Tricyclic Compounds Containing Nonenolizable Cyano Enones. A Novel Class of Highly Potent Anti-Inflammatory and Cytoprotective Agents

被引：62

作者：

Honda, Tadashi ^{[1
]}

Yoshizawa, Hidenori ^{[1
]}

Sundararajan, Chitra ^{[1
]}

David, Emilie ^{[1
]}

Lajoie, Marc J. ^{[1
]}

Favaloro, Frank G., Jr. ^{[1
]}

Janosik, Tomasz ^{[1
]}

Su, Xiaobo ^{[1
]}

Honda, Yukiko ^{[1
]}

Roebuck, Bill D. ^{[2
]}

Gribble, Gordon W. ^{[1
]}

机构：

[1] Dartmouth Coll, Dept Chem, Hanover, NH 03755 USA

[2] Dartmouth Med Sch, Dept Pharmacol & Toxicol, Hanover, NH 03755 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 06期

关键词：

NITRIC-OXIDE PRODUCTION; CDDO INDUCES APOPTOSIS; 2-CYANO-3,12-DIOXOOLEAN-1,9-DIEN-28-OIC ACID; EFFICIENT SYNTHESIS; SYNTHETIC OLEANANE; DIRECT INHIBITION; HEME OXYGENASE-1; METHYL-ESTER; RING-A; URSANE TRITERPENOIDS;

D O I：

10.1021/jm101445p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1762 / 1778

页数：17

共 85 条

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