Design and synthesis of potent antitumor 5,4'-diaminoflavone derivatives based on metabolic considerations

J Med Chem. 1997 Jun 6;40(12):1894-900. doi: 10.1021/jm9700326.


Recently, we reported that 5,4'-diaminoflavone (1) exhibits potent and specific growth-inhibitory activity against the estrogen receptor (ER)-positive human breast cancer cell line MCF-7. However, when compound 1 was incubated with S-9 mix, its metabolites were observed. Moreover, addition of S-9 mix to the medium caused the drastic decrease in activity of compound 1. Since the 6-, 8-, and 3'-positions were considered to be metabolized oxidatively in vivo from MO calculations, a series of 5,4'-diaminoflavone derivatives substituted at such putative metabolic positions with various functional groups were synthesized aiming at the metabolically stable derivatives. Among them, 5,4'-diamino-6,8,3'-trifluoroflavone (14d) exhibited strong growth-inhibitory activity against MCF-7 cells even in the presence of S-9 mix. Moreover, orally administered compound 14d completely suppressed the growth of MCF-7 inoculated into nude mice, and the effect was more potent than that of compound 1. In addition to ER-positive breast cancer cells, compound 14d exhibited growth-inhibitory activity against a panel of human cancer cell lines including a part of ER-negative breast, endometrial, ovarian, and liver cancers. From these results, fluorine introduction to the putative metabolic positions of compound 1 was elucidated to be effective in the enhancement of the in vivo antitumor activity, probably due to the block of the metabolic deactivation.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / pathology
  • Cell Division / drug effects
  • Drug Design*
  • Endometrial Neoplasms / pathology
  • Female
  • Flavonoids / chemical synthesis
  • Flavonoids / pharmacology
  • Flavonoids / therapeutic use
  • Humans
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Structure
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy
  • Ovarian Neoplasms / pathology
  • Receptors, Estradiol / analysis
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • 5,4'-diamino-6,8,3'-trifluoroflavone
  • Antineoplastic Agents
  • Flavonoids
  • Receptors, Estradiol