title: Novel synthetic pyridyl analogues of CDDO-Imidazolide are useful new tools in cancer prevention.
abstract: Two new analogues of CDDO-Imidazolide (CDDO-Im), namely 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole ("CDDO-2P-Im") and 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-3-yl)-1H-imidazole ("CDDO-3P-Im") have been synthesized and tested for their potential use as chemopreventive drugs. At nanomolar concentrations, they were equipotent to CDDO-Im for inducing differentiation and apoptosis in U937 leukemia cells. As inflammation and oxidative stress contribute to carcinogenesis, we also assessed their cytoprotective potential. The new compounds suppressed inducible nitric oxide synthase (iNOS) expression in RAW264.7 macrophage-like cells and significantly elevated heme oxygenase-1 (HO-1) and quinone reductase (NQO1) mRNA and protein levels in various mouse tissues in vivo. Most importantly, pharmacokinetic studies performed in vitro in human plasma and in vivo showed that each new analogue was more stable than CDDO-Im. Much higher concentrations of the new derivatives were found in mouse liver, lung, pancreas and kidney after gavage in contrast to CDDO-Im. Because of their better bioavailability and their excellent anti-inflammatory profile in vitro, CDDO-2P-Im and CDDO-3P-Im were tested for prevention in a highly relevant mouse lung cancer model, in which A/J mice develop lung carcinomas after injection of vinyl carbamate, a potent carcinogen. CDDO-2P-Im and CDDO-3P-Im were as effective as CDDO-Im for reducing the size and the severity of the lung tumors.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA.
authors.forename: Martine
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH, USA.
authors.forename: Evans O
authors.initials: EO
authors.lastname: Onyango
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Williams
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA.
authors.forename: Darlene B
authors.initials: DB
authors.lastname: Royce
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH, USA.
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Gribble
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA. Electronic address: Karen.T.Liby@Dartmouth.edu.
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D020298:U937 Cells
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D007093:Imidazoles; D012333:RNA, Messenger; D009828:Oleanolic Acid; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: CDDO-Imidazolide; Chemoprevention; HO-1; Lung carcinogenesis; NQO1; Nitric oxide; Nrf2; Pyridyl analogues; Vinyl carbamate