Design, synthesis and biological evaluation of novel histone deacetylase 6 inhibitors containing indole-based cap groups

Abstract

Based on our previous report, this study systematically elucidated the development process of a novel class of HDAC6 inhibitors containing indole-based cap groups. Starting from lead compound L9 identified via an in-house compound library screening, systematic structural optimization was performed, and a series of derivatives were designed and synthesized. Structure-activity relationship (SAR) studies demonstrated the advantages of cap groups derived from indole ring and the preference of different modification sites. We finally identified compound 10n, substituted with a cyclopropyl-methyl group in the N-1 position of its indole ring, as the most potent HDAC6 inhibitor (IC₅₀ = 3.11 ± 0.09 nM), with selectivity ratios of 27.8- to 622.2-fold over HDAC1/2/3/8 and >3000-fold over other isoforms. In vitro evaluations further demonstrated its potential anti-proliferative and apoptosis-inducing ability in gastric cancer, as well as good in vivo pharmacokinetic properties. Docking analysis revealed its strong binding affinity to the HDAC6 catalytic pocket: including spatial complementarity in conformation and the formation of strong interactions with nearby amino acid residues. These findings highlight 10n as a promising scaffold for developing HDAC6-selective inhibitors, with structural insights guiding future optimizations.