Design of N-substituted Amino Caproic Hydroxamic Acid Histone Deacetylase Inhibitors Reveal an Essential Role for Cap Atomic Composition

Jean      M. Brunel; Chanaz      Salmi-Smail; Audrey      Restouin; Thomas      Prebet; Norbert      Vey; Yves      Collette

doi:10.2174/187152012802650192

Abstract

A series of N-substituted amino caproic hydroxamic acid histone deacetylase inhibitors derivatives was designed in good-toexcellent yields and evaluated for their antiproliferative activity in a panel of human cancer cell lines, showing half maximum effective concentration varying from 700 nM to > 100 μM. Interestingly, the replacement of a furyl group by a thienyl one impacted very significantly the cap role on this antiproliferative activity and on histone acetylation induced by these drugs in cell-based but also in cell-free enzyme assays, suggesting an important role of the electronic density attached to the oxygen or sulfur atoms.

Keywords: N-substituted amino caproic hydroxamic acid, Histone deacetylase inhibitors, Anticancer agents, SAHA derivatives, carcinogenesis, dichloromethane, chromatography, aminohexanoic.