Synthesis and SAR assessment of novel Tubathian analogs in the pursuit of potent and selective HDAC6 inhibitors

Organic & Biomolecular Chemistry
Rob De VreeseMatthias D'hooghe

Abstract

The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emerging field in medicinal chemistry. In this paper, the preparation and assessment of thirteen selective HDAC6 inhibitors is disclosed, elaborating on a previously developed thiaheterocyclic Tubathian series. All compounds were evaluated in vitro for their ability to inhibit HDAC6, and a selection of five potent compounds was further screened toward all HDAC isoforms (HDAC1-11). The capability of these Tubathian analogs to inhibit α-tubulin deacetylation was assessed as well, and ADME/Tox data were collected. This thorough SAR evaluation revealed that the oxidized, para-substituted hydroxamic acids can be recognized as valuable lead structures in the pursuit of novel potent and selective HDAC6 inhibitors.

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Citations

Mar 7, 2017·Future Medicinal Chemistry·Rob De VreeseMatthias D'hooghe
Jun 2, 2018·Current Medicinal Chemistry·Faria SultanaAhmed Kamal
Feb 13, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Na ZhaoHua Zhang
Feb 8, 2018·Brain : a Journal of Neurology·Veronick BenoyLudo Van Den Bosch
Dec 14, 2016·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Veronick BenoyLudo Van Den Bosch
Jan 30, 2019·International Journal of Cancer. Journal International Du Cancer·Yves DepetterOlivier De Wever
Nov 11, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Sravani PulyaBalaram Ghosh
Apr 10, 2019·Journal of Medicinal Chemistry·Magalie GéraldyAubry K Miller

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