Topotecan dynamics, tautomerism and reactivity--1H/13C NMR and ESI MS study.
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.
Hyz
Karolina
K
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warszawa, Kasprzaka 44, Poland.
Kawecki
Robert
R
Bednarek
Elzbieta
E
Bocian
Wojciech
W
Sitkowski
Jerzy
J
Kozerski
Lech
L
D000970:Antineoplastic Agents / Q000737:chemistry*; D002247:Carbon Isotopes; D009682:Magnetic Resonance Spectroscopy / Q000592:standards; D000432:Methanol / Q000737:chemistry; D008968:Molecular Conformation; D011522:Protons; D012015:Reference Standards; D012822:Silicon Dioxide / Q000737:chemistry; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization / Q000592:standards; D013237:Stereoisomerism; D013816:Thermodynamics; D019772:Topotecan / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D002247:Carbon Isotopes; D011522:Protons; D014867:Water; D012822:Silicon Dioxide; D019772:Topotecan; D000432:Methanol