Synthesis and biological evaluation of the Fluoro analog of Romidepsin with improved selectivity for class I histone deacetylases (HDACs)

Selective inhibition of Class I HDACs has emerged as a promising approach for cancer therapy. Building on our previous work with Largazole (a member of the natural depsipeptide family), we have applied a similar fluorination modification to Romidepsin and synthesized its fluoro analog (12) in 12 steps. This analog exhibits potent inhibitory activity against Class I HDACs but shows no inhibitory effect on HDAC6, confirming its selectivity as a Class I HDAC inhibitor (IC50 HDAC1 0.95 nM, HDAC2 0.86, HDAC 3 1.1 nM, HDAC8 4.2 nM, HDAC6 > 103 nM). Compared with Romidepsin, compound 12 demonstrates significant growth inhibition in two cancer cell lines (NCI-H1975 and HT29) while exhibiting markedly less growth inhibition in two normal cell lines (WRL-68 and HEK293). Further studies reveal that 12 is capable of blocking the cell cycle and inducing apoptosis, thereby exerting anticancer activity. Moreover, 12 possesses metabolic stability comparable to Romidepsin. In a mouse model, 12 demonstrates strong in vivo antitumor efficacy similar to that of Romidepsin, yet with significantly reduced toxicity. These findings support the potential of this fluoro analog as a highly selective Class I HDAC inhibitor and highlight its promise as a superior alternative to Romidepsin for further development.

Keywords: Q1 2025