The mechanism of action of nitric oxide-donating aspirin
The mechanism of action of nitric oxide-donating aspirin
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DOI：
10.1016/j.bbrc.2007.05.038
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发表时间：
2007-07-13
影响因子：
3.1
通讯作者：
Rigas, Basil
中科院分区：
文献类型：
--
作者：
Kashfi, Khosrow;Rigas, Basil
NO供体阿司匹林（NO-ASA）是一种很有前途的抗肿瘤药物。我们研究了NO-ASA的组分（阿萨，NO释放部分和连接它们的间隔基）对其作用的贡献。阿萨和NO释放部分不起生物学作用：阿萨抑制结肠癌细胞生长的效力比NO-ASA低100倍以上;并且与NO-ASA释放相同量的NO的经修饰的NO-ASA加上NO供体SNAP抑制癌细胞生长的效力比NO-ASA低50倍以上。NO-ASA的生物活性部分是间隔物：它具有化学反应性（在间隔物处放射性标记的NO-ASA的研究表明它与蛋白质结合）;阿萨或NO释放基团被取代的化合物抑制细胞生长类似于NO-ASA。我们提出了一个机制的行动NO-ASA涉及形成醌甲基化从其帕拉和邻位异构体和碳正离子从Meta位，与NO-释放基团作为离去基团。(C)2007爱思唯尔公司All rights reserved.
NO-donating aspirin (NO-ASA) is a promising anticancer drug. We studied the contribution of NO-ASA's components (ASA, NO-releasing moiety, and spacer linking them) to its effect. The ASA and NO-releasing moieties play no biological role: ASA inhibits the growth of colon cancer cells >100-fold less potently that NO-ASA; and denitrated NO-ASA plus the NO-donor SNAP releasing the same amount of NO as NO-ASA, inhibit the growth of cancer cells >50-fold less potently than NO-ASA. The biologically active moiety of NO-ASA is the spacer: it is chemically reactive (studies with NO-ASA radiolabeled at the spacer demonstrated that it binds to proteins); and compounds in which the ASA or the NO-releasing groups are replaced inhibit cell growth similar to NO-ASA. We propose a mechanism of action of NO-ASA involving formation of quinone methide from its para and ortho isomers and of a carbocation from the meta, with the NO-releasing group functioning as a leaving group. (C) 2007 Elsevier Inc. All rights reserved.