期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 6, 页码 1762-1778出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm101445p
关键词
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资金
- NIH [R03-CA105294, R01-CA39416]
- Reata Pharmaceuticals
- American Cancer Society [RSG-07-157-01-CNE]
- Cancer Research UK [C20953/A10270]
- Arnold and Mabel Beckman Foundation
- John Zabriskie' 61
- Cancer Research UK [10270] Funding Source: researchfish
Forty-four novel tricycles containing nonenolizable cyano enones (TCEs) were designed and synthesized on the basis of a semisynthetic pentacyclic triterpenoid, bardoxolone methyl, which is currently being developed in phase II clinical trials for the treatment of severe chronic kidney disease in diabetic patients. Most of the TCEs having two different kinds of nonenolizable cyano enones in rings A and C are highly potent suppressors of induction of inducible nitric oxide synthase stimulated with interferon-gamma and are highly potent inducers of the cytoprotective enzymes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Among these compounds, (+/-)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile ((+/-)-31) is the most potent in these bioassays in our pool of drug candidates including semisynthetic triterpenoids and synthetic tricycles. These facts strongly suggest that an essential factor for potency is not a triterpenoid skeleton but the cyano enone functionality. Notably, TCE 31 reduces hepatic tumorigenesis induced with aflatoxin in rats. Further preclinical studies and detailed mechanism studies on 31 are in progress.
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