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

Recently, we have described non-peptidic, non-prenylic bisubstrate analogues as a novel type of farnesyltransferase inhibitor composed of a farnesyl-mimetic, a linker and an AAX-peptidomimetic substructure. With this study, we showed that the amide function connecting the farnesyl-mimetic and the linking substructures of our inhibitors is crucial for their activity. We suggest that the amide is bound to the essential zinc ion in the farnesyltransferases active center. We identified succinic and glutaric acid, respectively, in addition to the initially used β-alanyl moiety as suitable linking structures. Glycine can also be used in this function provided the distance between the α-amide group and the center of the peptidomimetic substructure is enlarged by introduction of an additional methylene unit into the peptidomimetic substructure.