Novel limonene phosphonate and farnesyl diphosphate analogues: Design, synthesis, and evaluation as potential protein-farnesyl transferase inhibitors
Novel limonene phosphonate and farnesyl diphosphate analogues: Design, synthesis, and evaluation as potential protein-farnesyl transferase inhibitors
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DOI：
10.1016/s0968-0896(98)00202-8
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发表时间：
1999-02-01
影响因子：
3.5
通讯作者：
Gibbs, RA
中科院分区：
文献类型：
--
作者：
Eummer, JT;Gibbs, BS;Gibbs, RA
柠檬烯及其代谢产物紫苏醇是天然存在的类异戊二烯，在体内和体外都能阻止癌细胞的生长。这种细胞抑制作用似乎至少部分是由于这些化合物是蛋白质戊酰化的弱但选择性和无毒抑制剂。蛋白法尼基转移酶（FTase）是一种负责蛋白法尼基化的酶，已成为合理设计癌症化疗药物的关键靶点。因此，一些α -羟基膦酸柠檬烯衍生物被设计和合成为潜在的更有效的FTase抑制剂。该合成的一个值得注意的特点是使用三甲基硅酸三酯作为温和、中性的脱保护方法，从相应的膦酸叔丁酯制备敏感的膦酸盐。对这些化合物的评估表明，它们在体外是非常差的FTase抑制剂（IC（50）大于或等于3 mM），并且它们对细胞中的蛋白质法尼化没有影响。相比之下，法尼基膦酰（甲基）膦酸盐是天然底物法尼基二磷酸的二磷酸盐修饰衍生物，在体外是一种非常有效的FTase抑制剂（K-i = 23 nM）。1999爱思唯尔科学有限公司版权所有。
Limonene and its metabolite perillyl alcohol are naturally-occurring isoprenoids 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 these compounds are weak yet selective and non-toxic inhibitors of protein prenylation. 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-phosphonate 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 phosphonate esters. Evaluation of these compounds demonstrates that they are exceptionally 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 contrast, farnesyl phosphonyl(methyl)phosphinate, a diphosphate-modified derivative of the natural substrate farnesyl diphosphate, is a very potent FTase inhibitor in vitro (K-i = 23 nM). (C) 1999 Elsevier Science Ltd. All rights reserved.