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), sherm ilamine C (2), and cystodytin J (3), in addition to the known compound s cystodytin A (4), kuanoniamine D (5), shermilamine B (6), and eilati n (7), were isolated from a Fijian Cystodytes sp. ascidian. Their stru ctures were determined by analyses of spectroscopic data. These compou nds along with a previously reported pyridoacridine, diplamine (8), sh owed 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 deca tenation of kDNA correlated with their cytotoxic potencies and their a bility to intercalate into calf thymus DNA. These results suggest that disruption of the function of TOPO II, subsequent to intercalation, i s a probable mechanism by which pyridoacridines inhibit the proliferat ion of HCT cells. Incorporation studies show that pyridoacridines disr upt 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 inter calators.