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

A study was performed on the structure-activity relationships of a series of phenol derivs., CVFM analogs, derived from the two most active compds. of a first series (1A and 1B) of inhibitors of Ras farnesyl transferase (FTase) that we have recently described. We report the synthesis and the activity of a second series of compds. in which the phenylalanine residue was replaced by unconventional arom. and non-arom. amino acids, with varying electronic, lipophilic, steric and conformational properties. The compds. showed to be significantly less active than ref. compds. against FT, with the only exception of deriv. 3A (IC50 = 3 mM), which is slightly more active than 1A but not 1B. Subsequently we tested the effects of compds. 1A, 1B and 3A, 3B on the anchorage-dependent growth of two epithelial cell lines of rats, FRTL-5 and the same line v-Ha-ras transformed. Compd. 3A derived from lead compd. 1A, showed an appreciable selectivity against transformed cells. In contrast, compds. derived from deriv. 1B had only a modest cellular activity.