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Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors.

作者信息

Dallavalle Sabrina, Cincinelli Raffaella, Nannei Raffaella, Merlini Lucio, Morini Gabriella, Penco Sergio, Pisano Claudio, Vesci Loredana, Barbarino Marcella, Zuco Valentina, De Cesare Michelandrea, Zunino Franco

机构信息

Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.

出版信息

Eur J Med Chem. 2009 May;44(5):1900-12. doi: 10.1016/j.ejmech.2008.11.005. Epub 2008 Nov 19.

DOI:10.1016/j.ejmech.2008.11.005
PMID:19084294
Abstract

A series of hydroxamic acid-based histone deacetylase (HDAC) inhibitors were designed on the basis of a model of the HDAC2 binding site and synthesized. They are characterized by a cinnamic spacer, capped with a substituted phenyl group. Modifications of the spacer are also reported. In an in vitro assay with the isoenzyme HDAC2, a good correlation of the activity with the docking energy was found. In human ovarian carcinoma IGROV-1 cells, selected compounds produced significant acetylation of p53 and alpha-tubulin. Most compounds showed an antiproliferative activity comparable to that of SAHA. At equitoxic concentrations, the tested compounds were more effective than SAHA in inducing apoptotic cell death. Compounds selected for in vivo evaluation exhibited a significant antitumor activity on three tumor models at well tolerated doses, thus suggesting a good therapeutic index.

摘要

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