Novel limonene phosphonate and farnesyl diphosphate analogues: Design, synthesis, and evaluation as potential protein-farnesyl transferase inhibitors

Limonene and its metabolite perillyl alcohol are naturally-occurring isopre noids that block the growth of cancer cells both in vitro and in vivo. This cytostatic effect appears to be due, at least in part, to the fact that th ese compounds are weak yet selective and non-toxic inhibitors of protein pr enylation. Protein-farnesyl transferase (FTase), the enzyme responsible for protein farnesylation, has become a key target for the rational design of cancer chemotherapeutic agents. Therefore, several alpha-hydroxy-phosphonat e derivatives of limonene were designed and synthesized as potentially more potent FTase inhibitors. A noteworthy feature of the synthesis was the use of trimethylsilyl triflate as a mild, neutral deprotection method for the preparation of sensitive phosphonates from the corresponding tert-butyl pho sphonate esters. Evaluation of these compounds demonstrates that they are e xceptionally poor FTase inhibitors in vitro (IC(50)greater than or equal to 3 mM) and they have no effect on protein farnesylation in cells. In contra st, farnesyl phosphonyl(methyl)phosphinate, a diphosphate-modified derivati ve of the natural substrate farnesyl diphosphate, is a very potent FTase in hibitor in vitro (K-i = 23 nM). (C) 1999 Elsevier Science Ltd. All rights r eserved.