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Extending Cross Metathesis To Identify Selective HDAC Inhibitors: Synthesis, Biological Activities, and Modeling

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posted on 09.05.2019, 00:00 by Samuel Bouchet, Camille Linot, Dusan Ruzic, Danica Agbaba, Benoit Fouchaq, Joëlle Roche, Katarina Nikolic, Christophe Blanquart, Philippe Bertrand
Dissymmetric cross metathesis of alkenes as a convergent and general synthetic strategy allowed for the preparation of a new small series of human histone deacetylases (HDAC) inhibitors. Alkenes bearing Boc-protected hydroxamic acid and benzamide and trityl-protected thiols were used to provide the zinc binding groups and were reacted with alkenes bearing aromatic cap groups. One compound was identified as a selective HDAC6 inhibitor lead. Additional biological evaluation in cancer cell lines demonstrated its ability to stimulate the expression of the epithelial marker E-cadherin and tumor suppressor genes like SEMA3F and p21, suggesting a potential use of this compound for lung cancer treatment. Molecular docking on all 11 HDAC isoforms was used to rationalize the observed biological results.