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Structure-Based Design, Synthesis, and Biological Evaluation Of Structure-Based Design, Synthesis, and Biological Evaluation of Triazole-Based smHDAC8 Inhibitors Dmitrii Kalinin, Sunit Jana, Maxim Pfafenrot, Alokta Chakrabarti, Jelena Melesina, Tajith Shaik, Julien Lancelot, Raymond Pierce, Wolfgang Sippl, Christophe Romier, et al. To cite this version: Dmitrii Kalinin, Sunit Jana, Maxim Pfafenrot, Alokta Chakrabarti, Jelena Melesina, et al.. Structure-Based Design, Synthesis, and Biological Evaluation of Triazole-Based smHDAC8 Inhibitors. ChemMedChem, Wiley-VCH Verlag, 2019, 15 (7), pp.571-584. 10.1002/cmdc.201900583. hal- 02999295 HAL Id: hal-02999295 https://hal.archives-ouvertes.fr/hal-02999295 Submitted on 23 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License Full Papers ChemMedChem doi.org/10.1002/cmdc.201900583 1 2 3 Structure-Based Design, Synthesis, and Biological 4 5 Evaluation of Triazole-Based smHDAC8 Inhibitors 6 [a, b, c, d] [c, e] [c] [f] 7 Dmitrii V. Kalinin, Sunit K. Jana, Maxim Pfafenrot, Alokta Chakrabarti, [g] [h] [i] [i] [g] 8 Jelena Melesina, Tajith B. Shaik, Julien Lancelot, Raymond J. Pierce, Wolfgang Sippl, 9 Christophe Romier,[h] Manfred Jung,[f] and Ralph Holl*[a, b] 10 11 12 Schistosomiasis is a neglected tropical disease caused by chemical modifications of 2b led to the discovery of 4- 13 parasitic flatworms of the genus Schistosoma, which affects over fluorophenoxy derivative 21 (1-[5-chloro-2-(4-fluorophenoxy) 14 200 million people worldwide and leads to at least 300,000 phenyl]-N-hydroxy-1H-1,2,3-triazole-4-carboxamide), a nanomo- 15 deaths every year. In this study, initial screening revealed the lar smHDAC8 inhibitor (IC50 =0.5 μM), exceeding the smHDAC8 16 triazole-based hydroxamate 2b (N-hydroxy-1-phenyl-1H-1,2,3- inhibitory activity of 2b and SAHA (vorinostat), while exhibiting 17 triazole-4-carboxamide) exhibiting potent inhibitory activity an improved selectivity profile over the investigated human 18 toward the novel antiparasitic target Schistosoma mansoni HDACs. Collectively, this study reveals specific interactions 19 histone deacetylase 8 (smHDAC8) and promising selectivity between smHDAC8 and the synthesized triazole-based inhib- 20 over the major human HDACs. Subsequent crystallographic itors and demonstrates that these small molecules represent 21 studies of the 2b/smHDAC8 complex revealed key interactions promising lead structures, which could be further developed in 22 between the inhibitor and the enzyme’s active site, thus the search for novel drugs for the treatment of schistosomiasis. 23 explaining the unique selectivity profile of the inhibitor. Further 24 25 Introduction strains and worrisome data on reduced efficacy of the drug 26 have already been reported, thus rendering the search for 27 Schistosomiasis, or bilharzia, is a neglected tropical disease, potential drug targets as well as novel drugs a strategic 28 which is caused by the trematode Schistosoma mansoni and priority.[5,8–10] 29 other platyhelminth parasites of the same genus.[1–3] The disease The treatment of S. mansoni with small-molecule histone 30 is prevalent in Africa, the Middle East, South America, and Asia, deacetylase (HDAC) inhibitors was shown to cause dose- 31 affecting over 200 million people worldwide and causing at dependent mortality of schistosomula as well as adult worms, 32 least 300,000 deaths every year.[4–6] Currently, praziquantel is making HDACs potential targets for the treatment of 33 the only drug available for treatment and control of schistosomiasis.[11–13] In eukaryotes, HDACs, which belong to the 34 schistosomiasis.[7] The intensive use of this drug increases the epigenetic machinery of the cells, catalyze the deacetylation of 35 probability of the emergence of praziquantel resistant parasite ɛ-amino groups of lysine residues in histone tails, leading in 36 37 38 [a] Dr. D. V. Kalinin, Prof. Dr. R. Holl [f] Dr. A. Chakrabarti, Prof. Dr. M. Jung 39 Department of Chemistry Institute of Pharmaceutical Sciences Institute of Organic Chemistry Albert-Ludwigs-Universität Freiburg 40 University of Hamburg Albertstr. 25, 79104 Freiburg (Germany) 41 Martin-Luther-King-Platz 6 [g] Dr. J. Melesina, Prof. Dr. W. Sippl 42 20146 Hamburg (Germany) Institute of Pharmacy E-mail: [email protected] Martin Luther University of Halle-Wittenberg 43 [b] Dr. D. V. Kalinin, Prof. Dr. R. Holl Wolfgang-Langenbeck Str. 4 44 German Center for Infection Research (DZIF) 06120 Halle/Saale (Germany) 45 partner site Hamburg-Lübeck-Borstel-Riems [h] Dr. T. B. Shaik, Dr. C. Romier [c] Dr. D. V. Kalinin, Dr. S. K. Jana, M. Pfafenrot Département de Biologie Structurale Intégrative 46 Institute of Pharmaceutical and Medicinal Chemistry Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC) 47 University of Münster Université de Strasbourg, CNRS, INSERM 48 Corrensstr. 48 1 rue Laurent Fries 48149 Münster (Germany) 67404 Illkirch Cedex (France) 49 [d] Dr. D. V. Kalinin [i] Dr. J. Lancelot, Dr. R. J. Pierce 50 Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM) Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille 51 University of Münster U1019-UMR 8204-CIIL-Centre d’Infection et d’Immunité de Lille Schlossplatz 4 59000 Lille (France) 52 48149 Münster (Germany) Supporting information for this article is available on the WWW under 53 [e] Dr. S. K. Jana https://doi.org/10.1002/cmdc.201900583 NRW Graduate School of Chemistry 54 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This University of Münster 55 is an open access article under the terms of the Creative Commons Attri- Wilhelm-Klemm-Str. 10 bution License, which permits use, distribution and reproduction in any 56 48149 Münster (Germany) medium, provided the original work is properly cited. 57 ChemMedChem 2020, 15, 571–584 571 © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA Wiley VCH Mittwoch, 25.03.2020 2007 / 155025 [S. 571/584] 1 Full Papers ChemMedChem doi.org/10.1002/cmdc.201900583 consequence to a more compact chromatin structure, which hydrogen bond to the aforementioned histidine in the active 1 usually results in an inhibition of transcription.[14–17] Being drug site, whereas the methionine, which the human orthologue has 2 targets in cancer therapy, human histone deacetylases in the same place, cannot be addressed in a similar fashion. 3 (hsHDACs) were intensively studied and various HDAC inhib- Several triazole derivatives like 2c, 2f, and 2g (Figure 1) 4 itors, like e.g. SAHA (1, Figure 1), were described.[18–21] The 18 have been reported to weakly inhibit hsHDAC1 and 5 human HDACs, which have been discovered so far, are grouped hsHDAC8.[31] As these hydroxamic acids contain a polar triazole 6 into 4 classes.[18,22] Whereas classes I, II, and IV comprise the ring, which could possibly interact with H292 of smHDAC8, 7 Zn2+-dependent HDACs, the class III enzymes require NAD+ for these compounds, along with other triazole derivatives, exhibit- 8 catalysis. In S. mansoni, three class I HDACs are known, ing further variations of the substituent in position 1 of the 9 representing orthologues of the human class I enzymes HDAC1, heterocycle, were synthesized, assayed for their inhibitory 10 HDAC3, and HDAC8.[12] These three S. mansoni class I HDACs are activity toward smHDAC8, and tested for their selectivity toward 11 expressed in the parasite at all stages of its life-cycle.[11] In hsHDAC1 and hsHDAC8 as well as the class IIb histone 12 contrast to hsHDAC8, showing in humans the lowest level of deacetylase hsHDAC6. 13 expression of the class I enzymes, in S. mansoni smHDAC8 is the 14 most abundantly expressed class I HDAC at all life-cycle stages 15 and was validated as drug target for schistosome-specific Results and Discussion 16 inhibitors. Down-regulation of smHDAC8 expression in schisto- 17 somula caused a decrease in their capacity to survive and Synthesis of triazole derivatives 2b-j 18 mature in infected mice. In addition, the tissue egg burden was 19 reduced by 45%.[5,12,23] Like its human orthologue, smHDAC8 The reported triazole derivatives 2c, 2f, and 2g comprise a 20 folds into a single α/β domain being composed of a central phenyl ring linked to the triazole core via a flexible alkyl chain 21 parallel β-sheet, which is sandwiched between several α- (from one to three methylene groups, respectively). To vary 22 helices.[5–6,24] The active sites of the enzymes consist of a long length and flexibility of the side chain, besides phenyl derivative 23 narrow tunnel, accommodating the incoming acetylated lysine 2b lacking a methylene linker, diphenylacetylene and diphenyl- 24 side chain of the substrate, which leads to a cavity containing butadiyne derivatives 2h-j exhibiting a rigidified side chain 25 the catalytic Zn2+ -ion. The active site residues of the two should be synthesized and tested for their inhibitory profile. 26 enzymes are highly conserved, with only M274 in hsHDAC8, Furthermore, to study the effect of an additional substituent in 27 being
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