Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability

…, J Lyle, PM Loadman, SJ Crabb, G Packham…

Index: Benelkebir, Hanae; Marie, Sabrina; Hayden, Annette L.; Lyle, Jason; Loadman, Paul M.; Crabb, Simon J.; Packham, Graham; Ganesan Bioorganic and Medicinal Chemistry, 2011 , vol. 19, # 12 p. 3650 - 3658

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Citation Number: 37

Abstract

The total synthesis of largazole and four analogues is reported. All analogues were nanomolar HDAC inhibitors. The antiproliferative activity is driven by lipophilicity and cell permeability. In murine liver homogenates, largazole is rapidly metabolized (half-life⩽ 5min) to the thiol which has a half-life of 51min.