Phenylpyrrole-based HDAC inhibitors: synthesis, molecular modeling and biological studies

Abstract

Aim: Histone deacetylases (HDACs) regulate the expression and activity of numerous proteins involved in the initiation and progression of cancer. Currently, three hydroxamate-containing HDAC pan-inhibitors have been approved as antitumor agents.

Results: We herein present the development of a series of novel phenylpyrrole-based derivatives stemmed from combined computational and medicinal chemistry efforts to rationally modulate HDAC1/6 isoform selectivity. In vitro activity on HDAC1 and HDAC6 isoforms and the effects of selected analogs on histone H3 and α-tubulin acetylation levels were determined. Cell-based data evidenced, for selected compounds, a promising antitumor potential and low toxicity on normal cells.

Conclusion: The newly developed compounds represent a valuable starting point for the development of novel anticancer agents.

Keywords: HDAC; antitumor agents; bioinformatics; drug design; enzyme inhibitors; epigenetics.