This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC50 = 1.48 μM), MDA-MB-468 (IC50 = 0.65 μM), and liver cancer cells HepG2 (IC50 = 2.44 μM), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC inhibitor SAHA, 14 showed a higher toxicity (IC50 = 0.33 μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563 μM respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents.
Keywords: Drug resistance; Histone deacetylase inhibitors; Isosters; Purines.
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