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

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.