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

• Published in: ACS medicinal chemistry letters Vol. 10; no. 6; pp. 863 - 868
• Main Authors: Bouchet, Samuel, Linot, Camille, Ruzic, Dusan, Agbaba, Danica, Fouchaq, Benoit, Roche, Joëlle, Nikolic, Katarina, Blanquart, Christophe, Bertrand, Philippe
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.06.2019; Amer Chemical Soc
• Subjects: Cancer; Chemistry, Medicinal; Letter; Life Sciences; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Cross metathesis; lung cancer; histone deacetylases; molecular modeling; epigenetics; DESIGN; THERAPY; HYDROXAMIC ACIDS; T-CELL LYMPHOMA; HISTONE DEACETYLASE INHIBITORS; INSERM; Universitéd'Angers; Nantes; Universitéde Nantes; France § KEYWORDS: Cross metathesis; CRCINA
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.8b00440

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.