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J Med Chem. 2008 Dec 11;51(23):7352-5. doi: 10.1021/jm801146d.

Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases.

Author information

1
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China.

Abstract

A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with K(i) of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay, induces cIAP-1 degradation, inhibits cell growth with an IC(50) of 68 nM in the MDA-MB-231 cancer cell line, and effectively induces cancer cells to undergo apoptosis.

PMID:
19012392
PMCID:
PMC2662380
DOI:
10.1021/jm801146d
[Indexed for MEDLINE]
Free PMC Article

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