Inhibitors of protein : farnesyl transferase and protein : geranylgeranyl transferase I: Synthesis of homologous diphosphonate analogs of isoprenylated pyrophosphate

Novel diphosphonate homologs 7a-7c, and their cyclic counterparts 8a-8c, of the previously synthesized farnesyl pyrophosphate analogs 1 and 2 were pre pared and tested for their inhibition potency and specificity of the enzyme s PFT and PGGT-I. Compound 2 was shown to be the most potent inhibitor of P FT (IC50 = 0.58 +/- 0.45 mu M) in this series. The novel compound 7a, the o ne carbon homolog of 2, proved to be the most potent inhibitor of PGGT-I (I C50 = 0.98 +/- 0.01 mu M). The cyclic analogs 8a-8c are generally less biol ogically active. The compounds 2 and 7a are nonspecific toward inhibition o f PFT and PGGT-I: and may inhibit both farnesylation and geranylgeranylatio n processing of oncogenic proteins. (C) 1998 Academic Press.