title: Design and synthesis of potent antitumor 5,4'-diaminoflavone derivatives based on metabolic considerations.
abstract: 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.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Ltd., Shizuoka-ken, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Akama
authors.forename: H
authors.initials: H
authors.lastname: Ishida
authors.forename: Y
authors.initials: Y
authors.lastname: Shida
authors.forename: U
authors.initials: U
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Gomi
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: E
authors.initials: E
authors.lastname: Fuse
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: N
authors.initials: N
authors.lastname: Yoda
authors.forename: M
authors.initials: M
authors.lastname: Kasai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000737:chemistry / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D016889:Endometrial Neoplasms / Q000473:pathology; D005260:Female; D005419:Flavonoids / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000473:pathology; D011959:Receptors, Estradiol / Q000032:analysis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C106597:5,4'-diamino-6,8,3'-trifluoroflavone; D000970:Antineoplastic Agents; D005419:Flavonoids; D011959:Receptors, Estradiol