Akama T, Ishida H, Kimura U, Gomi K, Saito H
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka-ken 411-8731, Japan.
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.
最近，我们报道了5,4'-二氨基-6,8,3'-三氟黄酮（1b）在体外和体内对某些类型的人类癌细胞系均表现出强大的抗肿瘤活性。由于1b的先导化合物5,4'-二氨基黄酮（1a）的抗增殖活性可通过添加芹菜素进行调节，我们推测7位对于与假定的靶分子相互作用很重要。基于这一假设，我们探索了1b中7位取代基的构效关系。结果发现，7-甲基（7a）、7-羟甲基（7l）、7-（酰氧基）甲基（9a、c、e、g、j）和7-氨甲基（12f）衍生物在体外和体内（腹腔注射给药）对MCF-7细胞均表现出与化合物1b相当或更强的抗肿瘤活性。特别是，与几乎不溶于水的1b相比，化合物9e、g、j和12f具有足够的水溶性。还发现一种亲脂性的7-（己酰氧基）甲基衍生物（9c）尤其在体内表现出强大的抗肿瘤活性。由于作用方式和靶分子尚不清楚，未来进行机制研究将很重要。
