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 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) (IC50 = 3 mu M), 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-aa-ras transformed. Compound 3, 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. (C) 1999 Elsevier Science S.A. All rights reserved.

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