Total Synthesis and Biological Evaluation of Largazole and Derivatives with Promising Selectivity for Cancers Cells

The efficient total synthesis of the natural substance largazole is described. Using this strategy, a small library of largazole analogs was developed. Structure-activity relationship studies suggested that the geometry of the alkene in the side chain is critical. While the largazole's analogues with trans-alkene are potent for the antiproliferative effect, those with cis-alkene are completely inactive. Most importantly, replacement of valine with tyrosine in largazole increased selectivity toward human cancer cells over human normal cells more than 100-fold.