In this study, a collection of N-(6-mercaptohexyl)-3-substituted-1H-pyrazole-5-carboxamide HDAC inhibitors was developed. Among them, 15k was identified as the most potent inhibitor against total HDACs with IC50 of 0.008 μM. Further isoenzyme assays revealed that 15k and its analogs have a preference for HDAC1-3 (class I) and HDAC6 (class IIb) isoforms. The enzyme-based potencies of 15k were 2- to 11-fold higher than those of Vorinostat. The disulfide prodrug 18 was found to be potent cytotoxic agent against a panel of seven tumor cells, causing hyper-acetylation of histone and non-histone proteins in cellular level. In addition, 18 demonstrated a notable in vivo anti-tumor activity in HCT-116 xenografted model. This study provides further possibility of developing novel thiol-based HDAC inhibitors for the treatment of cancer.
Keywords: Anti-tumor; Disulfide; Histone deacetylase inhibitor; Prodrug; Structure-activity relationship; Thiol.
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