title: Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent.
abstract: 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.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka-ken 411-8731, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Akama
authors.forename: H
authors.initials: H
authors.lastname: Ishida
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
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C106597:5,4'-diamino-6,8,3'-trifluoroflavone; D000970:Antineoplastic Agents; D005419:Flavonoids