Design, synthesis and anti-cervical cancer activity of aroylpyrrole-based derivatives as potent histone deacetylase 6 inhibitors

Abstract

Cancers, such as cervical carcinoma, are one of the most significant diseases affecting human health and histone deacetylases (HDACs) are striking targets in current antitumor drug development. Compared to pan-HDAC inhibitors with potential toxicity, the development of selective HDAC6 inhibitors (sHDAC6is) is a major research focus. In this study, a series of derivatives bearing an aroylpyrrole core were designed and synthesized using a scaffold-hopping strategy. Among these, the best compound 4-benzoyl-1-(4-fluorobenzyl)-N-(7-(hydroxyamino)-7-oxoheptyl)-1H-pyrrole-2-carboxamide (10g) inhibited HDAC6 with an IC₅₀ of 3.9 nM and superior selectivity over HDAC1 compared to ACY-1215. In vitro, these aroylpyrroles demonstrated promising antiproliferative activities against Hela and SiHa tumor cells. 10g also showed superior metabolic stability compared to ACY-1215 in a microsomal stability study. In summary, this work highlighted the therapeutic potential of aroylpyrrole-based sHDAC6 inhibitors and provided a valuable lead compound in treating cervical cancer.