Zhou Xiang, Ferree Sarah D, Wills Veronica S, Born Ella J, Tong Huaxiang, Wiemer David F, Holstein Sarah A
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA.
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Bioorg Med Chem. 2014 May 1;22(9):2791-8. doi: 10.1016/j.bmc.2014.03.014. Epub 2014 Mar 24.
When inhibitors of enzymes that utilize isoprenoid pyrophosphates are based on the natural substrates, a significant challenge can be to achieve selective inhibition of a specific enzyme. One element in the design process is the stereochemistry of the isoprenoid olefins. We recently reported preparation of a series of isoprenoid triazoles as potential inhibitors of geranylgeranyl transferase II but these compounds were obtained as a mixture of olefin isomers. We now have accomplished the stereoselective synthesis of these triazoles through the use of epoxy azides for the cycloaddition reaction followed by regeneration of the desired olefin. Both geranyl and neryl derivatives have been prepared as single olefin isomers through parallel reaction sequences. The products were assayed against multiple enzymes as well as in cell culture studies and surprisingly a Z-olefin isomer was found to be a potent and selective inhibitor of geranylgeranyl diphosphate synthase.
当基于天然底物的利用类异戊二烯焦磷酸的酶抑制剂存在时，实现对特定酶的选择性抑制可能是一项重大挑战。设计过程中的一个要素是类异戊二烯烯烃的立体化学。我们最近报道了一系列类异戊二烯三唑作为香叶基香叶基转移酶II潜在抑制剂的制备，但这些化合物是以烯烃异构体混合物的形式获得的。我们现在通过使用环氧叠氮化物进行环加成反应，然后再生所需的烯烃，完成了这些三唑的立体选择性合成。通过平行反应序列，香叶基和橙花基衍生物均已制备为单一烯烃异构体。对这些产物针对多种酶进行了测定，并开展了细胞培养研究，令人惊讶的是，发现一种Z-烯烃异构体是香叶基香叶基二磷酸合酶的有效且选择性抑制剂。
