Journal of the American Chemical Society 2008-07-02

Total synthesis and molecular target of largazole, a histone deacetylase inhibitor.

Yongcheng Ying, Kanchan Taori, Hyoungsu Kim, Jiyong Hong, Hendrik Luesch

Index: J. Am. Chem. Soc. 130(26) , 8455-9, (2008)

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Abstract

Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the preparation of a series of key analogues, and the molecular target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biological evaluation of largazole and its key analogues, including an acetyl analogue, a thiol analogue, and a hydroxyl analogue, suggested that histone deacetylases (HDACs) are molecular targets of largazole and largazole is a class I HDAC inhibitor. In addition, structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.