Bocian W, Kawecki R, Bednarek E, Sitkowski J, Williamson M P, Hansen P E, Kozerski L
National Medicines Institute, 00-725 Warszawa, Chełmska 30/34, Poland.
Chemistry. 2008;14(9):2788-94. doi: 10.1002/chem.200700732.
Topotecan (TPT) is in clinical use as an antitumor agent. It acts by binding to the covalent complex formed between nicked DNA and topoisomerase I, and inserts itself into the single-strand nick, thereby inhibiting the religation of the nick and acting as a poison. A crystal structure analysis of the ternary complex has shown how the drug binds (B. L. Staker, K. Hjerrild, M. D. Feese, C. A. Behnke, A. B. Burgin, L. Stewart, Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 15 387-15 392), but has left a number of unanswered questions. Herein, we use NMR spectroscopy and molecular modeling to show that the solution structure of a complex of TPT with nicked natural DNA is similar, but not identical to the crystal conformation, and that other geometries are of very low population. We also show that the lactone form of TPT binds approximately 40 times more strongly than the ring-opened carboxylate.
拓扑替康（TPT）作为一种抗肿瘤药物正在临床使用。它通过与切口DNA和拓扑异构酶I之间形成的共价复合物结合而起作用，并将自身插入单链切口中，从而抑制切口的重新连接并起到毒剂的作用。对三元复合物的晶体结构分析已经表明了药物的结合方式（B. L. 斯塔克、K. 赫里尔、M. D. 费斯、C. A. 贝恩克、A. B. 伯金、L. 斯图尔特，《美国国家科学院院刊》，2002年，99卷，15387 - 15392页），但仍留下了一些未解答的问题。在此，我们使用核磁共振光谱法和分子建模来表明，TPT与切口天然DNA复合物的溶液结构相似，但与晶体构象并不相同，并且其他几何结构的丰度非常低。我们还表明，TPT的内酯形式的结合力比开环羧酸盐强约40倍。
