Synthesis and Antiproliferative Activity of Nitric Oxide-Donor Largazole Prodrugs

Abstract

The marine natural product Largazole is the most potent Class I HDAC inhibitor identified to date. Since its discovery, many research groups have been attracted by the structural complexity and the peculiar anticancer activity, due to its capability to discriminate between tumor cells and normal cells. Herein, we discuss the synthesis and the in vitro biological profile of hybrid analogues of Largazole, as dual HDAC inhibitor and nitric oxide (NO) donors, potentially useful as anticancer agents. In particular, the metabolic stability of the modified thioester moiety of Largazole, bearing the NO-donor function/s, the in vitro release of NO, and the antiproliferative activity in tumor cell lines are presented.

Dual inhibitors of histone deacetylases and other cancer-related targets: A pharmacological perspective

“…Compound 84 [258], a close analog of 82 but with different NO-releasing group, might be severed as a therapeutic tool molecule for cardiovascular, neuromuscular, and inflammatory diseases as it possesses muscle differentiation function. The thio ester prodrug 85 [259] is found to release largazole (an HDACs inhibitor) and NO upon ester hydrolysis. In cellular assay, 85 shows greater anti-proliferative effects against U-2OS and IMR-32 cells than largazole alone, indicating additive effects contributed from NO release.…”