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J.Health Sci., 52(2), 186-191, 2006
Anti-Estrogenic Activity of Prenylated Isoflavones from Millettia pachycarpa: Implications for Pharmacophores and Unique Mechanisms
Yoshinori Okamoto,a Atsushi Suzuki,a Koji Ueda,a Chihiro Ito,a Masataka Itoigawa,b Hiroshi Furukawa,a Tsutomu Nishihara,c and Nakao Kojima*, a
aFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan, bFaculty of Human Wellness, Tokai Gakuen University, 2-901 Nakahira, Tempaku-ku, Nagoya 468-8514, Japan, and cCenter for Advanced Science and Innovation, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
Phytoestrogens containing isoflavonoids are thought to exhibit preventative effects on estrogen-responsive diseases. Chemical modifications, such as prenylation, in biosynthetic processes enhance the structural variety of isoflavonoids and prompted us to carry out a structure-activity relationship study. We determined the estrogenic/anti-estrogenic activities and estrogen receptor (ER)-binding affinities of eight kinds of prenylated isoflavones isolated from Millettia pachycarpa (Leguminosae), and those of two kinds of non-prenylated compounds (genistein and daidzein). By comparing these compounds, the pharmacophores for estrogenic/anti-estrogenic activities were elucidated. None of the tested compounds (except genistein) were estrogenic on ligand-dependent yeast-two hybrid assay. On the other hand, 5 isoflavones showed distinct anti-estrogenic activity. Unexpectedly, the most potent antagonists, isoerysenegalensein E and 6,8-diprenylorobol, showed anti-estrogenic activity comparable to that of 4-hydroxytamoxifen, a typical ER antagonist. This suggests that genistein became an antagonist after prenylation and hydroxylation. The pharmacophores providing genistein with strong anti-estrogenic activity were as follows: prenyl groups of the 6- and 8-positions on the A-ring, hydroxyl group of the 6-prenyl moiety or the B-ring (catechol form), non-cyclization of the prenyl group with the A-ring, and non-hydroxylation of the 8-prenyl group on the A-ring. The ER-binding affinities of the isoflavonoids were not sufficiently high to explain their potent antagonistic activities, thus suggesting 17beta-estradiol-non-competitive mechanisms.
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