Synthesis and evaluation of homofarnesoyl-substituted CAAX-peptidomimeticsas farnesyltransferase inhibitors and antiproliferative agents

Several CAAX-peptidomimetics were linked to homofarnesoic acid via a beta-a lanyl spacer with the intention to obtain a novel type of bisubstrate analo gue farnesyltransferase inhibitors. However, the compounds were found to be only weakly active in the farnesyltransferase inhibition assay. Neverthele ss, they displayed antiproliferative activity against different tumor cell lines in the low micromolar range. Replacement of the p-alanine moiety by a spartic acid-1-methyl ester resulted in a compound which inhibited the farn esyltransferase with an IC50 of 860 nM. The corresponding free acid showed a eightfold loss in activity (IC50 = 6.9 mu M). (C) 1999 Elsevier Science L td. All rights reserved.