Inhibitors of protein: Arnesyl transferase and protein:geranylgeranyl transferase I : Synthesis of homologous diphosphonate analogs of isoprenylated pyrophosphate
van Leeuwen, R.E.W.
van der Marel, G.A.
van Boom, J.H.
Gaubius Instituut TNO
Novel diphosphonate homologs 7a-7c, and their cyclic counterparts 8a- 8c, of the previously synthesized farnesyl pyrophosphate analogs 1 and 2 were prepared and tested for their inhibition potency and specificity of the enzymes PFT and PGGT-I. Compound 2 was shown to be the most potent inhibitor of PFT (1C50=0.58 ± 0.45 μM) in this series. The novel compound 7a, the one carbon homolog of 2, proved to be the most potent inhibitor of PGGT-I (IC50 = 0.98 ± 0.01 μM). The cyclic analogs 8a-8c are generally less biologically active. The compounds 2 and 7a are nonspecific toward inhibition of PFT and PGGT-I and may inhibit both farnesylation and geranylgeranylation processing of oncogenic proteins.
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bisphosphonic acid derivative
Bioorganic Chemistry, 26 (5), 269-282