Development of potent non-estrogenic estrone sulfatase inhibitors.


:Estrogen levels in breast tumors of post-menopausal women are as much as 10 times higher than estrogen levels in plasma, presumably due to in situ formation of estrogen. The major source of estrogen in breast cancer cells may be conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Thus, inhibitors of estrone sulfatase have potential for the treatment of estrogen-dependent breast cancers. Several steroidal agents have been developed that are potent estrone sulfatase inhibitors, most notably estrone-3-O-sulfamate. These compounds may have undesired actions, especially estrogenicity. Recently, non-steroidal estrone sulfatase inhibitors have been designed that avoid the problems associated with an active steroid nucleus; however, these have not achieved the potency of estrone-3-O sulfamate. We have designed and synthesized a series of compounds, 17 beta-(N-alkylcarbamoyl)-estra-1,3,5(10)-trien-3-O-sulfamates (6a-d) and 17 beta-(N-alkanoyl)-estra-1,3,5(10)-trien-3-O-sulfamates (11a-d) that combine the structural features of the steroidal estrone sulfatase inhibitors with a membrane insertion region that should increase the affinity for the sulfatase enzyme and decrease the estrogenicity of the steroid. We tested the compounds for estrone sulfatase inhibition by measuring estrone sulfatase activity in intact cultures of human breast cancer cells (MDA-MB-231). We tested for estrogenicity by measuring growth of estrogen-dependent MCF-7 human breast cancer cells. All of the test compounds (10 nM) substantially inhibited estrogen sulfatase activity of intact MDA-MB-231 cells. Dose-response analysis indicated an IC50 of approximately 0.5 nM for two of the compounds (6a and 11a). In the test for estrogenicity, estrone and estrone-3-O-sulfamate significantly stimulated MCF-7 cell growth. In contrast, neither the 17 beta-(N-alkylcarbamoyl)-estra-1,3,5,(10)-trien-3-O-sulfamates++ + nor the 17 beta-(N)-alkanoyl)-estra-1,3,5,(10)-trien-3-O-sulfamates stimulated growth of MCF-7 cells at a concentration of 1 microM, indicating that they are not estrogenic at levels 2000 times greater than their IC50 for estrone sulfatase. Our data indicate the utility of the new compounds for inhibition of breast cancer cell estrone sulfatase activity. Further, our data support the concept that estrone sulfatase inhibitors may be useful as therapeutic agents for estrogen-dependent breast cancers.






Li PK,Chu GH,Guo JP,Peters A,Selcer KW




Has Abstract


1998-07-01 00:00:00
















  • Fluoro-clomiphene and its synthetic precursors: synthesis and receptor binding.

    abstract::In an attempt to synthesize compounds with selective estrogen-receptor binding, fluoro- and amino-clomiphene were totally synthesized from benzyl chloride, and their estrogenic/antiestrogenic activity as well as that of some of their chemical intermediates was evaluated. The triazene prepared from the amino-clomiphene...


    pub_type: 杂志文章


    authors: Gazit A,Livshitz T,Shani J

    更新日期:1986-07-01 00:00:00

  • Evaluation of chemiluminescent estradiol conjugates by using a surface plasmon resonance detector.

    abstract::A series of chemiluminescent 17beta-estradiol probes were synthesized. Relative equilibrium dissociation constants (K(D)) for the interaction of an anti-E(2) Fab fragment for the probes in solution were evaluated using a single E(2)-analog biosensor surface on a BIAcore surface plasmon resonance instrument. The result...


    pub_type: 杂志文章


    authors: Adamczyk M,Chen YY,Gebler JC,Johnson DD,Mattingly PG,Moore JA,Reddy RE,Wu J,Yu Z

    更新日期:2000-06-01 00:00:00

  • Immunological interference of the synthetic aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) and its metabolite(s) in the radioimmunoassay for testosterone.

    abstract::Radioimmunoassay (RIA) for testosterone (T) in unchromatographed plasma extracts from ATD-treated rats gave spuriously high values for T. Cross-reaction and chromatographic studies subsequently showed that ATD and, to a much greater extent, its metabolite(s) were responsible for this overestimation. Celite column chro...


    pub_type: 杂志文章


    authors: Donaldson MD,Forest MG

    更新日期:1980-12-01 00:00:00

  • Synthesis and analgesic effects of kyotorphin-steroid linkers.

    abstract::Kyotorphin (KTP, H-Tyr-Arg-OH) was covalently bonded with hydrocortisone or estrone to form the corresponding hydrocortisone-21-O-yl-succinyl-Tyr-ArgOH or estrone-3-O-yl-acyl-Tyr-Arg-OH. Their analgesic activities were investigated using the tail flick test. The potency of the two linkers were significantly higher tha...


    pub_type: 杂志文章


    authors: Wang C,Zhao M,Yang J,Peng S

    更新日期:2001-11-01 00:00:00

  • Individual and cyclic estrogenic profile in women: Structure and variability of the data.

    abstract::The concentration of estrogens in the body fluids of women is highly variable, due to the menstrual cycle, circadian oscillations, and other physiological and pathological causes. To date, only the cyclic fluctuations of the principal estrogens (estradiol and estrone) have been studied, with limited outcome of general...


    pub_type: 杂志文章


    authors: Bozzolino C,Vaglio S,Amante E,Alladio E,Gerace E,Salomone A,Vincenti M

    更新日期:2019-10-01 00:00:00

  • Hyperglycaemia, stress oxidant, liver dysfunction and histological changes in diabetic male rat pancreas and liver: protective effect of 17 beta-estradiol.

    abstract::Oxidative stress is thought to play a crucial role in the pathogenesis of chronic diabetic complications. We investigated the protective effects of 17 beta-estradiol (E2) on alloxan-induced stress oxidant, hepatic dysfunction and histological changes in male rats liver and pancreas. Our results showed that 17 beta-est...


    pub_type: 杂志文章


    authors: Hamden K,Carreau S,Boujbiha MA,Lajmi S,Aloulou D,Kchaou D,Elfeki A

    更新日期:2008-05-01 00:00:00

  • Estrogen receptor signaling pathways in human non-small cell lung cancer.

    abstract::Lung cancer is the most common cause of cancer mortality in male and female patients in the US. The etiology of non-small cell lung cancer (NSCLC) is not fully defined, but new data suggest that estrogens and growth factors promote tumor progression. In this work, we confirm that estrogen receptors (ER), both ERalpha ...


    pub_type: 杂志文章


    authors: Márquez-Garbán DC,Chen HW,Fishbein MC,Goodglick L,Pietras RJ

    更新日期:2007-02-01 00:00:00

  • Purification of testosterone 5 alpha-reductase from human prostate by a four-step chromatographic procedure.

    abstract::Nuclear membrane bound testosterone 5 alpha-reductase solubilized in active form from human prostatic tissue by 0.5% n-octyl beta-D-glucopyranoside was purified by a four-step chromatographic procedure including DEAE-Trisacryl ion exchange, hydroxylapatite adsorption, testosterone-Sepharose affinity and Sepharose 4B g...


    pub_type: 杂志文章


    authors: Quemener E,Amet Y,di Stefano S,Fournier G,Floch HH,Abalain JH

    更新日期:1994-12-01 00:00:00

  • Identification of isoflavonoids in beer.

    abstract::The isoflavonoids, genistein (4',5,7-trihydroxyisoflavone), biochanin A (5,7-dihydroxy-4'-methoxyisoflavone), daidzein (4',7-dihydroxyisoflavone), and formononetin (7-hydroxy-4'-methoxyisoflavone) are supposed to be health-promoting dietary factors of plant origin. They are particularly abundant in seeds and other par...


    pub_type: 杂志文章


    authors: Lapcík O,Hill M,Hampl R,Wähälä K,Adlercreutz H

    更新日期:1998-01-01 00:00:00

  • Adrenal steroidogenesis in the guinea pig: effects of androgens.

    abstract::In humans, the onset of adrenache has been found to occur with the appearance of the zona reticularis, the inner zone of the adrenal cortex. Since an increase in the volume of adrenal cortex during maturation in the guinea pig has been associated with the growth of the zona reticularis, we were interested in investiga...


    pub_type: 杂志文章


    authors: Bélanger B,Caron S,Boudou P,Fiet J,Bélanger A

    更新日期:1992-02-01 00:00:00

  • Uptake and metabolism of androgens by bovine spermatozoa.

    abstract::Spermatozoa from bovine ejaculates and cauda epiditymidis were incubated with either tritiated 17 beta-hydroxy-5 alpha-androstane-3-one (DHT) or 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol). Examination of the medium incubations demonstrated metabolic conversion of both DHT and 3 alpha-diol when these steri...


    pub_type: 杂志文章


    authors: Djöseland O,Høglo S,Nyberg K,Hastings CD,Attramadal A

    更新日期:1978-03-01 00:00:00

  • In vitro effects of RU486 on proliferation and differentiation capabilities of human bone marrow mesenchymal stromal cells.

    abstract::Although exogenous glucocorticoids (GC) play a role in the regulation of bone marrow mesenchymal stem/stromal cells (MSCs) proliferation and differentiation, the function of endogenous GC is not well understood. The purpose of this study was to investigate the effect of the blockage of endogenous GC using RU486, an an...


    pub_type: 杂志文章


    authors: Yu Y,Wei N,Stanford C,Schmidt T,Hong L

    更新日期:2012-01-01 00:00:00

  • Serum asymmetric dimethylarginine, apelin, and tumor necrosis factor-α levels in non-obese women with polycystic ovary syndrome.

    abstract::Polycystic ovary syndrome (PCOS) is associated with multiple risk factors for cardiovascular disease (CVD), including insulin resistance, type 2 diabetes mellitus, obesity, hypertension, and dyslipidemia. In addition, hyperandrogenism may contribute to the pathogenesis of CVD, independent of obesity and insulin resist...


    pub_type: 杂志文章


    authors: Choi YS,Yang HI,Cho S,Jung JA,Jeon YE,Kim HY,Seo SK,Lee BS

    更新日期:2012-11-01 00:00:00

  • Synthesis of 13,14-secotestosterone derivatives.

    abstract::A number of testosterone analogs with a 13,14-secosteroidal fragment have been prepared from (13S)-13-iodo-6beta-methoxy-3alpha, 5-cyclo-13,14-seco-5alpha-androstan-14,17-dione. The key steps involved stereoselective deiodination of the starting compound with triphenylphosphine and selective protection of the 17-keto ...


    pub_type: 杂志文章


    authors: Khripach VA,Zhabinskii VN,Kuchto AI,Zhiburtovich YY,Fando GP,Lyakhov AS,Govorova AA,Groen MB,van der Louw J,de Groot A

    更新日期:2004-07-01 00:00:00

  • Elucidation of two new corticosteroids, betamethasone dibutyrate and betamethasone tributyrate.

    abstract::Corticosteroids were used normally as anti-inflammatory drugs. However, in some area certain corticosteroids might be illegally used as growth promoting agent in feed, and as prohibited doping substances in game and sport for human or/and animal performance-enhancing. Synthesized structural similar corticosteroids wer...


    pub_type: 杂志文章


    authors: Chen SY,Fang M,Lin YT,Tsai CF,Cheng HF,Wang DY

    更新日期:2021-01-01 00:00:00

  • Anabolic hormone profiles in elite military men.

    abstract::We recently characterized the awakening responses and daily profiles of the catabolic stress hormone cortisol in elite military men. Anabolic hormones follow a similar daily pattern and may counteract the catabolic effects of cortisol. This companion report is the first to characterize daily profiles of anabolic hormo...


    pub_type: 杂志文章


    authors: Taylor MK,Kviatkovsky SA,Hernández LM,Sargent P,Segal S,Granger DA

    更新日期:2016-06-01 00:00:00

  • Adenosine as substrate and receptor agonist in the ovary.

    abstract::In the present study the possible dual effects of adenosine as substrate and adenosine receptor agonist in rat granulosa cells, cumulus-oocyte complexes, luteal cells and ovarian membranes are discussed. Adenosine is an indispensable compound in cell energy metabolism, as precursor to cofactors, second messenger and n...


    pub_type: 杂志文章


    authors: Billig H,Rosberg S,Johanson C,Ahrén K

    更新日期:1989-11-01 00:00:00

  • Facile synthesis of carbon-11-labeled cholesterol-based cationic lipids as new potential PET probes for imaging of gene delivery in cancer.

    abstract::Gene therapy based on gene delivery is a promising strategy for the treatment of various human diseases such as cancer. Cationic lipids represent one of the important synthetic gene delivery systems. There is a great interest in imaging of gene therapy using the biomedical imaging technique positron emission tomograph...


    pub_type: 杂志文章


    authors: Gao M,Wang M,Miller KD,Sledge GW,Hutchins GD,Zheng QH

    更新日期:2010-10-01 00:00:00

  • Ultrahigh-performance liquid chromatography-ion trap mass spectrometry characterization of the steroidal saponins of Dioscorea panthaica Prain et Burkill and its application for accelerating the isolation and structural elucidation of steroidal saponins.

    abstract::Dioscorea panthaica is a traditional Chinese medicinal herb used in the treatment of various physiological conditions, including cardiovascular disease, gastropathy and hypertension. Steroidal saponins (SS) are the main active ingredients of this herb and have effects on myocardial ischemia and cancer. The phytochemic...


    pub_type: 杂志文章


    authors: Wang W,Zhao Y,Jing W,Zhang J,Xiao H,Zha Q,Liu A

    更新日期:2015-03-01 00:00:00

  • Direct binding and activation of protein kinase C isoforms by steroid hormones.

    abstract::The non-genomic action of steroid hormones regulates a wide variety of cellular responses including regulation of ion transport, cell proliferation, migration, death and differentiation. In order to achieve such plethora of effects steroid hormones utilize nearly all known signal transduction pathways. One of the key ...


    pub_type: 杂志文章,评审


    authors: Alzamora R,Harvey BJ

    更新日期:2008-10-01 00:00:00

  • A novel sterol from Chinese truffles Tuber indicum.

    abstract::From the fruiting bodies of Ascomycetes Tuber indicum, a new steroidal glucoside with polyhydroxy ergosterol nucleus, tuberoside (2), has been isolated along with additional four known ergosterol derivatives, (22E, 24R)-ergosta-7, 22-dien-3beta, 5alpha, 6beta-triol (1), 5alpha, 8alpha-epidioxy-(22E, 24R)-ergosta-6, 22...


    pub_type: 杂志文章


    authors: Jinming G,Lin H,Jikai L

    更新日期:2001-10-01 00:00:00

  • The synthesis of diazo, halo, and sulfoxy bile acid derivatives: potential affinity labels.

    abstract::Bile acid derivatives, with and without C-3 sulfate groups, and having either the diazo- or halomethylketone moieties, have been synthesized in good yield and purity. The synthetic sequence, COOH leads to COC1 leads to COCHN2 leads to COCH2X, was used with deoxycholic and cholic acids, which requires carefully control...


    pub_type: 杂志文章


    authors: Fried AA,Petrow V,Lack L

    更新日期:1979-08-01 00:00:00

  • The synthesis of androstane brassinosteroid analogues with alpha-azido acid ester groups in position 17beta.

    abstract::Androstane brassinosteroid analogues with alpha-azido acid ester groups in position 17beta were synthesized from 2alpha,3alpha,17beta-trihydroxy-5alpha-androstan-6-one after the protection of the 2alpha,3alpha-diols upon treatment with the corresponding alpha-azido acid and the subsequent deprotection of the diol grou...


    pub_type: 杂志文章


    authors: Hnilickova J,Kohout L,Capdevila E,Esteve A,Vilaplana M,Molist M,Brosa C,Swaczynova-Oklestkova J,Slavikova B

    更新日期:2010-12-01 00:00:00

  • A novel enzyme-linked immunosorbent assay for ethynylestradiol using a long-chain biotinylated EE2 derivative.

    abstract::Ethynylestradiol (EE2) is one of the most potent endocrine disrupting compounds capable to induce estrogenic effects even at trace level concentrations in the aquatic environment. Methods for detecting EE2 in such concentrations are generally based on GC or HPLC coupled to at least one mass spectrometer. Another appro...


    pub_type: 杂志文章


    authors: Schneider C,Schöler HF,Schneider RJ

    更新日期:2004-04-01 00:00:00

  • An expeditious synthesis of spinasterol and schottenol, two phytosterols present in argan oil and in cactus pear seed oil, and evaluation of their biological activities on cells of the central nervous system.

    abstract::Spinasterol and schottenol, two phytosterols present in argan oil and in cactus pear seed oil, were synthesized from commercially available stigmasterol by a four steps reactions. In addition, the effects of these phytosterols on cell growth and mitochondrial activity were evaluated on 158N murine oligodendrocytes, C6...


    pub_type: 杂志文章


    authors: Badreddine A,Karym el M,Zarrouk A,Nury T,El Kharrassi Y,Nasser B,Cherkaoui Malki M,Lizard G,Samadi M

    更新日期:2015-07-01 00:00:00

  • Expression of membrane progesterone receptors (mPRs) in rat peripheral glial cell membranes and their potential role in the modulation of cell migration and protein expression.

    abstract::The role played by progestogens in modulating Schwann cell pathophysiology is well established. Progestogens exert their effects in these cells through both classical genomic and non-genomic mechanisms, the latter mediated by the GABA-A receptor. However, there is evidence that other receptors may be involved. Membran...


    pub_type: 杂志文章


    authors: Castelnovo LF,Magnaghi V,Thomas P

    更新日期:2019-02-01 00:00:00

  • Counteraction of early circulatory derangement by administration of low dose steroid treatment at the onset of established endotoxemic shock is not directly mediated by TNF-α and IL-6.

    abstract:BACKGROUND:Once a septic condition is progressing, administration of steroids in the pro-inflammatory phase of septic shock ought to yield maximal effect on the subsequent, devastating inflammatory response. Recently, a retrospective study showed that early initiation of corticosteroid therapy improved survival in sept...


    pub_type: 杂志文章


    authors: Söderberg E,Lipcsey M,Sjölin J,Larsson A,Eriksson MB

    更新日期:2012-09-01 00:00:00

  • Progestin drives breast cancer growth by inducing p21(CIP1) expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2.

    abstract::Cell cycle regulator p21(CIP1) has controversial biological effects in breast cancer since in spite of its role as cell cycle inhibitor and promoter of cellular senescence, it also induces cell proliferation and chemoteraphy resistance. We here explored the molecular mechanisms involved in progestin regulation of p21(...


    pub_type: 杂志文章


    authors: Diaz Flaqué MC,Vicario R,Proietti CJ,Izzo F,Schillaci R,Elizalde PV

    更新日期:2013-06-01 00:00:00

  • Endocrine characterization of a human ovarian carcinoma (BG-1) established in nude mice.

    abstract::The steroid receptor-positive human ovarian cancer (BG-1) was evaluated to determine its usefulness as a tumor model. This tumor grows in intact male and female nude mice without hormone supplements. Moreover, its growth was significantly accelerated in ovariectomized mice, and the increased growth rate could be rever...


    pub_type: 杂志文章


    authors: Zimniski SJ,Garola RE,Fendl K,Peterson CM

    更新日期:1989-12-01 00:00:00

  • Reference intervals of urinary steroid metabolites using gas chromatography-mass spectrometry in Chinese adults.

    abstract:BACKGROUND:Urinary steroid profiling by GC or GC-MS are established clinical tools to complement other biochemical tests in the diagnosis and investigation of a wide range of adrenocortical disorders, but normative data on adults using the more specific GC-MS are lacking. Our objective was to set up the reference inter...


    pub_type: 杂志文章


    authors: Chan AO,Taylor NF,Tiu SC,Shek CC

    更新日期:2008-09-01 00:00:00