Extending Cross Metathesis To Identify Selective HDAC Inhibitors: Synthesis, Biological Activities, and Modeling
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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 Bocprotected 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.
Keywords:Cross metathesis / histone deacetylases / lung cancer / epigenetics / molecular modeling
Source:ACS Medicinal Chemistry Letters, 2019, 10, 6, 863-868
- Amer Chemical Soc, Washington