Impact of estradiol structural modifications (18-methyl and/or 17-hydroxy inversion of configuration) on the in vitro and in vivo estrogenic activity
Impact of estradiol structural modifications (18-methyl and/or 17-hydroxy inversion of configuration) on the in vitro and in vivo estrogenic activity
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DOI：
10.1016/j.jsbmb.2011.07.009
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发表时间：
2011-11-01
影响因子：
4.1
通讯作者：
Poirier, Donald
中科院分区：
文献类型：
--
作者：
Ayan, Diana;Roy, Jenny;Poirier, Donald
It is well recognized that the majority of breast cancers are initially hormone-dependent and that 17 beta-estradiol (17 beta-E2) plays a crucial role in their development and progression. For this reason, using a compound able to block a specific enzyme involved in the last steps of the biosynthesis of 17 beta-E2 remains a rational way to treat estrogen-dependent diseases such as breast cancer. The present study describes the biological in vitro and in vivo evaluation of a structural modification (inversion of C18-methyl group at position 13 from beta to alpha face) of 17 beta-E2 (1) and 17 alpha-estradiol (17 alpha-E2; 2). The two epimers 18-epi-17 beta-E2 (3) and 18-epi-17 alpha-E2 (4) were obtained in two chemical steps by inversion of the C18-methyl of estrone using 1,2-phenylendiamine in refluxing acetic acid and reduction of ketone at position C17 with LiAlH4. The new E2 isomers were tested on estrogen-sensitive cell lines (MCF-7 and T-47D), on estrogen-sensitive tissues (uterus and vagina of mice) and on estrogen receptor (ER) to determine their estrogenic potency relatively to natural estrogen 17 beta-E2 (1). The results show that 18-epi-17 beta-E2 (3) possesses the lower affinity for ER (RBA = 1.2%), the lower estrogenicity on estrogen-sensitive cells (1000 folds less estrogenic than 17 beta-E2 in MCF-7) and no uterotrophic (estrogenic) activity when tested on mice. In fact, we observed the following order of estrogenicity: 18-epi-17 beta-E2 (3) < 18-epi-17 alpha-E2 (4) < 17 alpha-E2 (2)
