Total Synthesis and Biological Evaluation of Largazole and Derivatives with Promising Selectivity for Cancers Cells
Organic Letters2010Vol. 12(6), pp. 1368–1371
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Xin Zeng, Biaolin Yin, Zheng Hu, Chenzhong Liao, Jinglei Liu, Shang Li, Zheng Li, Marc C. Nicklaus, Guang‐Biao Zhou, Sheng Jiang
Abstract
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.
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