Molecular Determinants of Topoisomerase I Poisoning by Lamellarins:  Comparison with Camptothecin and Structure−Activity Relationships

• Published in: Journal of medicinal chemistry Vol. 48; no. 11; pp. 3796 - 3807
• Main Authors: Marco, Esther, Laine, William, Tardy, Christelle, Lansiaux, Amélie, Iwao, Masatomo, Ishibashi, Fumito, Bailly, Christian, Gago, Federico
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 02.06.2005
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Camptothecin - chemistry; Camptothecin - pharmacology; Cell Line, Tumor; Computer Simulation; Coumarins - chemistry; Coumarins - pharmacology; DNA Topoisomerases, Type I - chemistry; Drug Resistance, Neoplasm; General aspects; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Isoquinolines - chemistry; Isoquinolines - pharmacology; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Structure-Activity Relationship; Thermodynamics; Topoisomerase I Inhibitors; Antineoplastic agent; Pentacyclic compound; Human; Enzyme; Leukemia; Benzene derivatives; DNA topoisomerase; Enzyme inhibitor; Polycyclic compound; Cytotoxicity; Lactone; Inhibitor enzyme complex; In vitro; Modeling; Alkaloid; Isomerases; Cell line; Structure activity relation; Molecular model; Phenols; Aromatic compound; Tumor cell; Comparative study; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049060w

A series of lamellarin derivatives have been studied as topoisomerase I (Top1) inhibitors. Molecular models of the ternary complexes formed between the DNA-Top1 ensemble and lamellarin D (LMD) or camptothecin (CPT) fully intercalated into the duplex DNA have been built and studied by means of nanosecond molecular dynamics simulations in aqueous solution. Our results show that the 20-OH and 8-OH of LMD can participate in hydrogen-bonding interactions with the side chains of Glu356 and Asn722, respectively, the latter being consistent with the finding that CEM/C2 cells, which are resistant to CPT, are cross-resistant to LMD. Our models also account for the observation that LMD stabilizes Top1 cleavage at CG sites in addition to the TG sites observed for CPT and rationalize the structure−activity relationships within the series. The deleterious effect of replacing the 20-OH in LMD with a hydrogen was confirmed using a set of thermodynamic integration free energy simulations.