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A series of potent and selective, triazolylphenyl-based histone deacetylases inhibitors with activity against pancreatic cancer cells and Plasmodium falciparum.

Authors
  • Chen, Yufeng
  • Lopez-Sanchez, Miriam
  • Savoy, Doris N
  • Billadeau, Daniel D
  • Dow, Geoffrey S
  • Kozikowski, Alan P
Type
Published Article
Journal
Journal of medicinal chemistry
Publication Date
Jun 26, 2008
Volume
51
Issue
12
Pages
3437–3448
Identifiers
DOI: 10.1021/jm701606b
PMID: 18494463
Source
Medline
License
Unknown

Abstract

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.

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