title: Calories from carbohydrates: energetic contribution of the carbohydrate moiety of rebeccamycin to DNA binding and the effect of its orientation on topoisomerase I inhibition.
abstract: BACKGROUND
  Only a few antitumor drugs inhibit the DNA breakage-reunion reaction catalyzed by topoisomerase. One is the camptothecin derivative topotecan that has recently been used clinically. Others are the glycosylated antibiotic rebeccamycin and its synthetic analog NB-506, which is presently in phase I of clinical trials. Unlike the camptothecins, rebeccamycin-type compounds bind to DNA. We set out to elucidate the molecular basis of their interaction with duplex DNA, with particular emphasis on the role of the carbohydrate residue.
  
  
  RESULTS
  We compared the DNA-binding and topoisomerase-I-inhibition activities of two isomers of rebeccamycin that contain a galactose residue attached to the indolocarbazole chromophore via an alpha (axial) or a beta (equatorial) glycosidic linkage. The modification of the stereochemistry of the chromophore-sugar linkage results in a marked change of the DNA-binding and topoisomerase-I- poisoning activities. The inverted configuration at the C-1' of the carbohydrate residue abolishes intercalative binding of the drug to DNA thereby drastically reducing the binding affinity. Consequently, the alpha isomer has lost the capacity to induce topoisomerase-I-mediated cleavage of DNA. Comparison with the aglycone allowed us to determine the energetic contribution of the sugar residue.
  
  
  CONCLUSIONS
  The optimal interaction of rebeccamycin analogs with DNA is controlled to a large extent by the stereochemistry of the sugar residue. The results clarify the role of carbohydrates in stereospecific drug-DNA interactions and provide valuable information for the rational design of new rebeccamycin-type antitumor agents.
mesh_terms: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism; D002227:Carbazoles; D050260:Carbohydrate Metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D018983:DNA Footprinting; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D015195:Drug Design; D004734:Energy Metabolism; D004926:Escherichia coli; D007211:Indoles; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D010957:Plasmids / Q000235:genetics; D059004:Topoisomerase I Inhibitors