Molecular Insights into Azumamide E Histone Deacetylases Inhibitory Activity

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• 作者：Nakia Maulucci ; Maria Giovanna Chini ; Simone Di Micco ; Irene Izzo ; Emiddio Cafaro ; Adele Russo ; Paola Gallinari ; Chantal Paolini ; Maria Chiara Nardi ; Agostino Casapullo ; Raffaele Riccio ; Giuseppe Bifu
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：March 14, 2007
• 年：2007
• 卷：129
• 期：10
• 页码：3007 - 3012
• 全文大小：534K
• 年卷期：v.129,no.10(March 14, 2007)
• ISSN：1520-5126

文摘

Azumamide E, a cyclotetrapeptide isolated from the sponge Mycale izuensis, is the most powerfulcarboxylic acid containing natural histone deacetylase (HDAC) inhibitor known to date. In this paper, wedescribe design and synthesis of two stereochemical variants of the natural product. These compoundshave allowed us to clarify the influence of side chain topology on the HDAC-inhibitory activity. The presentcontribution also reveals the identity of the recognition pattern between azumamides and the histonedeacetylase-like protein (HDLP) model receptor and reports the azumamide E unprecedented isoformselectivity on histone deacetylases class subtypes. From the present studies, a plausible model for theinteraction of azumamides with the receptor binding pocket is derived, providing a framework for the rationaldesign of new cyclotetrapeptide-based HDAC inhibitors as antitumor agents.