NYL)-3-(BETA-ARYLVINYLKETO)-1-ETHYL-4-PIPERIDINOLS AND RELATED-COMPOUNDS - A NOVEL CLASS OF CYTOTOXIC AND ANTICANCER AGENTS

The syntheses of a series of 1-aryl-5-diethylamino-1-penten-3-one hydr ochlorides 1 and 1-aryl-3-diethylamino-1-propanone hydrochlorides 4 we re accomplished. Attempts to prepare the corresponding bis(5-aryl-3-ox o-4-pentenyl)ethylamine hydrochlorides 2 and bis(3-aryl-3-oxo-propyl)e thylamine hydrochlorides 5 led to the formation of a series of inyl)-3 -(beta-arylvinylketo)-1-ethyl-4-piperidinol hydrochlorides 9 and 4-ary l-3-arylketo-1-ethyl-4-piperidinol hydrochlorides 11, most of which we re converted subsequently into the corresponding quaternary ammonium s alts 10 and 12, respectively. The structures of these compounds were d etermined by H-1 NMR spectroscopy and confirmed by X-ray crystallograp hy of representative molecules. Most compounds displayed significant c ytotoxicity toward murine P388 and L1210 cells as well as human tumors . In general, Mannich bases containing olefinic bonds were more cytoto xic than the analogues without this functional group, while the piperi dines 9 and 11 were more potent than the acyclic analogues 1 and 4, re spectively. Correlations were noted between various physicochemical co nstants in the aryl rings and cytotoxicity, Compound 9d displayed prom ising in vivo activity against colon cancers. This study has revealed that the piperidines 9 and 11 constitute new classes of cytotoxic agen ts.