title: Impact of estradiol structural modifications (18-methyl and/or 17-hydroxy inversion of configuration) on the in vitro and in vivo estrogenic activity.
abstract: It is well recognized that the majority of breast cancers are initially hormone-dependent and that 17β-estradiol (17β-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 17β-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 β to α face) of 17β-E2 (1) and 17α-estradiol (17α-E2; 2). The two epimers 18-epi-17β-E2 (3) and 18-epi-17α-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 LiAlH(4). 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 17β-E2 (1). The results show that 18-epi-17β-E2 (3) possesses the lower affinity for ER (RBA = 1.2%), the lower estrogenicity on estrogen-sensitive cells (1000 folds less estrogenic than 17β-E2 in MCF-7) and no uterotrophic (estrogenic) activity when tested on mice. In fact, we observed the following order of estrogenicity: 18-epi-17β-E2 (3)<18-epi-17α-E2 (4) << 17α-E2 (2)17β-E2 (1). These results suggest that the inversion of C18-methyl of natural 17β-E2 scaffold could be a useful strategy to decrease the estrogenicity of E2 derivatives used as enzyme inhibitors in the context of a treatment of estrogen-dependent diseases.
authors.affiliation: Laboratory of Medicinal Chemistry, CHUQ, CHUL-Research Center, Endocrinology and Genomic Unit, and Laval University, Faculty of Medicine, Quebec, Quebec G1V 4G2, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Ayan
authors.forename: Jenny
authors.initials: J
authors.lastname: Roy
authors.forename: René
authors.initials: R
authors.lastname: Maltais
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000818:Animals; D002460:Cell Line; D004958:Estradiol / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D011960:Receptors, Estrogen; D004958:Estradiol