Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Bioorg Med Chem. 2010 Oct 1;18(19):7029-33. doi: 10.1016/j.bmc.2010.08.012. Epub 2010 Aug 9.
Glyoxalase I (GLO I) is the rate-limiting enzyme for detoxification of methylglyoxal (MG), a side-product of glycolysis, which is able to induce apoptosis. Since GLO I is known to be highly expressed in the most tumor cells and little in normal cells, inhibitors of this enzyme has been expected to be new anticancer drugs. Here, we examined the inhibitory abilities to the human GLO I of anthocyanidins, such as delphinidin, cyanidin and pelargonidin. Among them, delphinidin was found to have the most potent inhibitory effect on human GLO I. Also, only delphinidin-induced apoptosis in HL-60 cells in a dose- and time-dependent manner. Furthermore, we determined a pharmacophore for delphinidin binding to the human GLO I by computational simulation analyses of the binding modes of delphinidin, cyanidin and pelargonidin to the enzyme hot spot. These results suggest that delphinidin could be a useful lead compound for the development of novel GLO I inhibitory anticancer drugs.
一氧戊二醛酶 I（GLO I）是糖酵解副产物甲基乙二醛（MG）解毒的限速酶，能够诱导细胞凋亡。由于 GLO I 在大多数肿瘤细胞中高度表达，而在正常细胞中表达很少，因此该酶的抑制剂有望成为新型抗癌药物。在这里，我们研究了矢车菊素、花青素和天竺葵素等花色苷对人 GLO I 的抑制能力。其中，矢车菊素对人 GLO I 的抑制作用最强。此外，只有矢车菊素以剂量和时间依赖的方式诱导 HL-60 细胞凋亡。此外，我们通过对矢车菊素、花青素和天竺葵素与酶热点的结合模式进行计算模拟分析，确定了矢车菊素与人类 GLO I 结合的药效团。这些结果表明，矢车菊素可能是开发新型 GLO I 抑制抗癌药物的有用先导化合物。
