Novel quinolinequinone antitumor agents:: structure-metabolism studies with NAD(P)H:quinone oxidoreductase (NQO1)
Novel quinolinequinone antitumor agents:: structure-metabolism studies with NAD(P)H:quinone oxidoreductase (NQO1)
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DOI：
10.1016/j.bmc.2004.01.021
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发表时间：
2004-04-01
影响因子：
3.5
通讯作者：
Moody, CJ
中科院分区：
文献类型：
--
作者：
Fryatt, T;Pettersson, HI;Moody, CJ
合成了一系列不同取代基的喹啉醌类化合物，研究了取代基对重组人NAD（P）H：醌氧化还原酶（hNQO 1）代谢喹啉醌类化合物的影响。选择了一系列的喹啉醌进行研究，并专门设计用于探测C-2位芳基取代基的影响。采用钯催化的2-氯喹啉偶联反应、经典的Friedlander合成法和乙酰苯胺的双Vilsmeier反应三种方法合成了28个喹啉醌化合物2-29。还制备了异喹啉醌30的一个实例，并通过循环伏安法测量了醌的还原电位。对于喹啉2-位上的简单取代基R-2，当R-2 = Cl> H时，hNQO 1对醌的代谢速率降低，托姆> Ph相似。对于芳香取代基，当R-2 = Ph > 1-萘基> 2-萘基> 4-联苯时，还原速率显著降低。含吡啶取代基的化合物是最好的底物，反应速率随R-24-吡啶基> 3-吡啶基> 2-吡啶基> 4-甲基-2-吡啶基> 5-甲基-2-吡啶基而降低。还在代表性醌中研究了对无可检测活性（H596或BE-WT）或高NQO 1活性（H460或BE-NQ）的人结肠癌细胞的毒性。作为hNQO 1良好底物的醌类对含有或表达NQO 1的细胞系（H460和BE-NQ）的毒性大于NQO 1缺陷细胞系（H596和BE-WT）。(C)2004 Elsevier Ltd.保留所有权利。
A series of quinolinequinones bearing various substituents has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (hNQO1) was studied. A range of quinolinequinones were selected for study, and were specifically designed to probe the effects of aryl substituents at C-2. A range of 28 quinolinequinones 2-29 was prepared using three general strategies: the palladium(0) catalyzed coupling of 2-chloroquinolines, the classical Friedlander synthesis and the double-Vilsmeier reaction of acetanilides. One example of an isoquinolinequinone 30 was also prepared, and the reduction potentials of the quinones were measured by cyclic voltammetry. For simple substituents R-2 at the quinoline 2-position, the rates of quinone metabolism by hNQO1 decrease for R-2 = Cl>Hsimilar toMe>Ph. For aromatic substituents, the rate of reduction decreases dramatically for R-2 = Ph > 1-naphthyl > 2-naphthyl > 4-biphenyl. Compounds containing a pyridine substituent are the best substrates, and the rates decrease as R-2 4-pyridyl > 3-pyridyl > 2-pyridyl > 4-methyl-2-pyridyl > 5-methyl-2-pyridyl. The toxicity toward human colon carcinoma cells with either no detectable activity (H596 or BE-WT) or high NQO1 activity (H460 or BE-NQ) was also studied in representative quinones. Quinones that are good substrates for hNQO1 are more toxic to the NQO1 containing or expressing cell lines (H460 and BE-NQ) than the NQO1 deficient cell lines (H596 and BE-WT). (C) 2004 Elsevier Ltd. All rights reserved.