Non-peptidic, Non-prenylic Bisubstrate Farnesyltransferase Inhibitors, 4. Effect on Farnesyltransferase Inhibitory Activity of Conformational Restrictions in the Central Group

We have recently described non-peptidic, non-prenylic bisubstrate analogues as novel farnesyltransferase inhibitors comprising three modules-a farnesylmimetic, a linker and an AAX-peptidomimetic substructure. In this study we replaced the originally used β-alanyl linker by several aliphatic and cyclic amino acids to investigate the effects on inhibitory potential of the stereochemistry of this central group. Whereas replacement of β-alanine by glycine did not affect inhibitory activity, all other modifications resulted in reduced activity. This result, which will be helpful for further development, shows that the bioactive conformation is none of those fixed by the rigid linkers.