Synthesis and topoisomerase I inhibitory properties of luotonin A analogues

• Published in: Bioorganic & medicinal chemistry Vol. 12; no. 23; pp. 6287 - 6299
• Main Authors: Cagir, Ali, Eisenhauer, Brian M., Gao, Rong, Thomas, Shannon J., Hecht, Sidney M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2004; Elsevier Science
• Subjects: Biological and medical sciences; Camptothecin; DNA - metabolism; DNA Topoisomerases, Type I - genetics; DNA Topoisomerases, Type I - metabolism; Humans; Luotonin A; Medical sciences; Miscellaneous; Organisms, Genetically Modified; Pharmacology. Drug treatments; Pyrroles - chemical synthesis; Pyrroles - pharmacology; Quinones - chemical synthesis; Quinones - pharmacology; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; Solvents; Structure-Activity Relationship; Structure–activity relationships; Topoisomerase I Inhibitors; Topoisomerase I–DNA inhibition; Luotonin A; Camptothecin; Topoisomerase I–DNA inhibition; Structure–activity relationships; Pentacyclic compound; Yeast; Enzyme; Angular nitrogen heterocycle; DNA topoisomerase; Cytotoxicity; In vitro; Scission; Alkaloid; Isomerases; Structure activity relation; DNA; Cleavage; Aromatic compound; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.08.052

[Display omitted] Luotonin A, a naturally occurring pyrroloquinazolinoquinoline alkaloid, has been previously demonstrated to be a topoisomerase I poison. A number of luotonin A derivatives have now been prepared through the condensation of anthranilic acid derivatives and 1,2-dihydropyrrolo[3,4-b]quinoline-3-one in the presence of phosphorus oxychloride. When dichloromethane was used as solvent the reaction proceeded to a single product. In contrast when the reaction was carried out in tetrahydrofuran or in phosphorus oxychloride, an additional isomeric product was obtained. The luotonin A analogues were evaluated for their ability to effect stabilization of the covalent binary complex formed between human topoisomerase I and DNA, and for cytotoxicity toward a yeast strain expressing the human topoisomerase I.