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.
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 known DNA intercalators.
McDonald
L A
LA
Department of Medicinal Chemistry, University of Utah, Salt Lake City 84112.
Eldredge
G S
GS
Barrows
L R
LR
Ireland
C M
CM
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002384:Catalysis; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014561:Urochordata / Q000737:chemistry
D000166:Acridines; D000470:Alkaloids; D007364:Intercalating Agents; D011728:Pyridones; D059005:Topoisomerase II Inhibitors; D012313:RNA; D004247:DNA