Synthesis and topoisomerase I inhibitory properties of luotonin A analogues |
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Authors: | Cagir Ali Eisenhauer Brian M Gao Rong Thomas Shannon J Hecht Sidney M |
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Affiliation: | Department of Chemistry and Department of Biology, University of Virginia, Charlottesville, VA 22901, USA. |
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Abstract: | 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. |
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