Pharmacological Research 2015-10-01

Novel synthetic pyridyl analogues of CDDO-Imidazolide are useful new tools in cancer prevention.

Martine Cao, Evans O Onyango, Charlotte R Williams, Darlene B Royce, Gordon W Gribble, Michael B Sporn, Karen T Liby

文献索引:Pharmacol. Res. 100 , 135-47, (2015)

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摘要

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. Copyright © 2015 Elsevier Ltd. All rights reserved.


相关化合物

  • 叠氮化钠
  • 氯化钠
  • 乙腈
  • 吡啶
  • 氯化钠-35cl
  • 苄磺酰氟
  • 苯醌
  • 4-苯基咪唑
  • 噻唑兰

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