Binding of topotecan to a nicked DNA oligomer in solution

Chemistry : a European Journal
Wojciech BocianLech Kozerski

Abstract

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.

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Citations

Jan 1, 2008·Acta Crystallographica. Section E, Structure Reports Online·Rehana AkramAmjid Iqbal
Jul 14, 2010·Magnetic Resonance in Chemistry : MRC·Karolina HyzLech Kozerski
Jun 6, 2014·Physical Chemistry Chemical Physics : PCCP·Francisco Adasme-CarreñoJans H Alzate-Morales
May 18, 2011·Organic & Biomolecular Chemistry·Karolina HyzLech Kozerski
May 29, 2021·Bioorganic & Medicinal Chemistry Letters·Beata NaumczukLech Kozerski
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Poul Erik Hansen
Jul 25, 2021·International Journal of Molecular Sciences·Wojciech BocianLech Kozerski
Nov 5, 2011·Journal of Medicinal Chemistry·Karolina HyzLech Kozerski

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