Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase

被引:94
作者
Holstein, SA
Cermak, DM
Wiemer, DF [1 ]
Lewis, K
Hohl, RJ
机构
[1] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA
[2] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA
[3] Univ Iowa, Dept Pharmacol, Iowa City, IA 52242 USA
关键词
Ras; FPTase; farnesyl pyrophosphate; inhibitor;
D O I
10.1016/S0968-0896(98)00034-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Several phosphonate and bisphosphonate analogues of farnesyl pyrophosphate have been prepared for an examination of their ability to inhibit farnesyl protein transferase (FPTase). A Horner-Wadsworth-Emmons condensation of farnesal or geranial with tetraethyl methylenediphosphonate gave the desired vinyl phosphonates, while alkylation of the dimethyl methylphosphonate anion with a terpenoid bromide gave the corresponding saturated phosphonates. Alkylation of tetraethyl methylenediphosphonate with farnesyl bromide gave the expected alkyl bisphosphonate, which was converted to its alpha,beta-unsaturated derivative by preparation of the phenyl selenide, oxidation to the selenoxide, and elimination. In a similar fashion, triethyl phosphonoacetate was converted to a farnesyl pyrophosphate analogue by reaction with farnesyl bromide. After preparation of the respective acids, each compound was tested for inhibition of FPTase at concentrations ranging up to 10 mu M. The effect of these compounds on FPTase activity varied substantially, ranging from depressed to surprisingly enhanced enzymatic activity. (C) 1998 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:687 / 694
页数:8
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