BINDING TO DNA AND CYTOTOXIC EVALUATION OF ASCIDIDEMIN, THE MAJOR ALKALOID FROM THE MEDITERRANEAN ASCIDIAN CYSTODYTES DELLECHIAJEI

The isolation of ascididemin from the Mediterranean ascidian Cystodyte s dellechiajei is described. This alkaloid consists of a planar pentac yclic chromophore which was investigated for its DNA-binding and cytot oxic properties. Spectroscopic measurements provided evidence that the drug intercalates into DNA. DNase I footprinting assays indicated tha t the binding of ascididemin to CC-rich sequences is favoured over bin ding to AT-rich and mixed sequences. Chemical probes were used to dete ct ligand-induced structural changes in DNA. The alkaloid induces a hy perreactivity of the DNA towards potassium permanganate, but not towar ds diethylpyrocarbonate, just as is the case with ethidium bromide;; i t has little effect on the catalytic activities of topoisomerases I an d II. Ascididemin exhibits marked cytotoxicity towards human leukaemic cells in vitro and appears to be practically equally toxic for drug-s ensitive and multidrug-resistant cell lines. The results suggest that DNA, but not topoisomerases, may represent the critical cellular targe t at which this marine alkaloid exhibits its potent cytotoxic properti es in vitro.