Struktur-Wirkungs-Beziehungen thiolfreier Farnesyltransferase-Inhibitoren: 5-Arylacylaminobenzophenone

Farnesyltransferase catalyzes the transfer of a farnesyl residue to cystein side chains of proteins with a specific C-terminal amino acid sequence. This posttranslational modification is necessary for protein anchorage in membranes. Most of the proteins modified in this fashion are involved in signal transduction or regulation of the cell cycle. Therefore, farnesyltransferase is an interesting target for the development of anti tumor drugs. Furthermore, because farnesyltransferase activity has been demonstrated in protozoans, farnesyltransferase inhibitors are interesting as potential anti malaria drugs, as well. The main focus of this work is the synthesis of phenylacylamino derivatives, which have been established as non-thiol farnesyltransferase inhibitors. These compounds exhibit activity with IC50-values in the low micromolar range. By evaluating the structure-activity relationship of this series and using computer-based analysis, we were able to develop different arylacrylic acid and biarylacrylic acid derivatives. These compounds showed enhanced activity against the isolated enzyme with IC50-values in the lower nanomolar range. In addition, ten compounds showed antiplasmodial activity against a multiresistent strain of plasmodium falciparum with IC50-values of less than 100 nM.