Inhibitors of Protein:Farnesyl Transferase and Protein:Geranylgeranyl Transferase I: Synthesis of Homologous Diphosphonate Analogs of Isoprenylated Pyrophosphate

Novel diphosphonate homologs7a–7c,and their cyclic counterparts8a–8c,of the previously synthesized farnesyl pyrophosphate analogs1and2were prepared and tested for their inhibition potency and specificity of the enzymes PFT and PGGT-I. Compound2was shown to be the most potent inhibitor of PFT (IC50= 0.58 ± 0.45 μM) in this series. The novel compound7a,the one carbon homolog of2,proved to be the most potent inhibitor of PGGT-I (IC50= 0.98 ± 0.01 μM). The cyclic analogs8a–8care generally less biologically active. The compounds2and7aare nonspecific toward inhibition of PFT and PGGT-I and may inhibit both farnesylation and geranylgeranylation processing of oncogenic proteins.