Synthesis, pharmacological evaluation, and molecular modeling studies of novel peptidic CAAX analogues as farnesyl-protein-transferase inhibitors

Fifteen analogues of the C-terminal CA₁A₂X motif were synthesized and evaluated for their inhibition potency against farnesyltransferase (FTase). Replacement of the A₂ residue by phenylalanine or tyrosine-derived analogues, in which a different number of methyl groups were introduced on the aromatic ring, resulted in compounds less active than the reference compound CVFM against FTase except for compounds I and VI (IC₅₀ = 1 μM and 2.5 μM, respectively) that were comparable to CVFM and compound IV (IC₅₀ = 0.1 μM), which was 6-fold more active than the reference compound. Because pseudopeptidic derivatives I-IX were inactive in the cellular assays, the N-formyl- and methyl-ester derivatives (compounds X-XV) were synthesized and tested on different cell lines, showing, in some cases, activity and appreciable selectivity against transformed cells. To rationalize the obtained results, molecular modeling experiments were carried out suggesting the molecular basis of FTase inhibition by these products.