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

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• 作者：Pravin Bhansali ; Christin L. Hanigan ; Robert A. Casero ; Jr. ; L. M. Viranga Tillekeratne
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7453-7463
• 全文大小：1101K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-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 Znp>2+p> were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of 伪-tubulin.