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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of attachment of a dimethylaminoethoxy or a dimethylaminopropoxy group at the 11 beta-position of estradiol (E2) on its relative binding affinity (RBA) to estrogen receptor (ER) and intrinsic biologic activity is described. The binding of 11 beta-[2-(N,N-dimethylamino) ethoxy]estra-1,3,5(10)-triene-3,17 beta-diol (4) and 11 beta-[3-(N,N- dimethylamino)propoxy]estra-1,3,5(10)-triene-3,17 beta-diol (5) to the ER from immature rat uterine tissue was measured relative to that of [3H]E2 by a competitive binding assay. It was found that the 11 beta-substituted E2 analogs have considerably lower RBA to ER than the corresponding parent compound. The intrinsic activity of compounds 4 and 5 were studied in terms of uterotrophic and antiuterotrophic activity. It was found that the uterotrophic activity of these compounds was drastically reduced compared with E2. However, no antiuterotrophic activity was observed in these compounds at dosages ranging from 1 to 100 micrograms/rat/d.
Steroids 1990 May
PMID:Synthesis and biologic activities of 11 beta-substituted estradiol as potential antiestrogens. 236 Feb 20

Immobilization of the estrogen receptor to the N-hydroxysuccinimide ester of succinylethylenediaminocarboxymethyl agarose (Reagent B) is described and compared with that to the charged N-hydroxysuccinimide ester derivative (Reagent A), previously described. The time course for immobilization was examined. Thirty-six percent of the input receptor was immobilized within 1 h. The optimum pH in immobilization is 7.0-7.4. The dissociation rate of [3H]estradiol(3,17 beta-1,3,5(10)-estratriene) from the [3H]estradiol-receptor complex immobilized to Reagent B was similar to that in Reagent A. The receptor immobilized to Reagent B was saturated with estradiol at 5 h. The [3H]estradiol concentration necessary for saturation was 10 nM. The dissociation constant (KD) for the receptor immobilized to Reagent B was 0.95 X 10(-9) M.
Steroids 1989 Aug
PMID:Covalent immobilization of the estrogen receptor to an electrostatically neutral N-hydroxysuccinimide ester derivative of agarose. 258 99

The conversion of estrone to 14,15-secoestratrien-15-ynes, inactivators of estradiol dehydrogenase from human term placenta, is described. The optically pure precursor 7-acetoxy-octahydro-2-phenanthrenecarboxylic acid methyl ester is prepared from estrone in five steps and 40% yield. The unsubstituted propargylic secoestratriene diol, a mechanism-based inactivator of estradiol dehydrogenase, and the corresponding acetylenic ketone, an affinity label inactivator of the same enzyme, arise from the phenanthrene ester in three and four steps. The propargylic secoestratriene diol also competes with [3H]estradiol for binding to calf uterus estrogen receptor and possesses weak uterotrophic activity.
Steroids
PMID:Preparation of 14,15-secoestra-1,3,5(10)-trien-15-ynes, inhibitors of estradiol dehydrogenase. 277 72

In this study, we assessed the rate of estradiol degradation via the 17 beta-hydroxysteroid dehydrogenase (HSD) enzyme in breast tumors from postmenopausal women. We initially studied the effects of time, level of enzyme activity, amount of tissue assayed, and substrate concentration on the linearity of conversion of estradiol to estrone in breast tumor homogenates. The reaction was demonstrated to be linear when less than 15% conversion of estradiol to estrone occurred over 30 min with homogenates produced from 2.5 mg of tissue. Detailed kinetic experiments demonstrated the presence of two classes of enzyme activity, one with high affinity and the other with low affinity. In 83% of the tumors examined, the high affinity form was present and had a median Km of 0.62 microM and Vmax of 82 nmol/g protein/h. In 29 tumors, HSD activity could be precisely quantified and correlated with clinical parameters. No statistically significant correlation of enzyme activity with estrogen receptor (r2 = 0.06) or progesterone receptor (r2 = 0.006) or with patient age could be detected (r2 = 0.001). In 12 additional tumors, activity exceeded 15% conversion of estradiol to estrone at 30 min and precise quantitation was not possible. The average content of progesterone receptor was similar for these 12 tumors as for the 19 with lower HSD activity. However, estrogen receptor content and patient age were lower in the group with high HSD activity. The finding of a high affinity form of HSD in this study provides support for the biological importance of this enzyme in breast cancer tissues.
Steroids
PMID:17 Beta-hydroxysteroid dehydrogenase in human breast cancer: analysis of kinetic and clinical parameters. 285 Dec

Uteri and cervices were obtained from estrous rabbits (controls) and from rabbits 24 h or 7 days after a single intramuscular injection of medroxyprogesterone acetate (MPA; 2.14 mg/kg). Estrogen and progesterone receptor concentrations were measured by Scatchard analysis, cell-free DNA synthesis was measured by (3H)-TTP incorporation, and tissue sections were examined histologically. The uterine endometrium underwent marked changes in histology, including extensive infoldings of the mucosal surface, glands were continuous into crypts and secretory epithelial cells were noted. In addition, total estrogen receptor content and DNA synthesis were decreased. In contrast, there was no significant change in the histology of the endocervical epithelial-stromal complex, and total estrogen receptor remained constant. However, DNA synthesis in the endocervix was decreased. Thus we conclude that: DNA synthesis is not linked to changes in estrogen receptor in the endocervix; and differential effects of progestogen on the estrogen receptor system occur coincident with different morphological responses within two target tissues from the same animal.
Steroids
PMID:Differential responses of rabbit endocervix and uterus to medroxyprogesterone acetate. 294 53

Microsomal preparations derived from bovine placenta cotyledons, previously investigated as a convenient source of fatty acyl coenzyme A: estradiol-17 beta-acyl transferase, have been shown to acylate other steroids bearing 3 beta- or 17 beta-hydroxyl groups. In the presence of 0.1 mM oleoyl CoA, the apparent Km values for dehydroepiandrosterone, testosterone, and 5-androstene-3 beta,17 beta-diol (delta 5-DIOL) were 45, 67, and 20 microM, respectively. Acylation of delta 5-DIOL occurred at either the 3 beta- or 17 beta-positions to give monoesters. Testosterone, estradiol-17 beta, and delta 5-DIOL acted as competitive inhibitors for the acylation of the 3 beta-hydroxyl group of dehydroepiandrosterone (Ki values 71, 75, and 41 microM, respectively). Such data indicate that a single enzyme of wide substrate specificity may be involved in these acylation reactions. When estrogen receptor (ER) positive and negative human mammary cancer cell lines were incubated with 10 nM [3H]delta 5-DIOL, intracellular accumulation of delta 5-DIOL long-chain fatty acid esters occurred; rates being higher (p less than 0.001) in ER negative cells (MDA-MB-231 and MDA-MB-330) compared to MCF-7 cells (ER positive), and higher (P less than 0.005) in MDA-MB-231 cells compared to ZR-75-1 cells (ER positive). After exposure to 10 nM [3H]delta 5-DIOL for 16 h, the total labeled steroid fatty acid fraction was composed predominantly of delta 5-DIOL-3 beta- and 17 beta-monoesters (approximately 85%), the remainder containing approximately equal amounts of delta 5-DIOL-diesters and dehydroepiandrosterone-3 beta-esters. Subsequent transfer to medium lacking delta 5-DIOL was accompanied by a breakdown of the labeled esters, which was more rapid in the ER positive cell lines. During this period, intracellular free delta 5-DIOL levels rapidly declined in MDA-MB-330 cells but were maintained in MCF-7 cells, presumably by binding to ER. This behavior parallels that of estradiol-17 beta previously observed in these cell lines and further emphasizes the potential importance of the adrenal-derived estrogen delta 5-DIOL in consideration of a hormone-based etiology of human breast cancer.
Steroids
PMID:Formation and turnover of long-chain fatty acid esters of 5-androstene-3 beta, 17 beta -diol in estrogen receptor positive and negative human mammary cancer cell lines in culture. 321 53

The tritium-labeled from of 11 beta-chloromethylestradiol was prepared by metal hydride reduction of the 17-keto derivative. Affinity labeling experiments were carried out using [3H] 11 beta-chloromethylestradiol and [3H]tamoxifen aziridine with estrogen receptor from crude, calf uterine cytosol and partially purified (heparin-sepharose chromatography) preparations. Both compounds formed highly stable receptor complexes. Estrogen specific, covalent binding, however, was indicated only for [3H]tamoxifen aziridine. An equilibrium dissociation constant of 2.8 x 10(-10) M was determined for the receptor-[3H] 11 beta-chloromethylestradiol interaction. Measurement of hormone dissociation kinetics at 30 degrees C revealed a slow, single phase dissociation of 11 beta-chloromethylestradiol from the receptor (dissociation rate constant, 1.3 x 10(-3) min-1). This contrasted with the normal biphasic dissociation pattern of estradiol in which the dissociation rate constant for the slower component was 16.7 x 10(-3) min-1. The results indicate that 11 beta-chloromethylestradiol readily converts the estrogen receptor to a high affinity binding form and suggest that the radiolabeled hormone may prove useful for studies of estrogen action.
Steroids
PMID:A comparison of 11 beta-chloromethylestradiol and tamoxifen aziridine as affinity labeling reagents for estrogen receptors. 324 73

In order to examine the tolerance of the estrogen receptor for 16 alpha-substituents in estradiol, we have synthesized various 16 alpha-substituted estrogens and determined their binding affinity for receptor by a competitive radiometric binding assay. The substituents ranged from small, single-atom substituents (halogens), two-atom substituents (halomethyl groups), to larger alkyl groups and ultimately alkyl groups bearing various functionality, including fluorescent (nitrobenzoxadiazole, NBD) and photoreactive (nitroazidophenyl, NAP) groups. The estrogen receptor seems to have a moderate tolerance for bulky substituents: All of the halogen and halomethyl substituents bind with an affinity at least 50% that of estradiol; in the three atom alkyl series, the affinity declined markedly from propargyl (44%) and allyl (38%) to propyl (5%), suggestive of detailed steric constraints or a preference for unsaturation. The larger, more highly functionalized derivatives ranged in affinity from 0.1-7%, with the highest affinity binders being benzyl (5%) and 4-phenoxy-2(E)-butenyl (7%); most of the lowest affinity ones were the bulky fluorescent and photoreactive derivatives. Thus, the estrogen receptor has good tolerance for estradiol derivatives substituted at the 16 alpha-position with nonpolar groups of moderate bulk; however, with groups of larger bulk, affinity is much lower and becomes highly dependent upon the polarity and detailed structure of the substituents.
Steroids
PMID:Estrogen receptor binding tolerance of 16 alpha-substituted estradiol derivatives. 324 72

Covalent immobilization of the soluble estrogen receptor from a rabbit uterus to N-hydroxysuccinimide ester derivative of agarose is shown. At first, the condition for the immobilization reaction was examined. The non-immobilized receptor was extracted with 0.4 M NaCl-containing medium. Sixty seven to 80% of the input receptor were immobilized within 30 min at 0 degrees C in 0.1 M HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, pH 7.4). The immobilized [3H]estradiol(3,17 beta-dihydroxy-1,3,5(10)-estratriene)-receptor complex was stable for at least 24 h. The optimum pH for immobilization was 7.4. Ca2+ or Na+ ions in the reaction media decreased the yields in immobilization of the receptor to the reagent with an electrostatically positive spacer arm. Next, influences of immobilization on the receptor were examined. The dissociation rate of [3H]estradiol from the immobilized receptor was a little slower than that from the native receptor. The estrogen-free immobilized receptor was saturated by incubating with 10 nM [3H]estradiol for 10 h at 0 degrees C in 0.1 M HEPES (pH 7.4). From Scatchard plot analysis, it was found that the hormone binding affinity in the immobilized receptor decreased to approximately one-fourth of that in the native receptor.
Steroids 1988 Sep
PMID:Covalent immobilization of the estrogen receptor to a cationic N-hydroxysuccinimide ester derivative of agarose. 325 23

Propargyl amine was protected by condensing it with 2,5-hexane-dione to give 2,5-dimethyl-N-(2'-propyn-1'-yl)pyrrole (2). The latter was converted to the corresponding Grignard reagent with ethylmagnesium bromide, and then condensed with estrone tetrahydropyranyl ether to give 17 alpha-[3'-(2'',5''-dimethyl-1''-pyrryl)-1'-propyn-1'-yl)-1,3 ,5( 10)- estratriene-3,17 beta-diol 3-tetrahydropyranyl ether (3), in 85% yield. Acetic acid and methanol cleaved the tetrahydropyranyl ether group, and hydroxylamine and sodium bicarbonate cleaved the pyrrole ring to give 17 alpha-(3'-amino-1'-propyn-1'-yl)-1,3,5(10)-estratriene-3,17 beta-diol (1), estrynamine. Several derivatives and analogs of 1 were also synthesized. Estrynamine binds to estrogen receptor with an RBA of 0.0045 (estradiol = 1.0). Several of the compounds, including estrynamine, are weak estrogens (stimulation of prolactin synthesis).
Steroids
PMID:Conjugates of steroids and anti-cancer agents. III. The synthesis of estrynamine and certain derivatives. 344 80


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