Quinone formation as a chemoprevention strategy for hybrid drugs: Balancing cytotoxicity and cytoprotection
Quinone formation as a chemoprevention strategy for hybrid drugs: Balancing cytotoxicity and cytoprotection
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DOI：
10.1021/tx7002257
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发表时间：
2007-12-01
影响因子：
4.1
通讯作者：
Thatcher, Gregory R. J.
中科院分区：
文献类型：
--
作者：
Dunlap, Tareisha;Chandrasena, R. Esala P.;Thatcher, Gregory R. J.
细胞防御机制，响应氧化和亲电子应激，如醌类的损害，代表了化学预防剂的目标。生物活化为醌类的药物有可能激活细胞保护性2相酶（如NAD（P）H依赖性醌氧化还原酶（NQO 1））基因的抗氧化剂/亲电响应元件（ARE）转录，但也可能导致细胞损伤。制备了两个异构体家族的化合物，包括NO-NSAID（NO供体非甾体抗炎药）NCX 4040和NCX 4016;假设一个家族在酯酶生物活化时释放醌甲基化物。在模型和细胞系统中的反应性和GSH结合的研究证实了这一假设。醌形成家族，包括NCX 4040和锥形溴化物和甲磺酸盐，被迅速生物激活为醌，从而激活ARE并随后诱导肝细胞中的NQO 1。虽然对照家族，包括NCX 4016和conisogenic溴化物和甲磺酸酯，不能形成醌，但观察到ARE活化和NQO 1诱导，与巯基传感器蛋白的较慢S（N）2反应以及随后的ARE-荧光素酶和NQO 1诱导相容。使用化学预防指数估计，醌形成的化合物遭受，因为高细胞毒性和更兼容的癌症治疗比化学预防。在彗星试验中，NCX 4040相对于NCX 4016具有高度遗传毒性。没有证据表明NO有助于观察到的生物活性，也没有证据表明NCX 4040是NO供体，而是快速释放NO3-和醌。这些结果表明了一种研究醌生物活性的策略，并通过NO和阿萨以外的结构元素增强NO-ASA的治疗属性。
Cellular defense mechanisms that respond to damage from oxidative and electrophilic stress, such as from quinones, represent a target for chemopreventive agents. Drugs bioactivated to quinones have the potential to activate antioxidant/electrophile responsive element (ARE) transcription of genes for cytoprotective phase 2 enzymes such as NAD(P)H-dependent quinone oxidoreductase (NQO1) but can also cause cellular damage. Two isomeric families of compounds were prepared, including the NO-NSAIDs (NO-donating nonsteroidal anti-inflammatory drugs) NCX 4040 and NCX 4016; one family was postulated to release a quinone methide on esterase bioactivation. The study of reactivity and GSH conjugation in model and cell systems confirmed the postulate. The quinone-forming family, including NCX 4040 and conisogenic bromides and mesylate, was rapidly bioactivated to a quinone, which gave activation of ARE and consequent induction of NQO1 in liver cells. Although the control family, including NCX 4016 and conisogenic bromides and mesylates, cannot form a quinone, ARE activation and NQO1 induction were observed, compatible with slower S(N)2 reactions with thiol sensor proteins, and consequent ARE-luciferase and NQO1 induction. Using a Chemoprevention Index estimate, the quinone-forming compounds suffered because of high cytoxicity and were more compatible with cancer therapy than chemoprevention. In the Comet assay, NCX 4040 was highly genotoxic relative to NCX 4016. There was no evidence that NO contributes to the observed biological activity and no evidence that NCX 4040 is an NO donor, instead, rapidly releasing NO3- and quinone. These results indicate a strategy for studying the quinone biological activity and reinforce the therapeutic attributes of NO-ASA through structural elements other than NO and ASA.