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/

4-Ipomeaol (4-IPO) is an investigational drug with specific toxicity t oward the lung. The tobacco-specific nitrosamine 4-(methylnitrosamino) - 1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen in severa l laboratory animals. Both IPO and NNK are toxic upon metabolic activa tion 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 inhibi tor of metabolic activation and tumorigenicity in A/J mouse lung. To e xtend these studies, we have synthesized 12 analogs of HPP, altering t he terminal alkyl group in 6 of them. In another 2 analogs we have sub stituted electron-donating or electron-withdrawing groups in the benze ne ring. Finally, we have altered the oxidation states of 1 and/or 4 p osition of HPP in the remaining 4 analogs. We have already examined th e effect of in vitro inhibition of NNK metabolism by these 12 IPO anal ogs. In the present study, we have examined 4 IPO analogs that are pot ent inhibitors of in vitro NNK metabolism namely; 4-hydroxy-1-phenyl-1 -octanone (4-HPO), 1,4-diphenyl-4-hydroxy-1-butanone (DPHB), 4-hydroxy -1-phenylpentane (HPPentane), and amyl benzene and tested their inhibi tory effects toward the NNK-induced lung tumorigenicity in A/J mice.