A DNA binding indolocarbazole disaccharide derivative remains highly cytotoxic without inhibiting topoisomerase I

NB-506 is a glucosylated indolocarbazole related to the antibiotic rebeccam ycin and is currently under clinical trials as an anticancer drug. This com pound is a DNA intercalating agent and a potent topoisomerase I poison. The glucose residue attached to the planar indolocarbazole chromophore plays a significant role in the interaction of the drug with nucleic acids and con tributes positively to the stabilization of topoisomerase I-DNA covalent co mplexes. To investigate further the influence of the carbohydrate moiety, w e studied the DNA binding and topoisomerase I inhibition properties of an a nalogue of NB-506 bearing a disaccharide side chain. Fluorescence and footp rinting studies indicate that the replacement of the glucose chain of NB-50 6 with a maltose residue does not hinder the capacity of the drug to bind t o DNA and to recognize GC-rich sequences. The addition of the second sugar residue does not reinforce the interaction with DNA but abolishes the capac ity of the drug to inhibit topoisomerase I. Unexpectedly, the disaccharide analogue of NB-506 has totally lost its capacity to stimulate DNA cleavage by topoisomerase I. In addition, like NB-506, the new analogue is not an in hibitor of topoisomerase II. However, despite the absence of topoisomerase poisoning activity, the cytotoxic activity is fully maintained. The maltosy l-indolocarbazole drug proved to be as potent as NB-506 at inhibiting the g rowth of various human and murine tumour cell lines. The study raises the q uestion as to whether topoisomerase I poisoning is important for the antitu mour activity of rebeccamycin analogues.