Largazole and Analogues with Modified Metal-Binding Motifs Targeting Histone Deacetylases: Synthesis and Biological Evaluation

The histone deacetylase inhibitor largazole <b>1</b> was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using <i>tert</i>-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn²⁺ were synthesized, and their biological activities were evaluated. They were less potent than largazole <b>1</b> in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole <b>1</b> and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin