Non-peptidic, non-prenylic bisubstrate farnesyltransferase inhibitors. Part 3: Structural requirements of the central moiety for farnesyltransferase inhibitory activity

Recently, we have described non-peptidic, non-prenylic bisubstrate analogue s as a novel type of farnesyltransferase inhibitor composed of a farnesyl-m imetic, a linker and an AAX-peptidomimetic substructure. With this study, w e showed that the amide function connecting the farnesyl-mimetic and the li nking substructures of our inhibitors is crucial for their activity. We sug gest that the amide is bound to the essential zinc ion in the farnesyltrans ferases active center. We identified succinic and glutaric acid, respective ly, in addition to the initially used beta-alanyl moiety as suitable linkin g structures. Glycine can also be used in this function provided the distan ce between the alpha-amide group and the center of the peptidomimetic subst ructure is enlarged by introduction of an additional methylene unit into th e peptidomimetic substructure. (C) 2000 Elsevier Science Ltd. All rights re served.