Kashfi Khosrow, Rigas Basil
Department of Physiology and Pharmacology, City University of New York Medical School, New York, NY 10031, USA.
Biochem Biophys Res Commun. 2007 Jul 13;358(4):1096-101. doi: 10.1016/j.bbrc.2007.05.038. Epub 2007 May 15.
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.
释放一氧化氮的阿司匹林（NO-ASA）是一种有前景的抗癌药物。我们研究了NO-ASA的成分（ASA、一氧化氮释放部分以及连接它们的间隔基团）对其效果的贡献。ASA和一氧化氮释放部分不发挥生物学作用：ASA抑制结肠癌细胞生长的效力比NO-ASA低100倍以上；去硝化的NO-ASA加上释放与NO-ASA相同量一氧化氮的一氧化氮供体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基团：它具有化学反应性（对间隔基团进行放射性标记的NO-ASA研究表明它能与蛋白质结合）；并且其中ASA或一氧化氮释放基团被取代的化合物抑制细胞生长的情况与NO-ASA相似。我们提出了一种NO-ASA的作用机制，涉及从其对位和邻位异构体形成醌甲基化物以及从间位形成碳正离子，其中一氧化氮释放基团起离去基团的作用。
