Syntheses and biological activities (topoisomerase inhibition and antitumor and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group

J Med Chem. 1997 Oct 10;40(21):3456-65. doi: 10.1021/jm9702084.


As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of rebeccamycin, with or without the chlorine atoms on the indole moieties, or modified sugar residues (galactopyranosyl, glucopyranosyl, or fucopyranosyl) linked to the aglycone via a beta- or alpha-N-glycosidic bond. Their inhibitory properties toward protein kinase C, topoisomerase I, and topoisomerase II were examined, and their DNA-binding properties were investigated. Their in vitro antitumor activities against murine B16 melanoma and P388 leukemia cells were determined. Their antimicrobial activities were tested against Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, Gram-negative bacterium Escherichia coli, and yeast Candida albicans. These compounds are inactive toward topoisomerase II but inhibit topoisomerase I. A substitution with a methyl group on the imide nitrogen led to a loss of proteine kinase C inhibition in the maleimide indolocarbazole series but did not prevent topoisomerase I inhibition. Compounds possessing a beta-N-glycosidic bond, which fully intercalated into DNA, were more efficient at inhibiting topoisomerase I than their analogues with an alpha-N-glycosidic bond; however, both were equally toxic toward P388 leukemia cells. Dechlorinated rebeccamycin possessing a methyl group on the imide nitrogen was about 10 times more efficient in terms of cytotoxicity and inhibition of topoisomerase I than the natural metabolite.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglycosides*
  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / toxicity
  • Antibiotics, Antineoplastic / chemical synthesis*
  • Antibiotics, Antineoplastic / pharmacology
  • Antibiotics, Antineoplastic / toxicity
  • Carbazoles*
  • Cell Division / drug effects
  • DNA / chemistry
  • DNA / drug effects
  • DNA / metabolism
  • DNA Footprinting
  • DNA Ligases / antagonists & inhibitors
  • DNA Ligases / metabolism
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / toxicity
  • Indoles*
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Monosaccharides / chemistry
  • Protein Kinase C / antagonists & inhibitors
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors*
  • Topoisomerase II Inhibitors*
  • Tumor Cells, Cultured


  • Aminoglycosides
  • Anti-Bacterial Agents
  • Antibiotics, Antineoplastic
  • Carbazoles
  • Enzyme Inhibitors
  • Indoles
  • Monosaccharides
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • DNA
  • rebeccamycin
  • Protein Kinase C
  • DNA Ligases