Syntheses and biological evaluation of new glyco-modified angucyclin-antibiotics

Bioorg Med Chem. 2000 Sep;8(9):2347-54. doi: 10.1016/s0968-0896(00)00166-8.

Abstract

The synthesis of novel aquayamycin-derived angucycline antibiotics 13a-d has been achieved. Glycosylation of aquayamycin (6) using 2-selenoglycosyl acetate 7 as glycosyl donor proceeded in excellent yield but attempts to reductively remove the selenyl group led to rearrangement or further aromatization of the aglycon. As a consequence of these results, it became possible to prepare urdamycinone B (10) starting from aquayamycin (6). In addition, silyl protected D-olivals 12a,b were attached to the C-glycoside domain of aquayamycin (6) under protic conditions. As expected, the hydroxy and phenol groups of the benz[a]anthracene framework of 6 did not react under the glycosylation conditions employed. Stepwise removal of the silyl protecting group starting with tetrabutyl ammonium fluoride followed by use of the HF/pyridine complex suppressed a possible rearrangement of the aglycon and successfully terminated the sequence. The new angucycline-antibiotics 13a and 13b are some of the most potent xanthine oxidase inhibitors known and show cytotoxic activity with ED50-values in the range of 12.6-2.9x 10(-6) M.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthraquinones / chemical synthesis*
  • Anthraquinones / pharmacology*
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Antibiotics, Antineoplastic / chemical synthesis
  • Antibiotics, Antineoplastic / pharmacology
  • Benz(a)Anthracenes / chemical synthesis
  • Benz(a)Anthracenes / pharmacology*
  • Cell Survival / drug effects
  • Colony-Forming Units Assay
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Glycosides / chemical synthesis
  • Glycosides / pharmacology
  • Humans
  • Mice
  • Structure-Activity Relationship
  • Tetracyclines
  • Tumor Cells, Cultured
  • Xanthine Oxidase / antagonists & inhibitors
  • Xanthine Oxidase / metabolism

Substances

  • Anthraquinones
  • Anti-Bacterial Agents
  • Antibiotics, Antineoplastic
  • Benz(a)Anthracenes
  • Enzyme Inhibitors
  • Glycosides
  • Tetracyclines
  • aquayamycin
  • Xanthine Oxidase