PMID: 7525959Oct 28, 1994Paper

Inhibition of topoisomerase II catalytic activity by pyridoacridine alkaloids from a Cystodytes sp. ascidian: a mechanism for the apparent intercalator-induced inhibition of topoisomerase II

Journal of Medicinal Chemistry
L A McDonaldC M Ireland

Abstract

Several new pyridoacridine alkaloids, dehydrokuanoniamine B (1), shermilamine C (2), and cystodytin J (3), in addition to the known compounds cystodytin A (4), kuanoniamine D (5), shermilamine B (6), and eilatin (7), were isolated from a Fijian Cystodytes sp. ascidian. Their structures were determined by analyses of spectroscopic data. These compounds along with a previously reported pyridoacridine, diplamine (8), showed dose-dependent inhibition of proliferation in human colon tumor (HCT) cells in vitro. All compounds inhibited the topoisomerase (TOPO) II-mediated decatenation of kinetoplast DNA (kDNA) in a dose-dependent manner. The pyridoacridines' ability to inhibit TOPO II-mediated decatenation of kDNA correlated with their cytotoxic potencies and their ability to intercalate into calf thymus DNA. These results suggest that disruption of the function of TOPO II, subsequent to intercalation, is a probable mechanism by which pyridoacridines inhibit the proliferation of HCT cells. Incorporation studies show that pyridoacridines disrupt DNA and RNA synthesis with little effect on protein synthesis. It appears that DNA is the primary cellular target of the pyridoacridine alkaloids. These results are consistent with those for kn...Continue Reading

Citations

May 9, 2009·Journal of Molecular Modeling·Kendall G BylerWilliam N Setzer
Jun 27, 2001·Bioorganic & Medicinal Chemistry·J Angel de la FuenteJ Carlos Menéndez
Jan 27, 2007·Journal of Natural Products·Paul RalifoPhillip Crews
Sep 1, 2007·Natural Product Research·Madhavi S Agrawal, Bruce F Bowden
Dec 10, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Concetta ImperatoreMarialuisa Menna
Jan 29, 2016·Marine Drugs·Alois Plodek, Franz Bracher
Jan 16, 2007·Environmental Microbiology·Manuel Martínez-GarcíaJosefa Antón
Dec 25, 2002·Medicinal Research Reviews·Evelyne Delfourne, Jean Bastide
Sep 15, 2012·Natural Product Reports·Klaus-Dieter FeussnerChris M Ireland
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Jul 25, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gabriela ChabowskaAnna Wójcicka
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Dec 21, 2002·The Journal of Organic Chemistry·Zia ThalePhillip Crews

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