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Your search keyword '"Hripsimee Kessedjian"' showing total 4 results
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4 results on '"Hripsimee Kessedjian"'

1. Chemoselective Synthesis and Anti-Kinetoplastidal Properties of 2,6-Diaryl-4H-tetrahydro-thiopyran-4-one S-Oxides: Their Interplay in a Cascade of Redox Reactions from Diarylideneacetones

Author

Thibault Gendron, Don Antoine Lanfranchi, Nicole I. Wenzel, Hripsimée Kessedjian, Beate Jannack, Louis Maes, Sandrine Cojean, Thomas J. J. Müller, Philippe M. Loiseau, and Elisabeth Davioud-Charvet

Subjects
anti-kinetoplastid, drug metabolites, Michael acceptor, redox, sulfide, sulfone, Organic chemistry, QD241-441
Abstract

2,6-Diaryl-4H-tetrahydro-thiopyran-4-ones and corresponding sulfoxide and sulfone derivatives were designed to lower the major toxicity of their parent anti-kinetoplatidal diarylideneacetones through a prodrug effect. Novel diastereoselective methodologies were developed and generalized from diarylideneacetones and 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones to allow the introduction of a wide substitution profile and to prepare the related S-oxides. The in vitro biological activity and selectivity of diarylideneacetones, 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones, and their S-sulfoxide and sulfone metabolites were evaluated against Trypanosoma brucei brucei, Trypanosoma cruzi, and various Leishmania species in comparison with their cytotoxicity against human fibroblasts hMRC-5. The data revealed that the sulfides, sulfoxides, and sulfones, in which the Michael acceptor sites are temporarily masked, are less toxic against mammal cells while the anti-trypanosomal potency was maintained against T. b. brucei, T. cruzi, L. infantum, and L. donovani, thus confirming the validity of the prodrug strategy. The mechanism of action is proposed to be due to the involvement of diarylideneacetones in cascades of redox reactions involving the trypanothione system. After Michael addition of the dithiol to the double bonds, resulting in an elongated polymer, the latter—upon S-oxidation, followed by syn-eliminations—fragments, under continuous release of reactive oxygen species and sulfenic/sulfonic species, causing the death of the trypanosomal parasites in the micromolar or submicromolar range with high selectivity indexes.

Published
2024
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2. Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432

Author

Philip G. Humphreys, Niall A. Anderson, Paul Bamborough, Andrew Baxter, Chun-wa Chung, Rosa Cookson, Peter D. Craggs, Toryn Dalton, Julie C. L. Fournier, Laurie J. Gordon, Heather F. Gray, Matthew W. Gray, Richard Gregory, David J. Hirst, Craig Jamieson, Katherine L. Jones, Hripsimee Kessedjian, David Lugo, Grant McGonagle, Vipulkumar K. Patel, Christopher Patten, Darren L. Poole, Rab K. Prinjha, Cesar Ramirez-Molina, Inmaculada Rioja, Gail Seal, Kayleigh A. J. Stafford, Rishi R. Shah, Daniel Tape, Natalie H. Theodoulou, Laura Tomlinson, Sabri Ukuser, Ian D. Wall, Natalie Wellaway, and Gemma White

Subjects
Histones, Protein Domains, Lysine, Drug Discovery, Humans, Molecular Medicine, Ligands, Transcription Factors
Abstract

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (

Published
2022
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3. Diastereoselective Synthesis of 2,6-Diaryltetrahydrothiopyran-4-ones by Phase-Transfer Catalysis

Author

Thibault Gendron, Don Antoine Lanfranchi, Hripsimee Kessedjian, and Elisabeth Davioud-Charvet

Subjects
Scope (project management), Chemistry, Phase (matter), Organic Chemistry, Michael reaction, Diastereomer, Organic chemistry, Physical and Theoretical Chemistry, Cis–trans isomerism, Catalysis
Abstract

Two efficient phase-transfer-catalyzed protocols for the diastereoselective synthesis of cis and trans isomers of 2,6-diaryltetrahydrothiopyran-4-ones (2,6-DATHTPs) have been developed. In a study of the scope of the reactions, differently substituted 2,6-DATHTPs were successfully accessed in high yields and diastereomeric excessses on both experimental and preparative scales.

Published
2015
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4. ChemInform Abstract: Diastereoselective Synthesis of 2,6-Diaryltetrahydrothiopyran-4-ones by Phase-Transfer Catalysis

Author

Elisabeth Davioud-Charvet, Don Antoine Lanfranchi, Thibault Gendron, and Hripsimee Kessedjian

Subjects
Chemistry, Phase (matter), General Medicine, Thiophene derivatives, Combinatorial chemistry, Cis–trans isomerism, Catalysis
Abstract

Two efficient phase-transfer-catalyzed protocols for the diastereoselective synthesis of cis and trans isomers of 2,6-diaryltetrahydrothiopyran-4-ones (2,6-DATHTPs) are developed.

Published
2015
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