Synthesis and biological activity of pseudopeptides inhibitors of Ras farnesyl transferase containing unconventional amino acids

Abstract

A study was performed on the structure–activity relationships of a series of phenol derivatives, CVFM analogs, derived from the two most active compounds of a first series ( 1 A and 1 B ) of inhibitors of Ras farnesyl transferase (FTase) that we have recently described. We report the synthesis and the activity of a second series of compounds in which the phenylalanine residue was replaced by unconventional aromatic and non-aromatic amino acids, with varying electronic, lipophilic, steric and conformational properties. The compounds showed to be significantly less active than reference compounds against FT, with the only exception of derivative 3 A (IC 50=3 μM), which is slightly more active than 1 A but not 1 B . Subsequently we tested the effects of compounds 1 A , 1 B and 3 A , 3 B on the anchorage-dependent growth of two epithelial cell lines of rats, FRTL-5 and the same line v-Ha-ras transformed. Compound 3 A derived from lead compound 1 A , showed an appreciable selectivity against transformed cells. In contrast, compounds derived from derivative 1 B had only a modest cellular activity.