Inhibitors of Human Histone Deacetylase: Synthesis and Enzyme Assay of Hydroxamates with Piperazine Linker

Abstract

The histone deacetylase (HDAC) enzyme plays an important role in gene transcription. Inhibitors of histone deacetylases induce cell differentiation and suppress cell proliferation in tumor cells. Hydroxamates with rigid linker have displayed better inhibition profiles than those with linear and flexible aliphatic linkers. We have designed and synthesized several potential histone deacetylase inhibitors with a piperazine moiety in the linker region to test the effect of reduced linker flexibility. Inhibitors were evaluated for their inhibitory action on human HDAC3/NCoR2 and HDAC8. N-Hydroxycarboxamide derivatives (compounds 4a-d) were found to be better than N-hydroxyacetamide derivatives (compounds 6a-d) against HDAC8. Amongst the synthesized compounds, 4a (HDAC8, IC50: 3.15 microM) with no substitution in the aryl cap was the most active and promising lead for further investigations.

Synthesis, Antimicrobial and Anticancer Activity of New Thiosemicarbazone Derivatives

“…The reaction comes to completion when evaluation of methyl mercaptan ceases 17, 18. The final hydroxamate derivatives 4a‐4l were obtained by the reaction of 3a–3l with phenyl chloroformate followed by hydroxylamine in THF at room temperature 19. An equimolar amount of triethylamine was added to neutralize the hydrochloric acid liberated during the course of reaction.…”