PHOSPHONATE AND BISPHOSPHONATE ANALOGS OF FARNESYL PYROPHOSPHATE AS POTENTIAL INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

Several phosphonate and bisphosphonate analogues of farnesyl pyrophosp hate have been prepared for an examination of their ability to inhibit farnesyl protein transferase (FPTase). A Horner-Wadsworth-Emmons cond ensation of farnesal or geranial with tetraethyl methylenediphosphonat e gave the desired vinyl phosphonates, while alkylation of the dimethy l methylphosphonate anion with a terpenoid bromide gave the correspond ing saturated phosphonates. Alkylation of tetraethyl methylenediphosph onate with farnesyl bromide gave the expected alkyl bisphosphonate, wh ich was converted to its alpha,beta-unsaturated derivative by preparat ion of the phenyl selenide, oxidation to the selenoxide, and eliminati on. In a similar fashion, triethyl phosphonoacetate was converted to a farnesyl pyrophosphate analogue by reaction with farnesyl bromide. Af ter preparation of the respective acids, each compound was tested for inhibition of FPTase at concentrations ranging up to 10 mu M. The effe ct of these compounds on FPTase activity varied substantially, ranging from depressed to surprisingly enhanced enzymatic activity. (C) 1998 Elsevier Science Ltd. All rights reserved.