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ACS Medicinal Chemistry Letters

Weihua Shi, Zhigan Jiang, Haiying He, Fubiao Xiao, Fusen Lin, Ya Sun, Lijuan Hou, Liang Shen, Lixia Han, Minggao Zeng, Kunmin Lai, Zhengxian Gu, Xinsheng Chen, Tao Zhao, Li Guo, Chun Yang, Jian Li, Shuhui Chen
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00418.].
April 12, 2018: ACS Medicinal Chemistry Letters
Juraj Velcicky, Achim Schlapbach, Richard Heng, Laszlo Revesz, Daniel Pflieger, Ernst Blum, Stuart Hawtin, Christine Huppertz, Roland Feifel, Rene Hersperger
MAP-activated protein kinase 2 (MK2) plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential for the treatment of inflammation and cancer, to date no MK2 low molecular weight inhibitors have reached the clinic, mainly due to inadequate absorption, distribution, metabolism, and excretion (ADME) properties. We describe here an approach based on specifically placed fluorine within a recently described pyrrole-based MK2 inhibitor scaffold for manipulation of its physicochemical and ADME properties...
April 12, 2018: ACS Medicinal Chemistry Letters
Surendra Dawadi, Helena I M Boshoff, Sae Woong Park, Dirk Schnappinger, Courtney C Aldrich
5'- O -[ N -(Salicyl)sulfamoyl]adenosine (Sal-AMS, 1 ) is a nucleoside antibiotic that inhibits incorporation of salicylate into siderophores required for bacterial iron acquisition and has potent activity against Mycobacterium tuberculosis ( Mtb ). Cinnolone analogues exemplified by 5 were designed to replace the acidic acyl-sulfamate functional group of 1 (p K a = 3) by a more stable sulfonamide linkage (p K a = 6.0) in an attempt to address potential metabolic liabilities and improve membrane permeability...
April 12, 2018: ACS Medicinal Chemistry Letters
Min Luo, Elisabetta Groaz, Steven De Jonghe, Robert Snoeck, Graciela Andrei, Piet Herdewijn
A series of amidate prodrugs of cyclic 9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (cHPMPA) featuring different amino acid motifs were synthesized. All phosphonamidates derived from ( S )-cHPMPA displayed a broad spectrum activity against herpesviruses with EC50 values in the low nanomolar range. A phosphonobisamidate prodrug of ( S )-HPMPA also exhibited a remarkably potent antiviral activity. In addition, the leucine ester prodrug of ( S )-cHPMPA and phosphonobisamidate valine ester prodrug of ( S )-HPMPA proved stable in human plasma...
April 12, 2018: ACS Medicinal Chemistry Letters
Chien-Hung Yeh, Shawn I Walsh, Arryn Craney, M Greg Tabor, Ana-Florina Voica, Ramkrishna Adhikary, Sydney E Morris, Floyd E Romesberg
β-Lactam antibiotics, one of the most important class of human therapeutics, act via the inhibition of penicillin-binding proteins (PBPs). The unparalleled success in their development has inspired efforts to develop them as inhibitors of other targets. Bacterial type I signal peptidase is evolutionarily related to the PBPs, but the stereochemistry of its substrates and its catalytic mechanism suggest that β-lactams with the 5 S stereochemistry, as opposed to the 5 R stereochemistry of the traditional β-lactams, would be required for inhibition...
April 12, 2018: ACS Medicinal Chemistry Letters
Dongwei Kang, Zhao Wang, Heng Zhang, Gaochan Wu, Tong Zhao, Zhongxia Zhou, Zhipeng Huo, Boshi Huang, Da Feng, Xiao Ding, Jian Zhang, Xiaofang Zuo, Lanlan Jing, Wei Luo, Samuel Guma, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Based on the detailed analysis of the binding mode of diarylpyrimidines (DAPYs) with HIV-1 RT, we designed several subseries of novel NNRTIs, with the aim to probe biologically relevant chemical space of solvent-exposed tolerant regions in NNRTIs binding pocket (NNIBP). The most potent compound 21a exhibited significant activity against the whole viral panel, being about 1.5-2.6-fold (WT, EC50 = 2.44 nM; L100I, EC50 = 4.24 nM; Y181C, EC50 = 4.80 nM; F227L + V106A, EC50 = 17.8 nM) and 4-5-fold (K103N, EC50 = 1...
April 12, 2018: ACS Medicinal Chemistry Letters
Masato Kaneda, Shinsaku Kawaguchi, Nobutaka Fujii, Hiroaki Ohno, Shinya Oishi
Odoamide is a cytotoxic peptide-polyketide hybrid molecule isolated from the Okinawan marine cyanobacterium Okeania sp. For an efficient structure-activity relationship study of the peptide part of odoamide, a facile synthetic protocol was established using a solid-phase peptide synthesis. Among a series of peptides, the d-MeAla6 isomer exhibited a more potent cytotoxicity than natural odoamide. It was also demonstrated that the 26-membered macrocyclic natural odoamide and the 24-membered isomer with comparable cytotoxicities were slowly interconvertible, and both isomers contributed to the potent cytotoxicity of odoamide...
April 12, 2018: ACS Medicinal Chemistry Letters
Yang Xiang, Cheng Chen, Wen-Ming Wang, Li-Wei Xu, Ke-Wu Yang, Peter Oelschlaeger, Yuan He
A series of rhodanines was constructed, their Z-configuration was confirmed by small molecule X-ray crystal structures, and their activity against metallo-β-lactamases (MβLs) was measured. The obtained 26 molecules and a thioenolate specifically inhibited the MβL L1 with an IC50 range of 0.02-1.7 μM, and compounds 2h - m exhibited broad-spectrum inhibition of the MβLs NDM-1, VIM-2, ImiS, and L1 with IC50 values <16 μM. All inhibitors increased the antimicrobial effect of cefazolin against E. coli cells expressing L1, resulting in a 2-8-fold reduction in MIC...
April 12, 2018: ACS Medicinal Chemistry Letters
Scott E Collibee, Gustave Bergnes, Alexander Muci, William F Browne, Marc Garard, Aaron C Hinken, Alan J Russell, Ion Suehiro, James Hartman, Raja Kawas, Pu-Ping Lu, Kenneth H Lee, David Marquez, Matthew Tomlinson, Donghong Xu, Adam Kennedy, Darren Hwee, Julia Schaletzky, Kwan Leung, Fady I Malik, David J Morgans, Bradley P Morgan
The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv ( 25 ), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.
April 12, 2018: ACS Medicinal Chemistry Letters
Henrik Antti, Magnus Sellstedt
Finding a new drug candidate for a selected target is an expensive and time-consuming process. Target guided-synthesis, or in situ click chemistry, is a concept where the drug target is used to template the formation of its own inhibitors from reactive building blocks. This could simplify the identification of drug candidates. However, with the exception of one example of an RNA-target, target-guided synthesis has always employed purified targets. This limits the number of targets that can be screened by the method...
April 12, 2018: ACS Medicinal Chemistry Letters
Anna-Christina Schulz-Fincke, Michael Blaut, Annett Braune, Michael Gütschow
Human leukocyte elastase plays a crucial role in a variety of inflammatory disorders and represents an important subject of biomedical studies. The chemotype of peptidic phosphonates was employed for the design of a new activity-based probe for human leukocyte elastase. Its structure combines the phosphonate warhead with an adequate peptide portion and a BODIPY fluorophore with a clickable ethinylphenyl moiety at meso position. The probe 6 was assembled by copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition...
April 12, 2018: ACS Medicinal Chemistry Letters
Michael S Christodoulou, Federico Dapiaggi, Francesca Ghiringhelli, Stefano Pieraccini, Maurizio Sironi, Marianna Lucafò, Debora Curci, Giuliana Decorti, Gabriele Stocco, Chandra Sekhar Chirumamilla, Wim Vanden Berghe, Patrick Balaguer, Benoît Y Michel, Alain Burger, Egle M Beccalli, Daniele Passarella, Nadine Martinet
Glucocorticoid receptor (GCR) transactivation reporter gene assays were used as an initial high-throughput screening on a diversified library of 1200 compounds for their evaluation as GCR antagonists. A class of imidazo[2,1- b ]benzothiazole and imidazo[2,1- b ]benzoimidazole derivatives were identified for their ability to modulate GCR transactivation and anti-inflammatory transrepression effects utilizing GCR and NF-κB specific reporter gene assays. Modeling studies on the crystallographic structure of the GCR ligand binding domain provided three new analogues bearing the tetrahydroimidazo[2,1- b ]benzothiazole scaffold able to antagonize the GCR in the presence of dexamethasone (DEX) and also defined their putative binding into the GCR structure...
April 12, 2018: ACS Medicinal Chemistry Letters
Zhipeng Huo, Heng Zhang, Dongwei Kang, Zhongxia Zhou, Gaochan Wu, Samuel Desta, Xiaofang Zuo, Zhao Wang, Lanlan Jing, Xiao Ding, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
A novel series of diarylpyrimidine derivatives, which could simultaneously occupy the classical NNRTIs binding pocket (NNIBP) and the newly reported "NNRTI Adjacent" binding site, were designed, synthesized, and evaluated for their antiviral activities in MT-4 cell cultures. The results demonstrated that six compounds ( 20 , 27 and 31 - 34 ) showed excellent activities against wild-type (WT) HIV-1 strain (EC50 = 2.4-3.8 nM), which were more potent than that of ETV (EC50 = 4.0 nM). Furthermore, 20 , 27 , 33 , and 34 showed more potent or equipotent activity against single mutant HIV-1 strains compared to that of ETV...
April 12, 2018: ACS Medicinal Chemistry Letters
Ángela P Hernández, Paula Díez, Pablo A García, José M Miguel Del Corral, Martín Pérez-Andrés, David Díez, Arturo San Feliciano, Manuel Fuentes, Ma Ángeles Castro
A new family of molecular hybrids, between cyclolignans related to podophyllic aldehyde and several diterpenylnaphthohydroquinones (DNHQ), was prepared and its biological activity evaluated in several human solid tumor cell lines, which are representative of the most prevalent solid tumors in the Western world. Both cyclolignan and quinone fragments were linked through aliphatic or aromatic spacers. The new hybrid family was evaluated for its cytotoxicity, and it was found that the hybrids were several times more potent against the osteosarcoma cell line MG-63 than against MCF-7 and HT-29 cell lines...
April 12, 2018: ACS Medicinal Chemistry Letters
Thumuganti Gayathri, A Vijayalakshmi, Sreejith Mangalath, Joshy Joseph, N Madhusudhana Rao, Surya Prakash Singh
We report a series of four efficient photosensitizers (PSs) based on a Bodipy core for photodynamic therapy (PDT). In the absence of hydrophilic functional groups, these PSs have been encapsulated in liposomes and examined for photocytotoxicity against human ovarian carcinoma cell line (SK-OV-3). The IC50 values obtained are as low as 0.350 μM, which compete with the classical photosensitizer chlorine E6 (IC50 = 0.39 μM) under similar experimental conditions.
April 12, 2018: ACS Medicinal Chemistry Letters
Anupama Tuladhar, Kathleen S Rein
The anticancer effect of manumycin A (Man A) has been attributed to the inhibition of farnesyl transferase (FTase), an enzyme that is responsible for post-translational modification of Ras proteins. However, we have discovered that Man A inhibits mammalian cytosolic thioredoxin reductase 1 (TrxR-1) in a time-dependent manner, with an IC50 of 272 nM with preincubation and 1586 nM without preincubation. The inhibition of TrxR-1 by Man A is irreversible and is the result of a covalent interaction between Man A and TrxR-1...
April 12, 2018: ACS Medicinal Chemistry Letters
Kun Fang, Guoqiang Dong, Yu Li, Shipeng He, Ying Wu, Shanchao Wu, Wei Wang, Chunquan Sheng
In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC50 = 69.0 nM) and HDAC1 (IC50 = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma...
April 12, 2018: ACS Medicinal Chemistry Letters
Pablo Garnica, Ignacio Encío, Daniel Plano, Juan A Palop, Carmen Sanmartín
A series of 16 new diselenide-acylselenourea conjugates have been designed following the fragment-based drug strategy. Compound in vitro cytotoxic potential was evaluated against six human cancer cell lines and two nonmalignant derived cell lines with the aim of determining their potency and selectivity. Nine derivatives exhibited GI50 values under 10 μM in at least four cancer cell lines. A clear gap situated phenyl substitution over heterocyclic moieties in terms of selectivity. Among carbocyclic compounds, derivatives 2 and 7 significantly inhibited cell growth of breast adenocarcinoma cells with GI50 values of 1...
April 12, 2018: ACS Medicinal Chemistry Letters
Janeta Popovici-Muller, René M Lemieux, Erin Artin, Jeffrey O Saunders, Francesco G Salituro, Jeremy Travins, Giovanni Cianchetta, Zhenwei Cai, Ding Zhou, Dawei Cui, Ping Chen, Kimberly Straley, Erica Tobin, Fang Wang, Muriel D David, Virginie Penard-Lacronique, Cyril Quivoron, Véronique Saada, Stéphane de Botton, Stefan Gross, Lenny Dang, Hua Yang, Luke Utley, Yue Chen, Hyeryun Kim, Shengfang Jin, Zhiwei Gu, Gui Yao, Zhiyong Luo, Xiaobing Lv, Cheng Fang, Liping Yan, Andrew Olaharski, Lee Silverman, Scott Biller, Shin-San M Su, Katharine Yen
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo...
April 12, 2018: ACS Medicinal Chemistry Letters
Robert B Kargbo
No abstract text is available yet for this article.
April 12, 2018: ACS Medicinal Chemistry Letters
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