A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex

2006/02/01 by Christophe Marchand, Smitha Antony, Kurt W. Kohn +6 · 5 citations
Biochemistry, Genetics and Molecular Biology · Pharmacology, Toxicology and Pharmaceutics · Medicine · #Cancer therapeutics and mechanisms #Bioactive Compounds and Antitumor Agents #Neutropenia and Cancer Infections

paper · pdf · doi:10.1158/1535-7163.mct-05-0456

openalex publication_date 2006/02/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

We show that five topoisomerase I inhibitors (two indenoisoquinolines, two camptothecins, and one indolocarbazole) each intercalate between the base pairs flanking the cleavage site generated during the topoisomerase I catalytic cycle and are further stabilized by a network of hydrogen bonds with topoisomerase I. The interfacial inhibition paradigm described for topoisomerase I inhibitors can be generalized to a variety of natural products that trap macromolecular complexes as they undergo catalytic conformational changes that create hotspots for drug binding. Stabilization of such conformational states results in uncompetitive inhibition and exemplifies the relevance of screening for ligands and drugs that stabilize ("trap") these macromolecular complexes.

Citations

• Topoisomerase I inhibitors: selectivity and cellular resistance
• Structures of Three Classes of Anticancer Agents Bound to the Human Topoisomerase I−DNA Covalent Complex
• Synthesis and Mechanism of Action Studies of a Series of Norindenoisoquinoline Topoisomerase I Poisons Reveal an Inhibitor with a Flipped Orientation in the Ternary DNA−Enzyme−Inhibitor Complex As Determined by X-ray Crystallographic Analysis
• Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187

Cited by

• Recent developments in topoisomerase-targeted cancer chemotherapy
• Next generation topoisomerase I inhibitors: Rationale and biomarker strategies
• The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives
• Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance
• Topoisomerase inhibitor [wikipedia]