ArticleEuropean journal of medicinal chemistry2022
Rational design of metabolically stable HDAC inhibitors: An overhaul of trifluoromethyl ketones.
Article in European journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Visible-light-induced trifluoroacetylation reaction of electron-deficient nitrogen heterocycles.Frontiers in chemistry · 2026Article
- Thermal shift engagement assay for Class IIA histone deacetylase inhibitor screening.Results in chemistry · 2025Article
- Quantification of the H-Bond-Donating Ability of Trifluoromethyl Ketone Hydrates Using a Colorimetric Sensor.The Journal of organic chemistry · 2025Article
- Computationally Guided Design, Synthesis, and Evaluation of Novel Non-Hydroxamic Histone Deacetylase Inhibitors, Based onPharmaceuticals (Basel, Switzerland) · 2025Article
- Development of ketalized unsaturated saccharides as multifunctional cysteine-targeting covalent warheads.Communications chemistry · 2024Article
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Authors and funding
10 authors.
Funding
Abstract
Epigenetic regulation of gene expression using histone deacetylase (HDAC) inhibitors is a promising strategy for developing new anticancer agents. The most common HDAC inhibitors are hydroxamates, which, though highly potent, have limitations due to their poor pharmacokinetic properties and lack of isoform selectivity. Trifluoromethylketones (TFMK) developed as alternatives to hydroxamates are rapidly metabolized to inactive trifluoromethyl alcohols in vivo, which prevented their further development as potential drug candidates. In order to overcome this limitation, we designed trifluoropyruvamides (TFPAs) as TFMK surrogates. The presence of an additional electron withdrawing group next to the ketone carbonyl group made the hydrate form of the ketone more stable, thus preventing its metabolic reduction to alcohol in vivo. In addition, this structural modification reduces the potential of the TFMK group to act as a covalent warhead to eliminate off-target effects. Additional structural changes in the cap group of the inhibitors gave analogues with IC
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