Syntheses, biochemical and biological evaluation of staurosporine analogues from the microbial metabolite rebeccamycin

Bioorg Med Chem. 1998 Sep;6(9):1597-604. doi: 10.1016/s0968-0896(98)00096-0.

Abstract

The indolocarbazole antibiotics staurosporine and rebeccamycin (1) are potent antitumor drugs targeting protein kinase C and topoisomerase I, respectively. To obtain staurosporine analogues from rebeccamycin, different structural modifications were performed: coupling of the sugar moiety to the second indole nitrogen, dechlorination and then reduction of the imide function to amide. The newly synthesized compounds (3-6) were tested for their abilities to bind to DNA and to inhibit topoisomerase I and protein kinase C. Their antiproliferative effects in vitro against B16 melanoma and P388 leukemia (including the related P388CPT cell line resistant to camptothecin) as well as their anti-HIV-1 and antimicrobial activities against various strains of microorganisms were determined. The cytotoxicity of the dechlorinated imide analogue 5 correlates well with its DNA binding and anti-topoisomerase I activities. These findings provide guidance for the development of new topoisomerase I-targeted antitumor indolocarbazoles equipped with a carbohydrate attached to the two indole nitrogens.

MeSH terms

  • Aminoglycosides*
  • Anti-Bacterial Agents / chemistry*
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / pharmacology
  • Anti-Infective Agents / chemical synthesis
  • Anti-Infective Agents / pharmacology
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Carbazoles*
  • Cell Line
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Evaluation Studies as Topic
  • Humans
  • Indoles*
  • Magnetic Resonance Spectroscopy
  • Protein Kinase C / antagonists & inhibitors
  • Spectrophotometry, Infrared
  • Staurosporine / analogs & derivatives*
  • Staurosporine / chemical synthesis
  • Staurosporine / pharmacology
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors
  • Tumor Cells, Cultured

Substances

  • Aminoglycosides
  • Anti-Bacterial Agents
  • Anti-HIV Agents
  • Anti-Infective Agents
  • Antineoplastic Agents
  • Carbazoles
  • Enzyme Inhibitors
  • Indoles
  • Topoisomerase I Inhibitors
  • rebeccamycin
  • Protein Kinase C
  • Staurosporine