Synthesis and biochemical evaluation of 3,7-disubstituted farnesyl diphosphate analogues.
Synthesis and biochemical evaluation of 3,7-disubstituted farnesyl diphosphate analogues.
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3,7-二取代法呢基二磷酸类似物的合成和生化评价。
DOI：
10.1021/jo701725b
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Gibbs,RichardA
中科院分区：
文献类型：
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作者：
Rawat,DiwanS;Krzysiak,AmandaJ;Gibbs,RichardA
法尼基二磷酸 (FPP) 类似物已被证明是蛋白质法尼基转移酶 (FTase) 的有效抑制剂，也是研究异戊二烯化蛋白质功能的有价值的探针。此前，我们已经证明某些 3-取代和 7-取代的 FPP 类似物可以作为 FTase 的抑制剂，而其他类似物则是有效的替代底物。我们现在已经利用乙烯基三氟甲磺酸酯介导的路线合成了前七个 FPP 变体，这些变体在异戊二烯单元的 3 位和 7 位均带有取代基。尽管 FPP 本身具有特殊的空间体积，但七种类似物中的六种仍与 FTase 结合。其中两种类似物是该酶的有效抑制剂，但更引人注目的发现是三种 FPP 变体（4a、4b 和 4f）是 FTase 的有效替代底物。
Farnesyl diphosphate (FPP) analogues have proven to be both potent inhibitors of protein-farnesyltransferase (FTase) and valuable probes for the investigation of the function of prenylated proteins. Previously, we have demonstrated that certain 3-substituted and 7-substituted FPP analogues can act as inhibitors of FTase, while others are effective alternative substrates. We have now utilized our vinyl triflate-mediated route to synthesize the first seven FPP variants bearing substituents in both the 3- and 7-positions of the isoprene unit. Despite their exceptional steric bulk with respect to FPP itself, six of the seven analogues bind to FTase. Two of the analogues are potent inhibitors of the enzyme, but a more striking finding is that three FPP variants (4a,4b, and4f) are efficient alternative substrates for FTase.