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J Med Chem. 2012 Nov 26;55(22):9891-9. doi: 10.1021/jm301098e. Epub 2012 Oct 23.

Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth.

Author information

1
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.

Abstract

The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5 g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ∼600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.

PMID:
23009203
PMCID:
PMC3562128
DOI:
10.1021/jm301098e
[Indexed for MEDLINE]
Free PMC Article

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