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

Abstract : 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.
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Submitted on : Tuesday, August 13, 2019 - 8:24:01 AM
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Samuel Bouchet, Camille Linot, Dusan Ruzic, Danica Agbaba, Benoit Fouchaq, et al.. Extending Cross Metathesis To Identify Selective HDAC Inhibitors: Synthesis, Biological Activities, and Modeling. ACS Medicinal Chemistry Letters, American Chemical Society, 2019, 10 (6), pp.863-868. ⟨10.1021/acsmedchemlett.8b00440⟩. ⟨inserm-02265954⟩

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