Naphthalene-based hydroxamate HDAC inhibitors with anti-breast tumor activity

Histone deacetylases (HDACs) are attractive therapeutic targets due to their established role in tumorigenesis. In this study, a series of naphthalene-based hydroxamate derivatives were designed and synthesized as novel HDAC inhibitors. Among them, compound 6e showed excellent inhibitory activities against HDAC1 and 4T1 cancer cell line, and it also increased the levels of acetylated histones H3 and H4. Moreover, 6e induced significant cell apoptosis and cycle arrest. Importantly, 6e exhibited significant antitumor activity in the 4T1 orthotopic autograft mouse model. Collectively, these results identify the naphthalene-hydroxamate scaffold as a promising template for the development of novel HDAC-targeted anticancer agents.