Synthesis and topoisomerase I inhibitory properties of luotonin A analogues.
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.
Cagir
Ali
A
Department of Chemistry and Department of Biology, University of Virginia, Charlottesville, VA 22901, USA.
Eisenhauer
Brian M
BM
Gao
Rong
R
Thomas
Shannon J
SJ
Hecht
Sidney M
SM
D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D030781:Organisms, Genetically Modified; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D011809:Quinones / Q000138:chemical synthesis* / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D012997:Solvents; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D011758:Pyrroles; D011809:Quinones; D012997:Solvents; D059004:Topoisomerase I Inhibitors; C480761:luotonin A; D004247:DNA; D004264:DNA Topoisomerases, Type I