title: Tricyclic compounds containing nonenolizable cyano enones. A novel class of highly potent anti-inflammatory and cytoprotective agents.
abstract: 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-γ 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.
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States. tadashi.honda@stonybrook.edu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yoshizawa
authors.forename: Chitra
authors.initials: C
authors.lastname: Sundararajan
authors.forename: Emilie
authors.initials: E
authors.lastname: David
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Lajoie
authors.forename: Frank G
authors.initials: FG
authors.lastname: Favaloro
authors.forename: Tomasz
authors.initials: T
authors.lastname: Janosik
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Su
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Honda
authors.forename: Bill D
authors.initials: BD
authors.lastname: Roebuck
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Gribble
mesh_terms: D016604:Aflatoxin B1; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D019610:Cytoprotection; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053978:Pentacyclic Triterpenes / Q000737:chemistry; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D013237:Stereoisomerism; D013270:Stomach / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D009570:Nitriles; D053978:Pentacyclic Triterpenes; D010616:Phenanthrenes; C531972:TBE 31; D007371:Interferon-gamma; D016604:Aflatoxin B1; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse