Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent

J Med Chem. 1998 Jun 4;41(12):2056-67. doi: 10.1021/jm970728z.


Recently, we reported that 5,4'-diamino-6,8,3'-trifluoroflavone (1b) exhibits potent antitumor activity against certain types of human cancer cell lines both in vitro and in vivo. Since the antiproliferative activity of 5,4'-diaminoflavone (1a), the lead compound of 1b, was modulated by the addition of apigenin, we hypothesized that the 7-position is important for the interaction with a putative target molecule. On the basis of this hypothesis, the structure-activity relationships of the substituents at the 7-position of 1b were explored. As a result, 7-methyl (7a), 7-hydroxymethyl (7l), 7-(acyloxy)methyl (9a,c,e,g,j), and 7-aminomethyl (12f) derivatives were found to exhibit comparable or superior antitumor activity to compound 1b against MCF-7 cells both in vitro and in vivo (po administration). In particular, compounds 9e,g,j, and 12f were sufficiently water-soluble as compared with 1b which hardly solubilizes in water. A lipophilic 7-(hexanoyloxy)methyl derivative (9c) was also found to exhibit strong antitumor activity especially in vivo. Since the modes of action and the target molecule(s) are unknown, a mechanistic study will be important in the future.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Female
  • Flavonoids* / chemical synthesis
  • Flavonoids* / chemistry
  • Flavonoids* / pharmacology
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


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