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ACS Medicinal Chemistry Letters

Mohammad Sharifian Gh, Michael J Wilhelm, Hai-Lung Dai
We present a nonlinear light scattering method for monitoring, with real-time resolution and membrane specificity, changes in molecular adsorption, and transport at bacterial membranes induced by an antimicrobial compound. Specifically, time-resolved second-harmonic light scattering (SHS) is used to quantify azithromycin-induced changes to bacterial membrane permeability in colloidal suspensions of living Escherichia coli . Variations in membrane properties are monitored through changes in the adsorption and transport rates of malachite green, a hydrophobic cation that gives SHS signal...
June 14, 2018: ACS Medicinal Chemistry Letters
Radu M Suciu, Armand B Cognetta, Zachary E Potter, Benjamin F Cravatt
Wnt proteins are secreted morphogens that play critical roles in embryonic development and tissue remodeling in adult organisms. Aberrant Wnt signaling contributes to diseases such as cancer. Wnts are modified by an unusual O -fatty acylation event ( O -linked palmitoleoylation of a conserved serine) that is required for binding to Frizzled receptors. O -Palmitoleoylation of Wnts is introduced by the porcupine (PORCN) acyltransferase and removed by the serine hydrolase NOTUM. PORCN inhibitors are under development for oncology, while NOTUM inhibitors have potential for treating degenerative diseases...
June 14, 2018: ACS Medicinal Chemistry Letters
Aruna Wijeratne, Junpeng Xiao, Christopher Reutter, Kelly W Furness, Rebecca Leon, Mohammad Zia-Ebrahimi, Rachel N Cavitt, John M Strelow, Robert D Van Horn, Sheng-Bin Peng, David A Barda, Thomas A Engler, Michael J Chalmers
The KRASG12C protein product is an attractive, yet challenging, target for small molecule inhibition. One option for therapeutic intervention is to design small molecule ligands capable of binding to and inactivating KRASG12C via formation of a covalent bond to the sulfhydryl group of cysteine 12. In order to better understand the cellular off-target interactions of Compound 1 , a covalent KRASG12C inhibitor, we have completed a series of complementary chemical proteomics experiments in H358 cells. A new thiol reactive probe (TRP) was designed and used to construct a cellular target occupancy assay for KRASG12C...
June 14, 2018: ACS Medicinal Chemistry Letters
Joseph B Sweeney, Marcus Rattray, Victoria Pugh, Lucy A Powell
Despite intense attention from biomedical and chemical researchers, there are few approved treatments for amyotrophic lateral sclerosis (ALS), with only riluzole (Rilutek) and edaravone (Radicava) currently available to patients. Moreover, the mechanistic basis of the activity of these drugs is currently not well-defined, limiting the ability to design new medicines for ALS. This Letter describes the synthesis of triazole-containing riluzole analogues, and their testing in a novel neuroprotective assay. Seven compounds were identified as having neuroprotective activity, with two compounds having similar activity to riluzole...
June 14, 2018: ACS Medicinal Chemistry Letters
Melanie L Dart, Thomas Machleidt, Emily Jost, Marie K Schwinn, Matthew B Robers, Ce Shi, Thomas A Kirkland, Michael P Killoran, Jennifer M Wilkinson, James R Hartnett, Kristopher Zimmerman, Keith V Wood
Protein thermal shift assays (TSAs) provide a means for characterizing target engagement through ligand-induced thermal stabilization. Although these assays are widely utilized for screening libraries and validating hits in drug discovery programs, they can impose encumbering operational requirements, such as the availability of purified proteins or selective antibodies. Appending the target protein with a small luciferase (NanoLuc) allows coupling of thermal denaturation with luminescent output, providing a rapid and sensitive means for assessing target engagement in compositionally complex environments such as permeabilized cells...
June 14, 2018: ACS Medicinal Chemistry Letters
John M Hatcher, Eric S Wang, Liv Johannessen, Nicholas Kwiatkowski, Taebo Sim, Nathanael S Gray
Cortistatin A is a natural product isolated from the marine sponge Corticium simplex and was found to be a potent and selective inhibitor of CDK8. Many synthetic groups have reported total syntheses of Cortistatin A; however, these syntheses require between 16 and 30 steps and report between 0.012-2% overall yields, which is not amenable to large-scale production. Owing to similarities between the complex core of Cortistatin A and the simple steroid core, we initiated a campaign to design simple, more easily prepared CDK8 inhibitors based on a steroid scaffold that would be more convenient for large-scale synthesis...
June 14, 2018: ACS Medicinal Chemistry Letters
Tony Fröhlich, Christoph Reiter, Mohamed E M Saeed, Corina Hutterer, Friedrich Hahn, Maria Leidenberger, Oliver Friedrich, Barbara Kappes, Manfred Marschall, Thomas Efferth, Svetlana B Tsogoeva
A series of hybrid compounds based on the natural products artemisinin and thymoquinone was synthesized and investigated for their biological activity against the malaria parasite Plasmodium falciparum 3D7 strain, human cytomegalovirus (HCMV), and two leukemia cell lines (drug-sensitive CCRF-CEM and multidrug-resistant subline CEM/ADR5000). An unprecedented one-pot method of selective formation of C-10α-acetate 14 starting from a 1:1 mixture of C-10α- to C-10β-dihydroartemisinin was developed. The key step of this facile method is a mild decarboxylative activation of malonic acid mediated by DCC/DMAP...
June 14, 2018: ACS Medicinal Chemistry Letters
Hakan Gunaydin, Michael D Altman, J Michael Ellis, Peter Fuller, Scott A Johnson, Brian Lahue, Blair Lapointe
Preclinical optimization of compounds toward viable drug candidates requires an integrated understanding of properties that impact predictions of the clinically efficacious dose. The importance of optimizing half-life, unbound clearance, and potency and how they impact dose predictions are discussed in this letter. Modest half-life improvements for short half-life compounds can dramatically lower the efficacious dose. The relationship between dose and half-life is nonlinear when unbound clearance is kept constant, whereas the relationship between dose and unbound clearance is linear when half-life is kept constant...
June 14, 2018: ACS Medicinal Chemistry Letters
Fabio Broccatelli, Ignacio Aliagas, Hao Zheng
The optimization of the pharmacokinetic profile of a drug is one of the crucial aspects of medicinal chemistry campaigns. When efficacy is driven by a continuous coverage of the minimum efficacious plasma concentration, half-life must be optimized to achieve the optimal pharmacokinetic profile. The consensus in the field is that decreasing clearance, as opposed to increasing volume of distribution, is a better strategy to prolong half-life. While both the pharmacokinetic theory and the need for an optimal safety profile support this approach, this needs to be integrated with practical indications concerning the strategy to optimize clearance...
June 14, 2018: ACS Medicinal Chemistry Letters
Daniel A Lorenz, Tanpreet Kaur, Samuel A Kerk, Erin E Gallagher, Jorge Sandoval, Amanda L Garner
Dysregulation of microRNA (miRNA) expression has been linked to many human diseases; however, because of the challenges associated with RNA-targeted drug discovery, additional approaches are needed for probing miRNA biology. The emerging regulatory role of miRNA-binding proteins in miRNA maturation presents such an alternative strategy. Exploiting our laboratory's click chemistry-based high-throughput screening (HTS) technology, catalytic enzyme-linked click chemistry assay or cat-ELCCA, we have designed a modular method by which to discover new chemical tools for manipulating pre-miRNA-miRNA-binding protein interactions...
June 14, 2018: ACS Medicinal Chemistry Letters
Stevan W Djuric, Anil Vasudevan
No abstract text is available yet for this article.
June 14, 2018: ACS Medicinal Chemistry Letters
Mahesh S Deshmukh, Nidhi Jain
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00263.].
May 10, 2018: ACS Medicinal Chemistry Letters
Xia Chen, Liu Liu, Yong Chen, Yuting Yang, Chao-Yie Yang, Tianyue Guo, Ming Lei, Haiying Sun, Shaomeng Wang
Telomeric repeat binding factor 2 (TRF2) is a telomere-associated protein that plays an important role in the formation of the 3' single strand DNA overhang and the "T loop", two structures critical for the stability of the telomeres. Apollo is a 5'-exonuclease recruited by TRF2 to the telomere and contributes to the formation of the 3' single strand DNA overhang. Knocking down of Apollo can induce DNA damage response similar to that caused by the knocking down of TRF2. In this Letter, we report the design and synthesis of a class of cyclic peptidic mimetics of the TRFH binding motif of Apollo (ApolloTBM )...
May 10, 2018: ACS Medicinal Chemistry Letters
Yalan Guo, Yujie Wang, Haihong Li, Ke Wang, Qi Wan, Jia Li, Yubo Zhou, Ying Chen
In this work, five new hybrids of phenylsulfonylfuroxan merging 3-benzyl coumarin and their seco-B-ring derivatives 2 - 6 were designed and synthesized. Among them, compound 3 showed the most potent antiproliferation activities with IC50 values range from 0.5 to 143 nM against nine drug-sensitive and four drug-resistant cancer cell lines. Preliminary pharmacologic studies showed that these compounds displayed lower toxicities than that of lead compound 1 . Compound 3 obviously induced the early apoptosis and hardly affected the cell cycle of A2780, which was significantly different from compound 1 ...
May 10, 2018: ACS Medicinal Chemistry Letters
An De Prins, Charlotte Martin, Yannick Van Wanseele, Csaba Tömböly, Dirk Tourwé, Vicky Caveliers, Birgitte Holst, Ann Van Eeckhaut, Mette M Rosenkilde, Ilse Smolders, Steven Ballet
Neuromedin U (NMU) is a multifunctional neuropeptide which is characterized by a high conservation through all species. Herein, we describe the synthesis of a novel set of NMU-analogs based on the truncated NMU-8. Through combination of previously reported modifications, an elaborate structure-activity relationship study was performed aiming for the development of peptides with an increased selectivity toward NMU receptor 1 (NMUR1). Compound 7 possessed the highest NMUR1 selectivity (IC50 = 0.54 nM, selectivity ratio = 5313) together with an increased potency (EC50 = 3...
May 10, 2018: ACS Medicinal Chemistry Letters
Anna Vulpetti, Nils Ostermann, Stefan Randl, Taeyoung Yoon, Aengus Mac Sweeney, Frederic Cumin, Edwige Lorthiois, Simon Rüdisser, Paul Erbel, Jürgen Maibaum
Complement Factor D, a serine protease of the S1 family and key component of the alternative pathway amplification loop, represents a promising target for the treatment of several prevalent and rare diseases linked to the innate immune system. Previously reported FD inhibitors have been shown to bind to the FD active site in its self-inhibited conformation characterized by the presence of a salt bridge at the bottom of the S1 pocket between Asp189 and Arg218. We report herein a new set of small-molecule FD ligands that harbor a basic S1 binding moiety directly binding to the carboxylate of Asp189, thereby displacing the Asp189-Arg218 ionic interaction and significantly changing the conformation of the self-inhibitory loop...
May 10, 2018: ACS Medicinal Chemistry Letters
Tianyun Fan, Xinxin Hu, Sheng Tang, Xiaojia Liu, Yanxiang Wang, Hongbin Deng, Xuefu You, Jiandong Jiang, Yinghong Li, Danqing Song
8-Acetoxycycloberberine ( 2 ) with a unique skeleton was first identified to display a potent activity profile against Gram-positive bacteria, especially methicillin-resistant S. aureus (MRSA) with minimum inhibitory concentration (MIC) values of 1-8 μg/mL, suggesting a possible novel mechanism of action against bacteria. Taking 2 as the lead, 23 new 8-substituted cycloberberine (CBBR) derivatives including ether, amine, and amide were synthesized and evaluated for their antibacterial effect. The structure-activity relationship revealed that the introduction of a suitable substituent at the 8-position could greatly enhance the potency against MRSA...
May 10, 2018: ACS Medicinal Chemistry Letters
Sho Kaide, Masahiro Ono, Hiroyuki Watanabe, Ayane Kitada, Masashi Yoshimura, Yoichi Shimizu, Masafumi Ihara, Hideo Saji
It is generally accepted that neurofibrillary tangles consisting of tau proteins are involved in the pathogenesis of Alzheimer's disease (AD). For selective detection of tau pathology, we synthesized and evaluated radioiodinated benzoimidazopyridine (BIP) derivatives with an alkylamino group as tau imaging probes. In vitro selectivity to tau aggregates and in vivo pharmacokinetics of BIP derivatives varied markedly, being strongly dependent on the alkylamino group. In in vitro autoradiography with AD brain sections, the BIP derivative with a dimethylamino group (BIP-NMe2 ) showed the highest selectivity to tau aggregates...
May 10, 2018: ACS Medicinal Chemistry Letters
Lawrence R Marcin, Jayakumar Warrier, Srinivasan Thangathirupathy, Jianliang Shi, George N Karageorge, Bradley C Pearce, Alicia Ng, Hyunsoo Park, James Kempson, Jianqing Li, Huiping Zhang, Arvind Mathur, Aliphedi B Reddy, G Nagaraju, Gopikishan Tonukunuru, Grandhi V R K M Gupta, Manjunatha Kamble, Raju Mannoori, Srinivas Cheruku, Srinivas Jogi, Jyoti Gulia, Tanmaya Bastia, Charulatha Sanmathi, Jayant Aher, Rajareddy Kallem, Bettadapura N Srikumar, Kumar Kuchibhotla Vijaya, Pattipati S Naidu, Mahesh Paschapur, Narasimharaju Kalidindi, Reeba Vikramadithyan, Manjunath Ramarao, Rex Denton, Thaddeus Molski, Eric Shields, Murali Subramanian, Xiaoliang Zhuo, Michelle Nophsker, Jean Simmermacher, Michael Sinz, Charlie Albright, Linda J Bristow, Imadul Islam, Joanne J Bronson, Richard E Olson, Dalton King, Lorin A Thompson, John E Macor
There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N -methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 ( 6 ) and its active parent molecule BMS-986169 ( 5 ), which demonstrated high binding affinity for the GluN2B allosteric site ( K i = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells...
May 10, 2018: ACS Medicinal Chemistry Letters
Gaia Fumagalli, Giulia Giorgi, Máté Vágvölgyi, Eleonora Colombo, Michael S Christodoulou, Veronica Collico, Davide Prosperi, Franco Dosio, Attila Hunyadi, Monica Montopoli, Mariafrancesca Hyeraci, Alessandra Silvani, Giordano Lesma, Lisa Dalla Via, Daniele Passarella
Heteronanoparticles (H-NPs) consisting of conjugates characterized by a squalene tail linked to doxorubicin and ecdysteroid derivatives are presented. Biological evaluation on A2780ADR cell line confirms not only the maintenance of the activity of the parental drug but also the ability to overcome cancer resistance. The in vitro cell uptake was demonstrated, and the involvement of an endosomal-mediated pathway was suggested.
May 10, 2018: ACS Medicinal Chemistry Letters
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