related biochemical markers showed that LEP-1b and CLEP-1b at doses (50, 100, 200mg/kg, respectively) increased the content of hepatic glycogen and decreased the level of serum urea nitrogen and lactic acid. Additionally, LEP-1b and CLEP-1b enhanced the antioxidant enzymes’ activities and reduced the lipid peroxidation. Moreover, results revealed that CLEP-1b had higher anti-fatigue activity than LEP-1b at same doses but without statistical significance, especially CLEP-1b (200mg/kg) had strong anti-fatigue effects. Therefore, LEP-1b and CLEP-1b can potentially be exploited as a kind of healthcare compound to combat fatigue and to boost physical strength. Graphical abstract image
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Novel potentially antifungal hybrids of 5-flucytosine and fluconazole: Design, synthesis and bioactive evaluation ()
Publication date: Available online 13 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Xian-Fu Fang, Di Li, Vijai Kumar Reddy Tangadanchu, Lavanya Gopala, Wei-Wei Gao, Cheng-He Zhou A series of novel potentially antifungal hybrids of 5-flucytosine and fluconazole were designed, synthesized and characterized by 1H NMR, 13C NMR, IR and HRMS spectra. Bioactive assay manifested that some prepared compounds showed moderate to good antifungal activities in comparison with fluconazole and 5-flucytosine. Remarkably, the 3,4-dichlorobenzyl hybrid 7h could inhibit the growth of C. albicans ATCC 90023 and clinical resistant strain C. albicans with MIC values of 0.008 and 0.02 mM, respectively. The active molecule 7h could not only rapidly kill C. albicans but also efficiently permeate membrane of C. albicans. Molecular docking study revealed that compound 7h could interact with the active site of CACYP51 through hydrogen bond. Quantum chemical studies were also performed to explain the high antifungal activity. Further preliminary mechanism research suggested that molecule 7h could intercalate into calf thymus DNA to form a steady supramolecular complex, which might block DNA replication to exert the powerful bioactivities. Graphical abstract image
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Design, Synthesis, and Biological Evaluation of Pyrrolobenzodiazepine-containing Hypoxia-activated Prodrugs ()
Publication date: Available online 13 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Peter S. Dragovich, Fabio Broccatelli, Jinhua Chen, Peter Fan, Hoa Le, Weiguang Mao, Thomas H. Pillow, Andrew G. Polson, John Wai, Zijin Xu, Hui Yao, Donglu Zhang The ability of various pyrrolobenzodiazepine(PBD)-containing cytotoxic compounds to function as hypoxia-activated prodrugs was assessed. These molecules incorporated a 1-methyl-2-nitro-1H-imidazole hypoxia-activated trigger (present in the clinically evaluated compound TH-302) in a manner that masked a reactive imine moiety required for cytotoxic activity. Incubation of the prodrugs with cytochrome P450-reductase under normoxic and hypoxic conditions revealed that some, but not all, were efficient substrates for the enzyme. In these experiments, prodrugs derived from PBD-monomers underwent rapid conversion to the parent cytotoxic compounds under low-oxygen conditions while related PBD-dimers did not. The ability of a given prodrug to function as an efficient cytochrome P450-reductase substrate correlated with the ratio of cytotoxic potencies measured for the compound against NCI460 cells under normoxic and hypoxic conditions. Graphical abstract image
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Quantitative structure–activity relationship of substituted imidazothiadiazoles for their binding against the ecdysone receptor of Sf-9 cells ()
Publication date: Available online 13 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Taiyo Yokoi, Yoshiaki Nakagawa, Hisashi Miyagawa Imidazothiadiazoles (ITDs) are a class of potent nonsteroidal ecdysone agonists with larvicidal activity. Previously, we performed the Hansch–Fujita type of quantitative structure–activity relationship (QSAR) analysis for ITD analogs (Yokoi et al., Pestic. Biochem. Physiol. 2015, 120, 40–50). The activity was reasonably explained by hydrophobicity and electronegativity of substituents on the imidazothiadiazole ring system. However, the limited data points (n = 8) hampered the examination of other physicochemical parameters. In the present study, we expanded the library of ITD congeners and evaluated their receptor-binding affinity using intact Sf-9 cells. The QSAR analysis for the expanded set revealed the significance of the third physicochemical parameter, the negative steric effect for long substituents. We also evaluated the larvicidal activity of the synthesized compounds against Spodoptera litura; however, it was not correlated to the binding affinity. The results obtained here suggests that the pharmacokinetic properties must be improved to enhance the larvicidal activity of ITDs. Graphical abstract image
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Examination of α-exosite inhibitors against Botulinum neurotoxin A protease through structure-activity relationship studies of chicoric acid ()
Publication date: Available online 12 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Song Xue, Hajime Seki, Marek Remes, Peter Šilhár, Kim Janda Botulinum neurotoxins (BoNT) are among the most toxic known substances and currently there are no effective treatments for intraneuronal BoNT intoxication. Chicoric acid (ChA) was previously reported as a BoNT/A inhibitor that binds to the enzyme’s α-exosite. Herein, we report the synthesis and structure-activity relationships (SARs) of a series of ChA derivatives, which revealed essential binding interactions between ChA and BoNT/A. Moreover, several ChA-based inhibitors with improved potency against the BoNT/A were discovered. Graphical abstract image
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Synthesis and anti-HCV activity of a series of β-D-2’-deoxy-2’-dibromo nucleosides and their corresponding phosphoramidate prodrugs ()
Publication date: Available online 12 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Zhe Chen, Bryan D. Cox, Ethel C. Garnier-Amblard, Tamara R. McBrayer, Steven J. Coats, Raymond F. Schinazi, Franck Amblard Several β-D-2’-deoxy-2’-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2’-deoxy,2’-dibromo substituted U, C, G and A nucleosides 10a-d and their corresponding phosphoramidate prodrugs 13a-d. The synthesized nucleosides 10a-d and prodrugs 13a-d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC50 = 1.5 ± 0.8 µM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5’-triphosphate formed from 13a and related 2’-modified nucleotides are discussed. Graphical abstract image
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Metastatic melanoma imaging using a novel Tc-99m-labeled lactam-cyclized alpha-MSH peptide ()
Publication date: Available online 12 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Liqin Liu, Jingli Xu, Jianquan Yang, Changjian Feng, Yubin Miao The purpose of this study was to determine the metastatic melanoma imaging property of 99mTc(EDDA)-HYNIC-Aoc-Nle-CycMSHhex {hydrazinonicotinamide-8-aminooctanoic acid-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2}. HYNIC-Aoc-Nle-CycMSHhex was synthesized using fluorenylmethyloxy carbonyl (Fmoc) chemistry. The IC50 value of HYNIC-Aoc-Nle-CycMSHhex was 0.78 ± 0.13 nM for B16/F10 melanoma cells. 99mTc(EDDA)-HYNIC-Aoc-Nle-CycMSHhex displayed significantly higher uptake (14.26 ± 2.74 and 10.45 ± 2.31% ID/g) in B16/F10 metastatic melanoma-bearing lung than that in normal lung (0.90 ± 0.15 and 0.53 ± 0.14% ID/g) at 2 and 4 h post-injection, respectively. B16/F10 pulmonary metastatic melanoma lesions were clearly visualized by SPECT/CT using 99mTc(EDDA)-HYNIC-Aoc-Nle-CycMSHhex as an imaging probe at 2 h post-injection, underscoring its potential as an imaging probe for metastatic melanoma detection. Graphical abstract image
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Design and synthesis of a novel series of (1'S,2R,4'S)-3H-4'-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,2'-bicyclo[2.2.2]octanes] with high affinity for the α7 neuronal nicotinic receptor ()
Publication date: Available online 10 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): James Cook, F. Christopher Zusi, Matthew D. Hill, Haiquan Fang, Bradley Pearce, Hyunsoo Park, Lizbeth Gallagher, Ivar M. McDonald, Linda Bristow, John E. Macor, Richard E. Olson We describe an efficient and convergent synthesis of a series of (1'S,2R,4'S)-3H-4'-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,2'-bicyclo[2.2.2]octanes] displaying potency for the α7 nicotinic acetylcholine receptor (nAChR) and good selectivity vs. the related 5-HT3A receptor. Graphical abstract image
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Preparation of 5’-Deoxy-5’-amino-5’-C-methyl adenosine Derivatives and Their Activity against DOT1L ()
Publication date: Available online 10 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Tongchao Liu, Wuchen Xie, Cong Li, Huanming Ren, Yudong Mao, Guohua Chen, Maosheng Cheng, Dongmei Zhao, Jingkang Shen, Jia Li, Yubo Zhou, Bing Xiong, Yue-Lei Chen From a readily available 5-C-Me ribofuranoside, we have realized a reliable route to valuable 5’-deoxy-5’-amino-5’-C-methyl adenosine derivatives at gram scale with confirmed stereochemistry. These adenosine derivatives are useful starting materials for the preparation of 5’-deoxy-5’-amino-5’-C-methyl adenosine derivatives with higher complexity. From one of the new adenosine derivatives, some 5’-deoxy-5’-amino-5’-C-methyl adenosine DOT1L inhibitors were preparaed in several steps. Data from DOT1L assay indicated that additional 5’-C-Me group improved the enzyme inhibitory activity. Graphical abstract image
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Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping ()
Publication date: Available online 9 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Madeline F. Long, Julie L. Engers, Sichen Chang, Xiaoyan Zhan, Rebecca L. Weiner, Vincent B. Luscombe, Alice L. Rodriguez, Hyekyung P. Cho, Colleen M. Niswender, Thomas M. Bridges, P. Jeffrey Conn, Darren W. Engers, Craig W. Lindsley This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M4 PAM activity in most M4 PAMs to date, within the thieno[2,3-b]pyridine core, as the β-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core. Graphical abstract image
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Enantioselective inhibitory abilities of enantiomers of notoamides against RANKL-induced formation of multinuclear osteoclasts ()
Publication date: Available online 9 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Hikaru Kato, Aika Kai, Tetsuro Kawabata, James D. Sunderhaus, Timothy J. McAfoos, Jennifer M. Finefield, Yukihiko Sugimoto, Robert M. Williams, Sachiko Tsukamoto The marine-derived Aspergillus protuberus MF297-2 and the terrestrial A. amoenus NRRL 35600 produce enantiomeric prenylated indole alkaloids. Investigation of biological activities of the natural and synthetic derivatives revealed that (−)-enantiomers of notoamides A and B, 6-epi-notoamide T, and stephacidin A inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)–induced osteoclastogenic differentiation of murine RAW264 cells more strongly than their respective (+)-enantiomers. Among them, (−)-6-epi-notoamide T was the most potent inhibitor with an IC50 value of 1.7μM. Graphical abstract image
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Antibacterial activities of viriditoxin congeners and synthetic analogues against fish pathogens ()
Publication date: Available online 9 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Tae Hwan Noh, Liu Sen, Jongki Hong, Joon-Hee Lee, Hyung Ryong Moon, Jee H. Jung Viriditoxin is a fungal secondary metabolite of the fungus Paecilomyces variotii derived from the inner tissues of the giant jellyfish Nemopilema nomurai. Viriditoxin exhibits antibacterial activity against Streptococcus iniae and Streptococcus parauberis, which are major pathogens of aqua cultured fish. Viriditoxin induced abnormal cell morphologies in the fish pathogens S. iniae and S. parauberis, presumably by inhibiting FtsZ polymerization as was previously observed in Escherichia coli. Synthetic analogues of viriditoxin, designed based on docking simulation results to FtsZ of Staphylococcus aureus, were prepared and compared with viriditoxin for antibacterial activity. Reconstitution of free hydroxyl or carboxyl groups of the methoxyl or methyl ester groups of viriditoxin led to significant reduction of antibacterial activity, implying that the natural molecule is optimized for antibacterial activity to deter bacteria potentially harmful to Paecilomyces. Graphical abstract image
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Development of a peptide-based inducer of protein degradation targeting NOTCH1 ()
Publication date: Available online 7 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Nobumichi Ohoka, Takashi Misawa, Masaaki Kurihara, Yosuke Demizu, Mikihiko Naito We previously developed a protein knockdown system by small-molecule hybrid compounds named SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers). Here we report a peptide-based protein knockdown system for inducing degradation of a transcriptional factor NOTCH1. The molecules designed were composed of two biologically active scaffolds: a peptide that binds to the surface of the target protein NOTCH1 and a small-molecule MV1 that binds to the E3 ubiquitin ligase inhibitor of apoptosis protein (IAP), which are expected to cross-link these proteins in cells. Hybrid molecules specifically induced the degradation of the NOTCH1 protein by the proteasome. This system could be a useful method to develop various degradation inducers against a large number of proteins to which small-molecule ligands have not been found. Graphical abstract image
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Identification of pyrrolo[2,3-d]pyrimidines as potent HCK and FLT3-ITD dual inhibitors ()
Publication date: Available online 7 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Yasuko Koda, Ko Kikuzato, Junko Mikuni, Akiko Tanaka, Hitomi Yuki, Teruki Honma, Yuri Tomabechi, Mutsuko Kukimoto-Niino, Mikako Shirouzu, Fumiyuki Shirai, Hiroo Koyama A series of novel pyrrolo[2,3-d]pyrimidines were synthesized by introducing 15 different amino acids to 7-cyclohexyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. Compounds with potent activities against HCK and FLT3-ITD were evaluated in viability studies with acute myeloid leukemia cell line MV4-11. Our structure activity relationship analyses lead to the identification of compound 31, which exhibited potent HCK and FLT3-ITD inhibition and activity against the MV4-11 cell line. Graphical abstract image
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Design and synthesis of novel nitrogen mustard-evodiamine hybrids with selective antiproliferative activity ()
Publication date: Available online 7 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Xu Hu, Yan Wang, Jingjing Xue, Tong Han, Runwei Jiao, Zhanlin Li, Weiwei Liu, Fanxing Xu, Huiming Hua, Dahong Li A series of novel nitrogen mustard-evodiamine hybrids were synthesized and evaluated for their antitproliferative properties. The antiproliferative activities of 10a–d, 11a–d, and 12a–d against four different kinds of human cancer cell lines (PC-3, HepG2, THP-1 and HL-60) and human normal peripheral blood mononuclear cells (PBMC) were determined. The results showed that all the target hybrid compounds exhibited antiproliferative activities against tested human tumor cell lines to some extent and no antiproliferative activities (>200 μM) against human normal PBMC cells. The antiproliferative selectivity between tumorous and normal cells was very useful for further antitumor drug development. Among the target compounds, 12c showed the strongest cytotoxicity against two tumor cell lines (THP-1 and HL-60) with IC50 values of 4.05 μM and 0.50 μM, respectively, and selected for further mechanism study in HL-60 cells. The results showed that 12c could induce HL-60 cells apoptosis and arrest at G2 phase at low sub-micromolar concentrations via mitochondria-related pathways. Graphical abstract image
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Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia ()
Publication date: Available online 7 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Mingxing Teng, Wentao Wu, Zhixiang Li, Guangwen Yang, Jian Qin, Yikai Wang, Zhijing Hu, Haiheng Dong, Lijuan Hou, Guoping Hu, Liang Shen, Yang Zhang, Jian Li, Shuhui Chen, Jingwei Tian, Liang Ye, Jianzhao Zhang, Hongbo Wang hNav1.7 receives a lot of attention owing to its attractive mechanism of action in pain processing pathway. We have previously reported our design of a novel series of tetrahydropyridine analogues towards hNav1.7 selective inhibitors. Herein, we disclose further efforts to the optimization of hit compound (−)-6, which led to the identification of aminocyclohexene analogues (−)-9 and (−)-17 with good potency, high selectivity, and minimal CYP inhibition. Both compounds (−)-9 and (−)-17 demonstrated improved pharmacokinetic profiles in rats, and robust efficacy in rat formalin-induced nociception and spinal nerve ligation (SNL) models. Graphical abstract image
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Enhanced Radical Scavenging Activity of a Procyanidin B3 Analogue Comprised of a Dimer of Planar Catechin ()
Publication date: Available online 6 October 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Mirei Mizuno, Ikuo Nakanishi, Ken-ichiro Matsumoto, Kiyoshi Fukuhara Proanthocyanidins are oligomers of catechins that exhibit potent antioxidative activity and inhibit binding of oxidized low-density lipoprotein OxLDL to the lectin-like oxidized LDL receptor (LOX-1), which is involved in the onset and development of arteriosclerosis. Previous attempts aimed at developing proanthocyanidin derivatives with more potent antioxidative activity and stronger inhibition for LOX-1 demonstrated the synthesis of a novel proanthocyanidin derivative (1), in which the geometry of one catechin molecule in procyanidin B3 was constrained to a planar orientation. The radical scavenging activity of 1 was 1.9-fold higher than that of procyanidin B3. Herein, we synthesized another procyanidin B3 analogue (2), in which the geometries of both catechin molecules in the dimer were constrained to planar orientations. The radical scavenging activity of 2 was 1.5-fold higher than that of 1, suggesting that 2 may be a more effective candidate than 1 as a therapeutic agent to reduce oxidative stress induced in arteriosclerosis or related cerebrovascular disease. Graphical abstract image
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