A new family of protein farnesyltransferase inhibitors, based on a ferrocene scaffold, was designed and synthesized. The biological evaluation of these compounds showed that ferrocenyl(2,3,4-trimethoxyphenyl)methanone (4c) and (ferrocen-1-yl)(2,3,4-trimethoxyphenyl)hydroxyimine (16) were two of the most active compounds, with protein farnesyltransferase inhibition potencies in the low micromolar range. The investigation of the influence of different bulky substituents (paracyclophane, noradamantane and adamantane) on the biological activity showed that these structural modifications abolished farnesyltransferase affinity. Molecular modeling studies revealed that the ferrocene unit of newly synthesized compounds was a well tolerated bulky group, for the A2 binding site of farnesyltransferase. Compounds were also evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. Paracyclophane derivative 13 exhibited the most potent in vitro cytostatic activity inhibiting the growth of MCF7, MDA-MB-468, T-47D and HT-29 cell lines.
