Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warszawa, Kasprzaka 44, Poland.
Magn Reson Chem. 2010 Aug;48(8):575-84. doi: 10.1002/mrc.2625.
Topotecan (TPT) is in clinical use as an antitumor agent, hycamtin. Because of this, it requires both biologically and chemically useful information to be available. TPT acts by binding to the covalent complex formed by nicked DNA and topoisomerase I. This has a poisonous effect since inserted into the single-strand nick and TPT inhibits its religation. We used NMR to trace TPT dynamics, tautomerism and solvolysis products in various solvents and conditions. Chemical stability was assessed in methanol and DMSO as compared to water, and the regioselectivity of the N- and O-methylation was studied using various alkylating agents. The reaction products of quaternization of the nitrogen atom and methylation of the oxygen atom were characterized by means of ESI MS, (1)H/(13)C-HMBC and -HSQCAD NMR. We have focused on the NMR characterization of TPT with an anticipation that its aggregation, tumbling properties and the intramolecular dipolar interactions will be a common feature for other compounds described in this article. These features can also be useful in tracing the interactions of this class of topoisomerase I (TopoI) poisons with DNA. Moreover, the results explained shed light on the recently disclosed problem of lack of stability of TPT in the heart tissue homogenate samples using the analytical assays developed for this class of compounds carried out in the presence of methanol.
拓扑替康（TPT）是一种临床使用的抗肿瘤药物，商品名为海姆汀。正因为如此，它需要提供生物学和化学上有用的信息。TPT 通过与切口 DNA 和拓扑异构酶 I 形成的共价复合物结合而起作用。由于插入单链切口，TPT 抑制其重新连接，因此具有毒性作用。我们使用 NMR 在各种溶剂和条件下追踪 TPT 的动力学、互变异构和溶剂解产物。在甲醇和 DMSO 中评估了与水相比的化学稳定性，并使用各种烷基化剂研究了 N-和 O-甲基化的区域选择性。氮原子季铵化和氧原子甲基化的反应产物通过 ESI MS、(1)H/(13)C-HMBC 和 -HSQCAD NMR 进行了表征。我们专注于 TPT 的 NMR 表征，预计其聚集、翻滚特性和分子内偶极相互作用将是本文中描述的其他化合物的共同特征。这些特征也可用于追踪该类拓扑异构酶 I（TopoI）抑制剂与 DNA 的相互作用。此外，所解释的结果阐明了在存在甲醇的情况下，使用为该类化合物开发的分析方法，在心脏组织匀浆样品中 TPT 稳定性缺乏的问题。
