Phenol-derived CVFM analog inhibitors of ras farnesyltransferase possessing cellular in vitro activity.

A study was performed on structure-activity relationships of a series of phenol-derived, CVFM analogs, inhibitors of Pas Farnesyltransferase (FTase). The effect of various substituents on the phenol ring was examined, while the VFM moiety of the potent inhibitor CVFM was kept constant. The FTase inhibitory activity, reported as IC50 in table I, was influenced by both the chemical properties and the relative position of the substituents on the phenolic ring. The most active compounds in this series contained a chloro or bromine substituent on the phenolic ring. Subsequently we have tested the effects of these FTase inhibitors on the anchorage-dependent growth of two rat epithelial cell lines, FRTL-5 and the same line v-Ha-ras transformed, While most of the compounds were inactive, two showed a growth inhibitory effect: compound 4 was active against normal as well against transformed cells while derivative 13 was active only against transformed cells.