A Series of Potent and Selective, Triazolylphenyl-Based Histone Deacetylases Inhibitors with Activity against Pancreatic Cancer Cells and Plasmodium falciparum

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• 作者：Yufeng Chen ; Miriam Lopez-Sanchez ; Doris N. Savoy ; Daniel D. Billadeau ; Geoffrey S. Dow ; Alan P. Kozikowski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 26, 2008
• 年：2008
• 卷：51
• 期：12
• 页码：3437 - 3448
• 全文大小：482K
• 年卷期：v.51,no.12(June 26, 2008)
• ISSN：1520-4804

文摘

The discovery of the rules governing the inhibition of the various HDAC isoforms is likely to be key to identifying improved therapeutics that act as epigenetic modulators of gene transcription. Herein we present results on the modification of the CAP region of a set of triazolylphenyl-based HDACIs, and show that the nature of substitution on the phenyl ring plays a role in their selectivity for HDAC1 versus HDAC6, with low to moderate selectivity (2−51-fold) being achieved. In light of the valuable selectivity and potency that were identified for the triazolylphenyl ligand 6b in the inhibition of HDAC6 (IC₅₀ = 1.9 nM), this compound represents a valuable research tool and a candidate for further chemical modifications. Lastly, these new HDACIs were studied for both their anticancer and antimalarial activity, which serve to validate the superior activity of the HDACI 10c.