title: Neighboring group participation. Part 16. Stereoselective synthesis and receptor-binding examination of the four stereoisomers of 16-bromomethyl-3,17-estradiols.
abstract: The four possible isomers of 3-benzyloxy-16-hydroxymethylestra-1,3,5(10)-trien-17-ol (1a-4a) with proven configurations were converted into the corresponding 3-benzyloxy-16-bromomethylestra-1,3,5(10)-triene-3,17-diols (5e-8e). Depending on the reaction conditions the cis isomers of 3-benzyloxy-16-hydroxymethylestra-1,3,5(10)-trien-17-ol (1a and 2a) were transformed into 3-benzyloxy-16-bromomethylestra-1,3,5(10)-trien-17-yl acetate (5b and 6b) or 16-bromomethyl-3-hydroxyestra-1,3,5(10)-trien-17-yl acetate (5c and 6c) on treatment with HBr and acetic acid. The mechanism of the process can be interpreted as involving front-side neighboring group participation. Under similar experimental conditions, the trans isomers (3a and 4a) yielded only 3-benzyloxy-16-acetoxymethylestra-1,3,5(10)-trien-17-yl acetates (3b and 4b) or 16-acetoxymethylestra-1,3,5(10)-triene-3,17-diyl diacetates (3d and 4d). Both the cis (1a and 2a) and the trans (3a, and 4a) isomers were transformed into 16-bromomethylestra-1,3,5(10)-trien-17-ol (5a-8a) by the Appel reaction on treatment with CBr4/Ph3P. Debenzylation of 5a-8a was carried out with HBr and acetic acid to yield 5e-8e. The debenzylation process in the presence of acetic anhydride produces the diacetates 5d-8d. The structures of the compounds were determined by means of MS, 1H NMR and 13C NMR spectroscopic methods. Compounds 5c-8c and 5e-8e were tested in a radioligand-binding assay. Except for the affinity of 7e for the estrogen receptor (Ki=2.55 nM), the affinities of the eight compounds (5c-8c and 5e-8e) for the estrogen, androgen and progesterone receptors are low (Ki > 0.55, 0.52 and 0.21 microM, respectively).
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.
authors.forename: Agota
authors.initials: A
authors.lastname: Szájli
authors.forename: János
authors.initials: J
authors.lastname: Wölfling
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Mernyák
authors.forename: Renáta
authors.initials: R
authors.lastname: Minorics
authors.forename: Arpád
authors.initials: A
authors.lastname: Márki
authors.forename: George
authors.initials: G
authors.lastname: Falkay
authors.forename: Gyula
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004965:Estrogen Antagonists; D005260:Female; D008297:Male; D008968:Molecular Conformation; D011282:Pregnenediones / Q000494:pharmacology; D011467:Prostate / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011944:Receptors, Androgen / Q000187:drug effects*; D011960:Receptors, Estrogen / Q000187:drug effects*; D011980:Receptors, Progesterone / Q000187:drug effects*; D013237:Stereoisomerism; D014599:Uterus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; D011282:Pregnenediones; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013196:Dihydrotestosterone; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; D004958:Estradiol