Abstract
Histone acetylation is a critical process in the regulation of chromatin structure and gene expression. Histone deacetylases (HDACs) remove the acetyl group, leading to chromatin condensation and transcriptional repression. HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects. This paper describes our work on the structural determination and structure-activity relationship (SAR) optimization of tetrahydroisoquinoline compounds as HDAC inhibitors. These compounds were tested for their ability to inhibit HDAC 1, 3, 6 and for their ability to inhibit the proliferation of a panel of cancer cell lines. Among these, compound 82 showed the greatest inhibitory activity toward HDAC 1, 3, 6 and strongly inhibited growth of the cancer cell lines, with results clearly superior to those of the reference compound, vorinostat (SAHA). Compound 82 increased the acetylation of histones H3, H4 and tubulin in a concentration-dependent manner, suggesting that it is a broad inhibitor of HDACs.