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The Journal of Thoracic and Cardiovascular Surgery
1 May 2018
Editorial Board
Publication date: 1 May 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8

1 May 2018
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/1b3a/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
1 May 2018
Sulfoximines as potent ROR
1 May 2018
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
1 May 2018
Synthesis and investigations into the anticancer and antibacterial activity studies of
1 May 2018
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.

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1 May 2018
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 (14) and adamantane-imine (58) CQ conjugates. All conjugates showed limited cytotoxicity against CHO cells (IC50
1 May 2018
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
1 May 2018
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.

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1 May 2018
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
1 May 2018
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
1 May 2018
Design, synthesis, and evaluation of simple phenol amides as ERR
1 May 2018
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
1 May 2018
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, 6a6f and 6h6i showed promising anticonvulsant activities in MES model, while 6f and 6g represented protection against seizures at doses of 100
1 May 2018
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 7k7n 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.

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1 May 2018
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).

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1 May 2018
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
1 May 2018
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
1 May 2018
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
1 May 2018
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.

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1 May 2018
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.

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1 May 2018
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.

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1 May 2018
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
1 May 2018
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.

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1 May 2018
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
1 May 2018
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.

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1 May 2018
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.

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1 May 2018
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.

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1 May 2018
Synthesis of novel isoxazoline-containing podophyllotoxin/2
1 May 2018
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, Ane
1 May 2018
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.

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1 May 2018
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Publication date: 1 May 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8

1 May 2018
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Publication date: 1 May 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8

Available online 19 April 2018
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Publication date: 1 May 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 8

Available online 19 April 2018
Development of piperazine-based hydroxamic acid inhibitors against falcilysin, an essential malarial protease
Publication date: Available online 19 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Jeff P. Chance, Hannah Fejzic, Obiel Hernandez, Eva S. Istvan, Armann Andaya, Nikolay Maslov, Ruby Aispuro, Teodulo Crisanto, Huyen Nguyen, Brian Vidal, Whitney Serrano, Bradley Kuwahara, Corey Pugne Andanado, Daniel E. Goldberg, Jeremy P. Mallari The human parasite Plasmodium falciparum kills an estimated 445,000 people a year, with the most fatalities occurring in African children. Previous studies identified falcilysin (FLN) as a malarial metalloprotease essential for parasite development in the human host. Despite its essentiality, the biological roles of this protease are not well understood. Here we describe the optimization of a piperazine-based hydroxamic acid scaffold to develop the first reported inhibitors of FLN. Inhibitors were tested against cultured parasites, and parasiticidal activity correlated with potency against FLN. This suggests these compounds kill P. falciparum by blocking FLN, and that FLN is a druggable target. These compounds represent an important step towards validating FLN as a therapeutic target and towards the development of chemical tools to investigate the function of this protease.

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Available online 19 April 2018
A constraint scaffold enhances affinity of a bivalent N-acetylglucosamine ligand against wheat germ agglutinin
Publication date: Available online 19 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Takahiko Matsushita, Koji Tsuchibuchi, Tetsuo Koyama, Ken Hatano, Koji Matsuoka Bivalent glycoconjugates have a minimal valence with avidity potential on protein-carbohydrate interactions as well as simplicity of chemical structures enabling simple synthesis with low cost. Understanding the way to maximize the affinities of bivalent glycoconjugates is important for the development of cost-effective tools for therapeutic and diagnostic research. However, there has been little discussion about the effects of constraints imposed from ligand scaffolds on the binding abilities. We synthesized three kinds of biantennary N-acetylglucosamine glycosides with different scaffolds using isobutenyl bis(propargyl) ether as a common scaffold precursor. Decoration of the scaffold branches with GlcNAc moieties through copper-catalyzed azide-alkyne cycloaddition and grafting of the alkenyl focal point to another bivalent biotin dendron through thiol-ene and nucleophilic substitution reactions were successfully carried out in an orthogonal manner. The association constants of the ligands against wheat germ agglutinin were determined by a fluorometric titration assay. A bivalent biotin counterpart provided higher affinity than an isobutyl scaffold, whereas an isobutenyl scaffold yielded more enhancement than a bivalent biotin counterpart. The present work suggested that the constraint and steric bulk of ligand scaffolds are possible factors for improving binding properties of glycoconjugates against lectins or proteins.

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Available online 19 April 2018
Inducing Protein-Protein interactions with Molecular Glues
Publication date: Available online 19 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Ye Che, Adam M. Gilbert, Veerabahu Shanmugasundaram, Mark C. Noe The drugable proteome is limited by the number of functional binding sites that can bind small molecules and respond with a therapeutic effect. Orthosteric and allosteric modulators of enzyme function or receptor signaling are well-established mechanisms of drug action. Drugs that perturb protein-protein interactions have only recently been launched. This approach is more difficult due to the extensive contact surfaces that must be perturbed antagonistically. Compounds that promote novel protein-protein interactions promise to dramatically expand opportunities for therapeutic intervention. This approach is precedented with natural products (rapamycin, FK506, sanglifehrin A), synthetic small molecules (thalidomide and IMiD derivatives) and indisulam analogues.

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Available online 18 April 2018
Targeting Lysine Specific Demethylase 4A (KDM4A) Tandem TUDOR Domain – A Fragment Based Approach.
Publication date: Available online 19 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Anup K. Upadhyay, Russell A. Judge, Leiming Li, Ron Pithawalla, Justin Simanis, Pierre M. Bodelle, Violeta L. Marin, Rodger F. Henry, Andrew M. Petros, Chaohong Sun The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A TUDOR domain in complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem TUDOR domain.

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Available online 17 April 2018
Hit Discovery of Mycobacterium tuberculosis Inosine 5
Available online 17 April 2018
1,2,4-Triazolsulfone: A Novel Isosteric Replacement of Acylsulfonamides in the Context of NaV1.7 Inhibition
Publication date: Available online 17 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Alessandro A. Boezio, Kristin Andrews, Christiane Boezio, Margaret Chu-Moyer, Katrina W. Copeland, Erin F. DiMauro, Robert S. Foti, Robert T. Fremeau, Hua Gao, Stephanie Geuns-Meyer, Russell F. Graceffa, Hakan Gunaydin, Hongbing Huang, Daniel S. La, Joseph Ligutti, Bryan D. Moyer, Emily A. Peterson, Violeta Yu, Matthew M. Weiss Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit NaV1.7 and demonstrate high levels of selectivity over other NaV isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective NaV1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over NaV1.5 and favorable pharmacokinetics in rodents.

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Available online 17 April 2018
Antiviral properties and interaction of novel chalcone derivatives containing a purine and benzenesulfonamide moiety
Publication date: Available online 17 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Dagui Zhou, Dandan Xie, Fangcheng He, Baoan Song, Deyu Hu A new concise and facile method was explored to synthesize a series of novel chalcone derivatives containing a purine and benzenesulfonamide moiety and their antiviral properties were evaluated against TMV and CMV. Biological assays indicated that several of the derivatives exhibited significant anti-TMV and anti-CMV activities in vivo. In particular, compound d2 displayed excellent inactivating activity against TMV, with the EC50 value of 51.65
Available online 17 April 2018
2-Methylacrylamide as a Bioisoster of Thiourea Group for 1,3-Dibenzylthioureido TRPV1 Receptor Antagonists
Publication date: Available online 17 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Seol Rin Park, Juhyun Kim, Sun Young Lee, Young-Ho Park, Hee-Doo Kim In order to replace thiourea group with the more drug-like moiety for 1,3-dibenzylthioureas having TRPV1 antagonist activity, we introduced a set of functional groups between the two aromatic rings based on bioisosteric replacement. The synthesized bioisosteres of 1,3-dibenzylthioureas were tested for their antagonist activities on TRPV1 by 45Ca2+-influx assay using neonatal rat cultured spinal sensory neurons. Among the tested 14 kinds of bioisosters, 2-methylacrylamide group was the best candidate to replace thiourea group. Compound 7c, 2-methylacrylamide analog of ATC-120, showed as potent as ATC-120 in its antagonist activity. In addition, 2-methylacrylamide analog 7e having vinyl moiety showed the most potent activity with 0.022
Available online 16 April 2018
Design, synthesis and evaluation of substituted piperidine based KCNQ openers as novel antiepileptic agents
Publication date: Available online 17 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Shaoning Yang, Dingqiang Lu, Pingkai Ouyang Epilepsy is a kind of disease with complicated pathogenesis. KCNQ (Kv7) is a voltage dependent potassium channel that is mostly associated with epilepsy and thus becomes an important target in the treatment of epilepsy. In this paper, a series of substituted piperidine derivatives targeting KCNQ were designed and synthesized by using scaffold hopping and active substructure hybridization. Compounds were evaluated by fluorescence-based thallium influx assay, Rb+ flow assay and electrophysiological patch-clamp assay. Results showed that some compounds possessed more potent potassium channel opening activity than Retigabine. More significantly, compound 11 was found to have good pharmacokinetic profiles in vivo.

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Available online 16 April 2018
Synthesis, structure and bioactivity of primary sulfamate-containing natural products
Publication date: Available online 16 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Prashant Mujumdar, Silvia Bua, Caludiu T. Supuran, Thomas S. Peat, Sally-Ann Poulsen Here we report the synthesis of natural products (NPs) 5
Available online 16 April 2018
Synthesis and in vitro evaluation of homoisoflavonoids as potent inhibitors of nitric oxide production in RAW-264.7 cells
Publication date: Available online 16 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Kongara Damodar, Jeong Tae Lee, Jin-Kyung Kim, Jong-Gab Jun Syntheses of natural homoisoflavonoids, (±)-portulacanones A-C (4, 8 and 9), portulacanone D (6), isolated from Portulaca oleracea L (POL) and their derivatives (3, 5 and 7) have been achieved for the first time along with the synthesis of known derivatives (1 and 2) and their in vitro inhibitory effect against NO production in LPS-induced RAW-264.7 macrophages was evaluated as an indicator of anti-inflammatory activity. All the compounds tested had a concentration-dependent inhibitory effect on NO production by RAW-264.7 macrophages without obvious cytotoxicity. Compounds 3 (97.2% at 10
Available online 16 April 2018
Antimicrobial evaluation and action mechanism of pyridinium-decorated 1,4-pentadien-3-one derivatives
Publication date: Available online 16 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Jian Zhou, Qing-Qing Tao, Pei-Yi Wang, Wu-Bin Shao, Zhi-Bing Wu, Zhong Li, Song Yang A type of pyridinium-decorated 1,4-pentadien-3-one derivatives possessing flexible alkyls were designed and synthesized by integrating the key scaffolds of pyridinium cations and 1,4-pentadien-3-one skeleton in a single molecular architecture. Antimicrobial bioassays indicated that some of the target molecules exerted considerable bioactivities against six phytopathogenic strains, especially for Xanthomonas oryzae pv. oryzae, the minimal EC50 value can reach to 0.504
15 April 2018
Discovery of novel 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid derivatives as HIF prolyl hydroxylase inhibitors for treatment of renal anemia
Publication date: Available online 16 April 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Makoto Hamada, Tetsuo Takayama, Tsuyoshi Shibata, Akira Hiratate, Masato Takahashi, Miyoko Yashiro, Noriko Takayama, Lisa Okumura-Kitajima, Hiroko Koretsune, Hiromitsu Kajiyama, Takumi Naruse, Sota Kato, Hiroki Takano, Hiroyuki Kakinuma Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3–5.6
15 April 2018
Editorial Board
Publication date: 15 April 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 7

15 April 2018
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 Fjellstr

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.

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Start: 06 Nov 2017 | End: 06 Nov 2018

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