Synthesis and bioassay of 4-ipomeanol analogs as potential chemopreventive agents against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced tumorigenicity in A/J mice

Cancer Letters
D DesaiS Amin

Abstract

4-Ipomeanol (4-IPO) is an investigational drug with specific toxicity toward the lung. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen in several laboratory animals. Both IPO and NNK are toxic upon metabolic activation by cytochrome P450 enzyme(s) present in Clara cells of the lung. IPO and NNK are similar in structure and thus non-toxic analog of IPO could be competitive inhibitors of NNK metabolism in lung. 4-Hydroxyl-phenyl-1-pentanone (HPP), a non-toxic analog of IPO is a potent inhibitor of metabolic activation and tumorigenicity in A/J mouse lung. To extend these studies, we have synthesized 12 analogs of HPP, altering the terminal alkyl group in 6 of them. In another 2 analogs we have substituted electron-donating or electron-withdrawing groups in the benzene ring. Finally, we have altered the oxidation states of 1 and/or 4 position of HPP in the remaining 4 analogs. We have already examined the effect of in vitro inhibition of NNK metabolism by these 12 IPO analogs. In the present study, we have examined 4 IPO analogs that are potent inhibitors of in vitro NNK metabolism namely; 4-hydroxy-1-phenyl-1-octanone (4-HPO), 1,4-diphenyl-4-hydroxy-1-butanone (DPH...Continue Reading

Citations

Feb 9, 2000·Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology·Y K Leung, J W Ho
Jun 5, 2015·Acta Biochimica Et Biophysica Sinica·Guang-Zhe GeCeshi Chen
Jul 27, 2012·The Journal of Organic Chemistry·Hashim F MotiwalaJeffrey Aubé
Jun 24, 1998·Chemical Research in Toxicology·S S Hecht
May 17, 2005·Chemical Research in Toxicology·Brian R BaerKirk R Henne

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