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Action models for the antitumor drug camptothecin: formation of alkali-labile complex with DNA and inhibition of human DNA topoisomerase I.
J Biomol Struct Dyn. 2002 Dec; 20(3):447-54.JB

Abstract

The antitumor activity of camptothecin (CPT) and its derivatives, including water-soluble topotecan (TPT), is determined by their ability to inhibit human DNA topoisomerase I (top 1). On the other hand, TPT has been recently shown to bind to DNA. The proposed models are based on a two-step mechanism of TPT (CPT) dimer interaction with two spatially close DNA duplexes. At the first step, the CPT lactone form binds to DNA (Streltsov et al., Mol. Biol. vol. 36, no. 5 (2002)) through hydrogen bonding of its C16a carbonyl with the guanine 2-amino group. At the second step, CPT is converted to the carboxylate form. In the absence of top 1, the C17 hydroxyl of CPT is involved in ester exchange (nicking of the DNA sugar-phosphate backbone followed by covalent joining of free phosphate to C17) whereas its C20 carboxyl forms two hydrogen bonds with the same guanine nucleotide at the opposite end of the broken DNA backbone. As a result, CPT binds to both ends of the broken DNA. The resulting CPT-DNA complex is alkali-labile. In the presence of top 1, after CPT conversion to the carboxylate form and DNA nicking, the C17 hydroxyl makes a branching hydrogen bond with N1 and N3 of guanine while the C20 carboxyl makes two hydrogen bonds with the NH of Tyr723 and N(delta2)H(2) of Asp722. Owing to this, rotation of one end of the broken sugar-phosphate backbone about the other becomes impossible; hence the CPT inhibitory effect on top 1. The proposed models are consistent with the current body of experimental data.

Authors+Show Affiliations

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov st., Moscow 119991, Russia. strelcov@imb.ac.ru

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12437383

Citation

Streltsov, Sergei A.. "Action Models for the Antitumor Drug Camptothecin: Formation of Alkali-labile Complex With DNA and Inhibition of Human DNA Topoisomerase I." Journal of Biomolecular Structure & Dynamics, vol. 20, no. 3, 2002, pp. 447-54.
Streltsov SA. Action models for the antitumor drug camptothecin: formation of alkali-labile complex with DNA and inhibition of human DNA topoisomerase I. J Biomol Struct Dyn. 2002;20(3):447-54.
Streltsov, S. A. (2002). Action models for the antitumor drug camptothecin: formation of alkali-labile complex with DNA and inhibition of human DNA topoisomerase I. Journal of Biomolecular Structure & Dynamics, 20(3), 447-54.
Streltsov SA. Action Models for the Antitumor Drug Camptothecin: Formation of Alkali-labile Complex With DNA and Inhibition of Human DNA Topoisomerase I. J Biomol Struct Dyn. 2002;20(3):447-54. PubMed PMID: 12437383.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Action models for the antitumor drug camptothecin: formation of alkali-labile complex with DNA and inhibition of human DNA topoisomerase I. A1 - Streltsov,Sergei A, PY - 2002/11/20/pubmed PY - 2003/6/17/medline PY - 2002/11/20/entrez SP - 447 EP - 54 JF - Journal of biomolecular structure & dynamics JO - J Biomol Struct Dyn VL - 20 IS - 3 N2 - The antitumor activity of camptothecin (CPT) and its derivatives, including water-soluble topotecan (TPT), is determined by their ability to inhibit human DNA topoisomerase I (top 1). On the other hand, TPT has been recently shown to bind to DNA. The proposed models are based on a two-step mechanism of TPT (CPT) dimer interaction with two spatially close DNA duplexes. At the first step, the CPT lactone form binds to DNA (Streltsov et al., Mol. Biol. vol. 36, no. 5 (2002)) through hydrogen bonding of its C16a carbonyl with the guanine 2-amino group. At the second step, CPT is converted to the carboxylate form. In the absence of top 1, the C17 hydroxyl of CPT is involved in ester exchange (nicking of the DNA sugar-phosphate backbone followed by covalent joining of free phosphate to C17) whereas its C20 carboxyl forms two hydrogen bonds with the same guanine nucleotide at the opposite end of the broken DNA backbone. As a result, CPT binds to both ends of the broken DNA. The resulting CPT-DNA complex is alkali-labile. In the presence of top 1, after CPT conversion to the carboxylate form and DNA nicking, the C17 hydroxyl makes a branching hydrogen bond with N1 and N3 of guanine while the C20 carboxyl makes two hydrogen bonds with the NH of Tyr723 and N(delta2)H(2) of Asp722. Owing to this, rotation of one end of the broken sugar-phosphate backbone about the other becomes impossible; hence the CPT inhibitory effect on top 1. The proposed models are consistent with the current body of experimental data. SN - 0739-1102 UR - https://www.unboundmedicine.com/medline/citation/12437383/Action_models_for_the_antitumor_drug_camptothecin:_formation_of_alkali_labile_complex_with_DNA_and_inhibition_of_human_DNA_topoisomerase_I_ L2 - https://www.tandfonline.com/doi/full/10.1080/07391102.2002.10506863 DB - PRIME DP - Unbound Medicine ER -