Syntheses and characterization of non-bisphosphonate quinoline derivatives as new FPPS inhibitors.
Syntheses and characterization of non-bisphosphonate quinoline derivatives as new FPPS inhibitors.
复制标题
DOI：
10.1016/j.bbagen.2013.11.006
复制
发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Jinggong Liu;Weilin Liu;H. Ge;Jinbo Gao;Qingqing He;L. Su;Jun Xu;L. Gu;Zhishu Huang;
中科院分区：
文献类型：
--
作者：
Jinggong Liu;Weilin Liu;H. Ge;Jinbo Gao;Qingqing He;L. Su;Jun Xu;L. Gu;Zhishu Huang;
研究背景法尼基焦磷酸合酶（FPPS）是胆固醇生物合成和信号蛋白翻译后修饰的关键调控酶。据报道，针对其变构结合口袋的非双膦酸盐FPPS抑制剂对于有前途的抗癌药物的开发具有潜在的重要性。非二膦酸盐喹啉衍生物的有机合成、酶抑制研究、荧光滴定分析、喹啉衍生物与唑来膦酸盐的协同效应研究、FPPS与喹啉衍生物结合的ITC研究，基于NMR的HAP结合分析，分子建模研究，荧光成像分析和MTT assessment.ResultsWe报告我们的一系列喹啉衍生物的合成作为新的FPPS抑制剂可能针对酶的变构位点。化合物6b显示出对FPPS的有效抑制，而没有显著的羟基磷灰石结合亲和力。该化合物与活性部位抑制剂唑来膦酸具有协同抑制作用。ITC实验证实了化合物6b与FPPS的良好结合效果，并进一步表明结合比例为1：1。分子模拟研究表明，6b可能与酶的变构结合口袋结合。结论喹啉衍生物6b有望成为一种新型的先导化合物，为进一步优化其抗癌活性提供理论依据。开发具有良好细胞膜渗透性的新型非双膦酸盐FPPS抑制剂具有潜在的重要意义。
BackgroundFarnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme in the biosynthesis of cholesterol and in the post-translational modification of signaling proteins. It has been reported that non-bisphosphonate FPPS inhibitors targeting its allosteric binding pocket are potentially important for the development of promising anti-cancer drugs.MethodsThe following methods were used: organic syntheses of non-bisphosphonate quinoline derivatives, enzyme inhibition studies, fluorescence titration assays, synergistic effect studies of quinoline derivatives with zoledronate, ITC studies for the binding of FPPS with quinoline derivatives, NMR-based HAP binding assays, molecular modeling studies, fluorescence imaging assay and MTT assays.ResultsWe report our syntheses of a series of quinoline derivatives as new FPPS inhibitors possibly targeting the allosteric site of the enzyme. Compound6bshowed potent inhibition to FPPS without significant hydroxyapatite binding affinity. The compound showed synergistic inhibitory effect with active-site inhibitor zoledronate. ITC experiment confirmed the good binding effect of compound6bto FPPS, and further indicated the binding ratio of 1:1. Molecular modeling studies showed that6bcould possibly bind to the allosteric binding pocket of the enzyme. The fluorescence microscopy indicated that these compounds could get into cancer cells.ConclusionsOur results showed that quinoline derivative6bcould become a new lead compound for further optimization for cancer treatment.General significanceThe traditional FPPS active-site inhibitors bisphosphonates show poor membrane permeability to tumor cells, due to their strong polarity. The development of new non-bisphosphonate FPPS inhibitors with good cell membrane permeability is potentially important.