title: Boron estrogens: synthesis, biochemical and biological testing of estrone and estradiol-17 beta 3-carboranylmethyl ethers.
abstract: Synthesis, biochemical and biological testing of the first carborane derivatives of estrogens are described. Estrone 3-carboranylmethyl ether was synthesized in two steps from estrone. Reduction of estrone 3-carboranylmethyl ether with sodium borohydride provided estradiol-17 beta 3-carboranylmethyl ether. Enzyme kinetic measurements showed that estrone 3-carboranylmethyl ether is a substrate for human placental 17 beta-hydroxysteroid dehydrogenase with Km = 5 x 10(-6)M, and Vmax = 0.016 mumol min-1 microgram -1. The relative affinity constant of estradiol-17 beta 3-carboranylmethyl ether for rat uterine estrogen receptor was 0.5 (compared with a value of 100 for estradiol-17 beta). Consistent with its low affinity for estrogen receptor, the dose-dependent uterotropic response to estradiol-17 beta 3-carboranylmethyl ether in castrated female rats was one sixtieth that of estradiol-17 beta. None of the tested rats had a toxic reaction to estradiol-17 beta 3-carboranylmethyl ether. These results demonstrate that exceptionally stable carborane derivatives of estrogens can be synthesized with preservation of their biochemical and biological properties. Boron-containing estrogens may be useful for thermal neutron capture therapy of cancers with estrogen receptors to concentrate boron in the cell nucleus.
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D001894:Borohydrides; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D004970:Estrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D005260:Female; D006801:Humans; D007700:Kinetics; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014599:Uterus / Q000378:metabolism
chemical_list: D001894:Borohydrides; D011960:Receptors, Estrogen; D004970:Estrone; D004958:Estradiol; C029526:estrone 3-carboranylmethyl ether; C029527:estradiol-17beta 3-carboranylmethyl ether; D015067:17-Hydroxysteroid Dehydrogenases