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

Recently, we reported that 5,4'-diamino-6,8,3'-trifluoroflavone (Ib) 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 (la), the lead compound of Ib, 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 Ib were explored. As a result, 7-methyl (7a), 7-hydroxymethyl (71), 7-(acyloxy)methyl (9a,c,e,g,j), and 7-aminomethyl (12f) derivatives were found to exhibit comparable or superior antitumor activity to compound Ib 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 Ib 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.