Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group

Abstract

Vorinostat (SAHA) with great therapeutic potential has been approved by the FDA for the treatment of cutaneous T-cell lymphoma as the first HDACs inhibitor, but the drawbacks associated with hydroxamic acid group (poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity) have been exposed during the continuous clinical application. Based on the pharmacophore of HDAC inhibitors, two series of compounds with novel zinc binding group (ZBG) were designed and synthesized, and the antitumor bioactivities were evaluated in four human cancer cell lines (A549, Hela, HepG2, and MCF-7). Among the synthesized compounds, compounds <b>a6</b>, <b>a9</b>, <b>a10</b>, <b>b8</b>, and <b>b9</b> exhibited promising inhibitory activities against the selected tumor cell lines, especially compounds <b>a9</b> and <b>b8</b> on Hela's cytostatic activity (<b>a9</b>: IC₅₀ = 11.15 ± 3.24 μM; <b>b8</b>: IC₅₀ = 13.68 ± 1.31 μM). The enzyme inhibition assay against Hela extracts and HDAC1&6 subtypes showed that compound <b>a9</b> had a certain broad-spectrum inhibitory activity, while compound <b>b8</b> had selective inhibitory activity against HDAC6, which was consistent with Western blot results. In addition, the inhibitory mechanism of compounds <b>a9</b> and <b>b8</b> in HDAC1&6 were both compared through computational approaches, and the binding interactions between the compounds and the enzymes target were analyzed from the perspective of energy profile and conformation. In summary, the compounds with novel ZBG exhibited certain antitumor activities, providing valuable hints for the discovery of novel HDAC inhibitors.