- ANDROGEN METABOLISM IN MALE AND FEMALE BREAST TISSUE
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Incubation studies have been carried out using normal breast tissue and breast tissue from patients with gynecomastia, mammary dysplasia and breast carcinoma to determine the pattern of androstenedione metabolism.All tissues formed estrone (E1) and testosterone (T) in all incubations.Estradiol (E2) was isolated in incubations of tissue from 1 of 6 patients with mammary dysplasia, 5 of 6 patients with gynecomastia and in all incubations with normal and carcinoma tissue.Estrone formation was lowest in mammary dysplasia and gynecomastia, and higher in apparently normal breast tissue.The greatest E1 formation was found in incubations with breast carcinoma tissue, although there was considerable variation within this tissue group.Estradiol formation was low in all tissues, with the highest conversion rates in carcinoma tissue.Testosterone formation in carcinoma tissue was greater than in mammary dysplasia or gynecomastia, but similar to apparently normal tissue.These results indicate that breast tissue from different pathological states varies in its capacity to aromatize androstenedione (A) to estrogenic products and to convert it to other androgens.They have also shown that the pattern of metabolism is distinctive for the nature of the pathological abnormality.
- Perel, E.,Davis, S.,Killinger, D. W.
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- Mechanism of action of bolandiol (19-nortestosterone-3β,17β-diol), a unique anabolic steroid with androgenic, estrogenic, and progestational activities
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Bolandiol is a synthetic anabolic steroid that increases lean body mass and bone mineral density without significant stimulation of sex accessory glands in castrate adult male rats. Since bolandiol suppresses gonadotropins and endogenous testosterone (T) production, we investigated its mechanism of action. We compared the potency of bolandiol in vitro and in vivo with T, 5α-dihydrotestosterone (DHT), 19-nortestosterone (19-NT) and estradiol (E2). Bolandiol bound with lower affinity to the recombinant rat androgen receptor (AR) than the other androgens and had low, but measurable, affinity for recombinant human progestin receptors (PR-A, PR-B), and estrogen receptors (ERα and β-1). Functional agonist activity was assessed in transcription assays mediated by AR, PR, or ER. Bolandiol was stimulatory in all these assays, but only 4-9% as potent as T, DHT, and 19-NT via AR, 1% as potent as progesterone via PR, and 3% and 1% as potent as E2 acting through ERα or ERβ, respectively. In immature castrate rats, bolandiol was equipotent to T in stimulating growth of the levator ani muscle but less potent than T in stimulating growth of the sex accessory glands. Bolandiol also stimulated uterine weight increases in immature female rats, which were partly blocked by ICI 182,780, but it was not aromatized in vitro by recombinant human aromatase. In contrast to T, stimulation of sex accessory gland weights by bolandiol was not inhibited by concomitant treatment with the dual 5α-reductase inhibitor dutasteride. As bolandiol exhibits tissue selectivity in vivo, it may act via AR, PR, and/or ER, utilize alternative signaling pathway(s) or transcriptional coregulators, and/or be metabolized to a more potent selective steroid.
- Attardi, Barbara J.,Page, Stephanie T.,Hild, Sheri A.,Coss, Christopher C.,Matsumoto, Alvin M.
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- Substrate specificity of the placental microsomal aromatase
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Using an accurate and sensitive assay for the human placental aromatase we apparent found apparant Km values for androstenedione (4-androstene-3, 17-dione) and testosterone to be 14 ± 4.0 nM and 41 ± 12 nM respectively. These values were significantly different (p 0.001). Analyses at substrate concentrations 5-10 fold above and below the Km values did not indicate any anomalous kinetic behavior. Mixed substrate experiments were consistent with a single enzyme metabolizing both steroids; each competitively inhibited the aromatization of the other, and the 'Ki' values were the same as their apparent Km values. Sodium chloride (1.2M) significantly increased the rate of testosterone aromatization by decreasing its Km value and had no significant effect on the aromatization of androstenedione. However, in the presence of this salt testosterone still inhibited the aromatization of androstenedione competitively with a 'Ki' equal to its apparent Km. Our data is therefore consistent with the proposal that human placental microsomes contain a single 'high affinity' site for the aromatization of androstenedione and testosterone.
- Gibb,Lavoie
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- Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer
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Aldo-keto reductase (AKR) 1C3 (type 5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase), may stimulate proliferation via steroid hormone and prostaglandin (PG) metabolism in the breast. Purified recombinant AKR1C3 reduces PGD2 to 9α,11β-PGF2, Δ4-androstenedione to testosterone, progesterone to 20α-hydroxyprogesterone, and to a lesser extent, estrone to 17β-estradiol. We established MCF-7 cells that stably express AKR1C3 (MCF-7-AKR1C3 cells) to model its over-expression in breast cancer. AKR1C3 expression increased steroid conversion by MCF-7 cells, leading to a pro-estrogenic state. Unexpectedly, estrone was reduced fastest by MCF-7-AKR1C3 cells when compared to other substrates at 0.1 μM. MCF-7-AKR1C3 cells proliferated three times faster than parental cells in response to estrone and 17β-estradiol. AKR1C3 therefore represents a potential target for attenuating estrogen receptor α induced proliferation. MCF-7-AKR1C3 cells also reduced PGD2, limiting its dehydration to form PGJ2 products. The AKR1C3 product was confirmed as 9α,11β-PGF2 and quantified with a stereospecific stable isotope dilution liquid chromatography-mass spectrometry method. This method will allow the examination of the role of AKR1C3 in endogenous prostaglandin formation in response to inflammatory stimuli. Expression of AKR1C3 reduced the anti-proliferative effects of PGD2 on MCF-7 cells, suggesting that AKR1C3 limits peroxisome proliferator activated receptor γ (PPARγ) signaling by reducing formation of 15-deoxy-Δ12,14-PGJ2 (15dPGJ2).
- Byrns, Michael C.,Duan, Ling,Lee, Seon Hwa,Blair, Ian A.,Penning, Trevor M.
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- INHIBITION OF ESTROGEN SYNTHESIS IN HUMAN BREAST TUMORS BY TESTOLOLACTONE AND BROMOANDROSTENEDIONE
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The inhibition of aromatase enzyme in human breast tumors by Δ1-testololactone, testololactone, 6α-bromoandrostenedione, and 6β-bromoandrostenedione was investigated.Estrone and estradiol synthesis from androstenedione was reduced in 3 tumor incubations by the presence of 0.13 mmol Δ1-testololactone and testololactone. 6α- and 6β-bromoandrostenedione (2.0 μM) were also shown to block estrogen synthesis in 2 tumors.Furthermore, Lineweaver-Burk plots revealed that all 4 compounds are competitive inhibitors of androstenedione aromatization.An apparent Km of the aromatase enzyme for androstenedione of 0.08 μM and a Vmax of 23 pmol of estrone synthesized/g tumor/hr were determined for one human breast tumor specimen.These results demonstrate that these aromatase inhibitors may be useful for the treatment of breast cancer.
- Budnick, Rose Marie,Dao, Thomas L.
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- Complexation of steroid hormones with cyclodextrin derivatives: Substituent effects of the guest molecule on solubility and stability in aqueous solution
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The inclusion complexation of homologous derivatives of steroid hormones with cyclodextrins and 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) was investigated with regard to underlying structure-interaction relationship. The interaction was studied by phase solubility analysis and stabilization effects of complex formation with 2-HP-β-CD. The solubilizing and stabilizing abilities of 2-HP-β-CD were generally more effective for testosterone derivatives than for estradiol esters. Within a homologous series of steroid hormones, the steepest linear solubility isotherms were found for 17-methyl and 3-methyl derivatives. The solubilization of steroid esters by 2-HP-β-CD depended on the structure and length of the ester side chain. The interaction of 2-HP-β-CD with the steroids was hindered by long- chain fatty acid ester groups. With increasing length of the side chain, a decline of the isotherms occurred and the phase solubility behavior changed from linear to exponential. Contrary to expectations, benzoylation of steroids considerably decreased the guest-host interaction. The observed rates of degradation of the steroid esters were significantly reduced by 2- HP-β-CD, depending on the chain length, and correlated well with the order found in phase solubility analysis. The degradation showed no deviations from pseudo-first-order kinetics, and the degradation mechanism was not changed because of complexation. The results suggest that interaction of 2-HP-β-CD with steroid esters involves the ester functions of the prodrugs and is more suitable for unsubstituted guest molecules.
- Albers,Muller
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- Thermodynamic Meerwein-Ponndorf-Verley reduction in the diastereoselective synthesis of 17α-estradiol
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The synthesis of 17α-hydroxy steroids generally requires multiple synthetic manipulations. The synthesis of 17α-estradiol is no exception, as this process involves the protection and release of the 3-hydroxy functional group. The diastereoselective reduction of the 17-keto-steroid can be utilized to prepare 17α-hydroxy-steroids. Here, 17α-estradiol was synthesized from commercially available estrone under thermodynamic Meerwein-Ponndorf-Verley (MPV) conditions in a single step, followed by simple chromatographic separation over silica gel. The remaining mixture of unreacted estrone and estradiols was easily recycled through Oppenauer oxidation to estrone, with an overall yield of 68% 17α-estradiol.
- Ahmed, Gulzar,Nickisch, Klaus
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- 177. The Enantioselective Synthesis of (+)-Estradiol from 1,3-Dihydrobenzothiophene-2,2-dioxide by Successive Thermal SO2-Extrusion and Cycloaddition Reactions
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The optically pure steroid (+)-15 has been synthesized from the easily accessible (+)-carboxylic acid 11 by a sequence of 7 steps in 50percent overall yield.The key steps are the regioselective deprotonation/alkylation 7+13->14 and the thermal SO2-extrusion/cycloaddition 14->15 (Scheme 3).The compound (+)-15 has been readily converted to the naturally occurring (+)-estradiol (17) in 60percent yield.
- Oppolzer, Wolfgang,Roberts, David Anthony
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- Estramustine binding in rat, baboon and human prostate measured by high pressure liquid chromatography
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High pressure liquid chromatography (HPLC) was used to determine 3H-estramustine (estradiol-17β3N-bis-[2-chlorethyl] carbamate), 3H-17β-hydroxy-5α-androstan-3-one (3H-dihydrotestosterone or 3H-DHT), 3H-estradiol-17β (3H-E2) and 3H-3β-hydroxy-5-pregnen-20-one (3H-pregnenolone) binding in 50μl of cytosol utilizing a column which separates proteins in the molecular weight range of 2,000 to 70,000 daltons. The rat prostate contains a protein in considerable concentration and with the highest affinity for estramustine (375,000dpm 3H-estramustine per mg. cytosol protein) among the substances tested. Operationally, we have named this protein 'estramustine binding protein' (EBP), though it is very likely similar to other previously described prostatic proteins (e.g., α-protein, prostatein, prostatic binding protein). The sensitivity of the HPLC method disclosed EBP-like proteins, but in much lesser concentrations, in some of the other tissues tested. The concentration of these proteins in the human and baboon prostates was much lower (average for the baboon cranial lobe 4800dpm/mg cytosol protein, with a somewhat higher value for the caudal lobe) than that in the rat gland. The amount of the EBP-like protein was higher in prostatic cancer than in that of benign prostatic hypertrophy (BPH) (range 9350 - 25,900 vs. 2200 - 18,900 dpm/mg cytosol protein). In the human, the highest value was found in one normal prostate tested (106,000 dpm/mg) cytosol protein).
- Kirdani,Corrales,Hoisaeter,Karr,Murphy,Sandberg
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- Purification and characterization of aromatase from human placenta
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Aromatase from human placenta has been purified to homogeneity (MW 55000).Enzymatic activity can be reconstituted with reductase from pig liver in an aqueous buffer or after incorporation of the enzyme into liposomes.In both cases the enzyme converts androstenedione to estrone and testosterone to estradiol.Aromatase shows a typical CO-spectrum when reduced with dithionite and a type I spectral shift with both substrates.The NH2 terminal amino acid sequence is hydrophobic but shows no homology to that of other cytochromes P-450.Five cysteine peptides have been isolated by HPLC following tryptic digestion of the -carboxymethylated protein.Amino acid sequence of these peptides reveal that histidine is the carboxy-terminal amino acid of the protein and that significant homology exists with corresponding peptides from other cytochromes P-450.Unique oligonucleotides (62 and 30 MER) synthesized on the basis of a 45 amino acid sequence near the center of the molecular have been used to clone the aromatase gene from a cDNA expresssion library from human placenta in λgt11.
- Hall, Peter F.,Chen, Shiuan,Nakajin, Shizuo,Shinoda, Masato,Shively, John E.
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- An environmentally friendly and cost effective synthesis of estradiol featuring two novel reagents: Si(0)/KF and PMHS/hexamethyldisiloxane/pTSA
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Si(0)/KF is introduced as a strong, inexpensive, environmentally friendly, and safe reagent for 'dissolving metal'-type reduction. PMHS/hexamethyldisiloxane/pTSA is introduced as an inexpensive substitute for Et3SiH/TFA for 'ionic hydrogenation', where the hexamethyldisiloxane functions as a capping agent to block the oligomeric silicone by-product from cross-linking to a gel, rubber, or plastic. An environmentally friendly and cost effective synthesis of estradiol is described which showcases these new reagents.
- Lim, Chongsoo,Evenson, Gerald N.,Perrault, William R.,Pearlman, Bruce A.
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- A COMPARISON OF THREE METHODS OF HYDROLYSIS FOR ESTROGEN CONJUGATES
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The efficiencies for estrogen conjugate hydrolysis were compared between enzyme hydrolysis, acid solvolysis and a new method, ammonolysis.Samples included: 1) crystalline 1,3,5(10)-estratriene-3,17β-diol disulfate (estradiol 3,17-disulfate), 2) squirrel monkey urine collected following an intravenous injection of 1,3,5(10)-estratriene-3,17β-diol (estradiol) and 3) a pool of human pregnancy urine.Ammonolysis demonstrated a significant increase over the other techniques in "free" estrogen yields, specifically, from estradiol 3,17-disulfate.
- Bain, J. D.,Kasman, L. H.,Bercovitz, A. B.,Lasley, B. L.
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- Catalytic properties of pristine and defect-engineered Zr-MOF-808 metal organic frameworks
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Various defect-engineered Zr-trimesate MOF-808 compounds (DE-MOF-808) have been prepared by mixing the tricarboxylate ligands with dicarboxylate ligands; viz. isophthalate, pyridine-3,5-dicarboxylate, 5-hydroxy-isophthalate, or 5-amino-isophthalate. The resulting mixed-ligand compounds, MOF-808-X (X = IP, Pydc, OH or NH2) were all found to be highly crystalline and isostructural to the unmodified MOF-808. Pristine MOF-808 showed better catalytic performance than a UiO-66 reference compound for the Meerwein-Ponndorf-Verley (MPV) reduction of carbonyl compounds. This was attributed to a higher availability of coordinatively unsaturated Zr4+ sites (cus) in MOF-808 upon removal of formate ions. Meanwhile, cus in UiO-66 are only located at defect sites and are thus much less abundant. Further improvement of the catalytic activity of defect-engineered MOF-808-IP and MOF-808-Pydc was observed, which may be related with the occurrence of less crowded Zr4+ sites in DE-MOF-808. The wider pore structure of MOF-808 with respect to UiO-66 compounds translates into a sharp improvement of the activity for the MPV reduction of bulky substrates, as shown for estrone reduction to estradiol. Interestingly, MOF-808 produces a notable diastereoselectivity towards the elusive 17-α-hydroxy estradiol.
- Mautschke,Drache,Senkovska,Kaskel,Llabrés Xamena
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- 6α-Fluorotestosterone: a nonaromatizable androgen inhibitor of aromatase cytochrome P450
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In an early survey of steroids which might serve as estrogen precursors, Gual et al. reported that 6α-fluorotestosterone is not aromatized by human placental microsomes.Subsequently, 6α-fluorotestosterone has been used to distinguish between androgen- and estrogen-mediated physiologic effects.We have reexamined the interaction of 6α-fluorotestosterone with human placental and rat ovarian microsomes and with reconstituted purified aromatase cytochrome P450.Under conditions in which testosterone was readily aromatized, no aromatization of 6α-fluorotestosterone was observed using either fluorescence detection of dansyl-estrogens separated by high-performance liquid chromatography or estrogen radioimmunoassay methods.The lack of aromatization is not due to failure of 6α-fluorotestosterone to bind P450arom, because 6α-fluorotestosterone acts as a competitive inhibitor of the enzyme, and it exhibits a binding affinity similar to that of testosterone.Moreover, the addition of 6α-fluorotestosterone to human placental microsomes elicits a spectral shift indicative of conversion of the heme from a low to a high spin state as observed for androgen substrates, cosistent with its binding to the substrate site.The mechanism by which substitution of a fluorine at the 6α-position interferes with the aromatization reaction remains to be determined, but the inhibitory action on estrogen formation may potentiate the androgenic properties of 6α-fluorotestosterone in vivo due to a lowering of estrogen levels.
- Kellis, James T.,Vickery, Larry E.
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- Potent aromatase inhibitors through fungal transformation of anti-cancer drug testolactone: An approach towards treatment of breast cancer
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Biotransformation of an aromatase inhibitor, testolactone (1), yielded five new metabolites, 7α-hydroxy-3-oxo-13,17-secoandrosta-1,4-dieno-17,13α-lactone (2), 7β-hydroxy-3-oxo-13,17-seco-5β-androsta-1-eno-17,13α-lactone (3), 3α,11β-dihydroxy-13,17-seco-5β-androsta-17,13α-lactone (4), 4β,5β-epoxy-3β-hydroxy-13,17-secoandrosta-1-eno-17,13α-lactone (5), and 4β,5β-epoxy-3α-hydroxy-13,17-secoandrosta-1-eno-17,13α-lactone (6). Aromatase (estrogen synthase) involves in the synthesis of estrogen, and promotes the growth of breast cancerous cells. It is a key target for the discovery of chemotherapeutic agents against ER+ (estrogen-positive) breast-cancers and several other diseases caused by overexpression of aromatase enzyme. Metabolites 3 (IC50=8.60±0.402 nM), and 4 (IC50=9.23±1.31 nM) were identified as potent inhibitors against human aromatase enzyme, in comparison to 1 (IC50=0.716±0.031 μM), and the standard aromatase inhibiting drug, exemestane (IC50=0.232±0.031 μM). Derivatives 2 (IC50=11.68±0.73 μM), 5 (IC50=10.37±0.50 μM) and 6 (IC50=0.82±0.059 μM) have also a good inhibition against aromatase enzyme. Therefore, metabolites 2-6 have the potential to serve as therapeutic agents against diseases caused by aromatase enzyme, including breast cancer.
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Paragraph 0021
(2021/07/30)
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- One-Step Chemo-, Regio- and Stereoselective Reduction of Ketosteroids to Hydroxysteroids over Zr-Containing MOF-808 Metal-Organic Frameworks
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Zr-containing MOF-808 is a very promising heterogeneous catalyst for the selective reduction of ketosteroids to the corresponding hydroxysteroids through a Meerwein-Ponndorf-Verley (MPV) reaction. Interestingly, the process leads to the diastereoselective synthesis of elusive 17α-hydroxy derivatives in one step, whereas most chemical and biological transformations produce the 17β-OH compounds, or they require several additional steps to convert 17β-OH into 17α-OH by inverting the configuration of the 17 center. Moreover, MOF-808 is found to be stable and reusable; it is also chemoselective (only keto groups are reduced, even in the presence of other reducible groups such as C=C bonds) and regioselective (in 3,17-diketosteroids only the keto group in position 17 is reduced, while the 3-keto group remains almost intact). The kinetic rate constant and thermodynamic parameters of estrone reduction to estradiol have been obtained by a detailed temperature-dependent kinetic analysis. The results evidence a major contribution of the entropic term, thus suggesting that the diastereoselectivity of the process is controlled by the confinement of the reaction inside the MOF cavities, where the Zr4+ active sites are located.
- Llabrés i Xamena, F. X.,Mautschke, H.-H.
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p. 10766 - 10775
(2021/06/15)
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- Promiscuity of an unrelated anthrol reductase ofTalaromyces islandicusWF-38-12
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An anthrol reductase ofTalaromyces islandicusWF-38-12 (ARti-2) from an unrelated biosynthetic gene cluster (BGC) has been identified and characterized. It catalyses the NADPH-dependent reduction of anthrols (hydroanthraquinones), estrone and a naphthol with high stereo- and regioselectivity. The role of ARti-2, theCRG89872.1gene of the same BGC and non-enzymatic oxidation in the biosynthesis of (?)-flavoskyrin has been proposed.
- Singh, Shailesh Kumar,Rajput, Anshul,De, Arijit,Chakraborti, Tapati,Husain, Syed Masood
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p. 474 - 478
(2021/02/09)
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- Solvent- and Wavelength-Dependent Photolysis of Estrone
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The direct photolysis of estrone in solvents ranging from water to cyclohexane is reported. The photodegradation is dominated by lumiestrone, an epimer of estrone resulting from the inversion of the methyl group at carbon 13, regardless of solvent and pho
- Adriano, Natalie,Ahearn, Ceilidh,Black, Cory,Cracchiolo, Michael,Ghere, Daniel,Hare, Patrick M.,Nu?ez, Alexandra,Olivan, Lars,Patel, Raj,Saner, Stephanie,Smith, Krista R.,Watkins, Barbie
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- Chiral Imidazo[1,5- a]pyridine-Oxazolines: A Versatile Family of NHC Ligands for the Highly Enantioselective Hydrosilylation of Ketones
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Herein we report the synthesis and application of a versatile class of N-heterocyclic carbene ligands based on an imidazo[1,5-a]pyridine-3-ylidine backbone that is fused to a chiral oxazoline auxiliary. The key step in the synthesis of these ligands involves the installation of the oxazoline functionality via a microwave-assisted condensation of a cyano-azolium salt with a wide variety of 2-amino alcohols. The resulting chiral bidentate NHC-oxazoline ligands form stable complexes with rhodium(I) that are efficient catalysts for the enantioselective hydrosilylation of structurally diverse ketones. The corresponding secondary alcohols are isolated in good yields (typically >90%) with good to excellent enantioselectivities (80-93% ee). The reported hydrosilylation occurs at ambient temperatures (40 °C), with excellent functional group tolerability. Even ketones bearing heterocyclic substituents (e.g., pyridine or thiophene) or complex organic architectures are hydrosilylated efficiently, which is discussed further in this report.
- Chinna Ayya Swamy,Varenikov, Andrii,Ruiter, Graham De
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supporting information
p. 247 - 257
(2020/02/04)
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- Identification and characterization of an anthrol reductase from: Talaromyces islandicus (Penicillium islandicum) WF-38-12
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An NADPH-dependent oxidoreductase from Talaromyces islandicus WF-38-12 has been identified through genome analysis. It has been shown to catalyze a regio- and stereoselective reduction of anthrols (formed in situ by the reduction of anthraquinones in the presence of Na2S2O4) to (R)-dihydroanthracenones, with high enantiomeric excess (>99%). The implications of results on the biosynthesis of deoxygenated (bis)anthraquinones and modified (bis)anthraquinones are discussed.
- Singh, Shailesh Kumar,Mondal, Amit,Saha, Nirmal,Husain, Syed Masood
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supporting information
p. 6594 - 6599
(2019/12/26)
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- Identification and Directed Development of Non-Organic Catalysts with Apparent Pan-Enzymatic Mimicry into Nanozymes for Efficient Prodrug Conversion
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Nanozymes, nanoparticles that mimic the natural activity of enzymes, are intriguing academically and are important in the context of the Origin of Life. However, current nanozymes offer mimicry of a narrow range of mammalian enzymes, near-exclusively performing redox reactions. We present an unexpected discovery of non-proteinaceous enzymes based on metals, metal oxides, 1D/2D-materials, and non-metallic nanomaterials. The specific novelty of these findings lies in the identification of nanozymes with apparent mimicry of diverse mammalian enzymes, including unique pan-glycosidases. Further novelty lies in the identification of the substrate scope for the lead candidates, specifically in the context of bioconversion of glucuronides, that is, human metabolites and privileged prodrugs in the field of enzyme-prodrug therapies. Lastly, nanozymes are employed for conversion of glucuronide prodrugs into marketed anti-inflammatory and antibacterial agents, as well as “nanozyme prodrug therapy” to mediate antibacterial measures.
- Walther, Raoul,Winther, Anna K.,Fruergaard, Anne Sofie,van den Akker, Wouter,S?rensen, Lise,Nielsen, Signe Maria,Jarlstad Olesen, Morten T.,Dai, Yitao,Jeppesen, Henrik S.,Lamagni, Paolo,Savateev, Aleksandr,Pedersen, S?ren Lykke,Frich, Camilla Kaas,Vigier-Carrière, Cécile,Lock, Nina,Singh, Mandeep,Bansal, Vipul,Meyer, Rikke L.,Zelikin, Alexander N.
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supporting information
p. 278 - 282
(2018/12/05)
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- Efficient dealkylation of aryl alkyl ethers catalyzed by Cu2O
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An efficient protocol for dealkylation of aryl alkyl ethers under the catalysis of inexpensive and easily reusable Cu2O has been described. The phenol products were obtained in high yields, and a range of functional groups were well tolerated. The choice of solvent is critical to the catalysis, and CH3OH proved to be the optimal choice. Mechanistic investigations showed that this reaction possibly proceeds via a single-electron transfer (SET) process.
- Liu, Lingxian,Li, Zengguang,Chen, Changjun,Li, Huanrong,Xu, Lijin,Yu, Zhiyong
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supporting information
p. 2447 - 2453
(2018/04/11)
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- Triclocarban and Triclosan Inhibit Human Aromatase via Different Mechanisms
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Human aromatase (CYP19A1) is an important enzyme, which produces estrogen from androgen for maintaining the female reproductive function and pregnancy. Triclocarban and triclosan are antimicrobial chemicals added to personal care, household, and industrial products. They could be endocrine disruptors and may disrupt human CYP19A1 activity. In the present study, we investigated the effects of triclocarban and triclosan on estradiol production and human CYP19A1 activity in JEG-3 cells. Triclocarban and triclosan reduced estradiol production in JEG-3 cells. Triclocarban and triclosan inhibited human CYP19A1 with IC50 values of 15.81 and 6.26 μM, respectively. Triclosan competitively inhibited CYP19A1, while triclocarban noncompetitively inhibited this enzyme. Docking study showed that triclosan bound to the steroid-binding pocket of CYP19A1, while triclocarban was off this target, suggesting a different mechanism. In conclusion, triclocarban and triclosan are inhibitors of human CYP19A1.
- Li, Huitao,Zhao, Yu,Chen, Lanlan,Su, Ying,Li, Xiaoheng,Jin, Lixu,Ge, Ren-Shan
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- Regio- and stereoselective reduction of 17-oxosteroids to 17β-hydroxysteroids by a yeast strain Zygowilliopsis sp. WY7905
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The reduction of 17-oxosteroids to 17β-hydroxysteroids is one of the important transformations for the preparation of many steroidal drugs and intermediates. The strain Zygowilliopsis sp. WY7905 was found to catalyze the reduction of C-17 carbonyl group of androst-4-ene-3,17-dione (AD) to give testosterone (TS) as the sole product by the constitutive 17β-hydroxysteroid dehydrogenase (17β-HSD). The optimal conditions for the reduction were pH 8.0 and 30 °C with supplementing 10 g/l glucose and 1% Tween 80 (w/v). Under the optimized transformation conditions, 0.75 g/l AD was reduced to a single product TS with >90% yield and >99% diastereomeric excess (de) within 24 h. This strain also reduced other 17-oxosteroids such as estrone, 3β-hydroxyandrost-5-en-17-one and norandrostenedione, to give the corresponding 17β-hydroxysteroids, while the C-3 and C-20 carbonyl groups were intact. The absence of by-products in this microbial 17β-reduction would facilitate the product purification. As such, the strain might serve as a useful biocatalyst for this important transformation.
- Liu, Yuanyuan,Wang, Yu,Chen, Xi,Wu, Qiaqing,Wang, Min,Zhu, Dunming,Ma, Yanhe
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- Aldo-keto Reductase 1B15 (AKR1B15): A mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates
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Alto-keto reductases (AKRs) comprise a superfamily of proteins involved in the reduction and oxidation of biogenic and xenobiotic carbonyls. In humans, at least 15 AKR superfamily members have been identified so far. One of these is a newly identified gene locus, AKR1B15, which clusters on chromosome 7 with the other human AKR1B subfamily members (i.e. AKR1B1 and AKR1B10). We show that alternative splicing of the AKR1B15 gene transcript gives rise to two protein isoforms with different N termini: AKR1B15.1 is a 316-amino acid protein with 91% amino acid identity to AKR1B10; AKR1B15.2 has a prolonged N terminus and consists of 344 amino acid residues. The two gene products differ in their expression level, subcellular localization, and activity. In contrast with other AKR enzymes, which are mostly cytosolic, AKR1B15.1 co-localizes with the mitochondria. Kinetic studies show that AKR1B15.1 is predominantly a reductive enzyme that catalyzes the reduction of androgens and estrogens with high positional selectivity (17β-hydroxysteroid dehydrogenase activity) as well as 3-ketoacyl-CoA conjugates and exhibits strong cofactor selectivity toward NADP(H). In accordance with its substrate spectrum, the enzyme is expressed at the highest levels in steroid-sensitive tissues, namely placenta, testis, and adipose tissue. Placental and adipose expression could be reproduced in the BeWo and SGBS cell lines, respectively. In contrast, AKR1B15.2 localizes to the cytosol and displays no enzymatic activity with the substrates tested. Collectively, these results demonstrate the existence of a novel catalytically active AKR, which is associated with mitochondria and expressed mainly in steroid-sensitive tissues.
- Weber, Susanne,Salabei, Joshua K.,M?ller, Gabriele,Kremmer, Elisabeth,Bhatnagar, Aruni,Adamski, Jerzy,Barski, Oleg A.
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p. 6531 - 6545
(2015/03/30)
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- Photoactivatable, biologically-relevant phenols with sensitivity toward 2-photon excitation
-
Spatio-temporal release of biologically relevant small molecules provides exquisite control over the activation of receptors and signaling pathways. This can be accomplished via a photochemical reaction that releases the desired small molecule in response to irradiation with light. A series of biologically-relevant signaling molecules (serotonin, octopamine, capsaicin, N-vanillyl-nonanoylamide, estradiol, and tyrosine) that contain a phenol moiety were conjugated to the 8-bromo-7-hydroxyquinolinyl (BHQ) or 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting groups (PPGs). The CyHQ caged compounds proved sensitive toward 1PE and 2PE processes with quantum efficiencies of 0.2-0.4 upon irradiation at 365 nm and two-photon action cross sections of 0.15-0.31 GM when irradiated at 740 nm. All but one BHQ caged compound, BHQ-estradiol, were found to be sensitive to photolysis through 1PE and 2PE with quantum efficiencies of 0.30-0.40 and two photon cross sections of 0.40-0.60 GM. Instead of releasing estradiol, BHQ-estradiol underwent debromination.
- McLain, Duncan E.,Rea, Adam. C.,Widegren, Magnus B.,Dore, Timothy M.
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p. 2151 - 2158
(2015/12/04)
-
- Proton-exchanged montmorillonite-mediated reactions of methoxybenzyl esters and ethers
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Proton-exchanged montmorillonite (H-mont) was found to be an eco-friendly and cost-effective catalyst for the generation of O-methylated quinone methides (QM) from the corresponding p or o-methoxybenzyl esters and ethers. Nucleophilic trapping of the O-methylated QM with arenes, alcohols, 1,3-dicarbonyl compounds, silyl enol ethers, and allylsilanes has been carried out, respectively, leading to eco-friendly benzylation reactions. Using this protocol, H-mont-mediated deprotection of PMB-protected esters and ethers have been realized for the first time. This work would pave the way for further exploration in O-alkylated QM that are of chemical and biological significance.
- Chen, Dongyin,Xu, Chang,Deng, Jie,Jiang, Chunhuan,Wen, Xiaoan,Kong, Lingyi,Zhang, Ji,Sun, Hongbin
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p. 1975 - 1983
(2014/03/21)
-
- Substrate specificity and inhibitor sensitivity of rabbit 20α-hydroxysteroid dehydrogenase
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In this study, we examined the substrate specificity and inhibitor sensitivity of rabbit 20α-hydroxysteroid dehydrogenase (AKR1C5), which plays a role in the termination of pregnancy by progesterone inactivation. AKR1C5 moderately reduced the 3-keto group of only 5α-dihydrosteroids with 17β- or 20α/β-hydroxy group among 3-ketosteroids. In contrast, the enzyme reversibly and efficiently catalyzed the reduction of various 17- and 20-ketosteroids, including estrogen precursors (dehydroepiandrosterone, estrone and 5α-androstan-3β- ol-17-one) and tocolytic 5β-pregnane-3,20- dione. In addition to the progesterone inactivation, the formation of estrogens and metabolism of the tocolytic steroid by AKR1C5 may be related to its role in rabbit parturition. AKR1C5 also reduced various non-steroidal carbonyl compounds, including isatin, an antagonist of the C-type natriuretic peptide receptor, and 4-oxo-2-nonenal, suggesting its roles in controlling the bioactive isatin and detoxification of cytotoxic aldehydes. AKR1C5 was potently and competitively inhibited by flavonoids such as kaempferol and quercetin, suggesting that its activity is affected by ingested flavonoids.
- Endo, Satoshi,Arai, Yuki,Hara, Akira,Kitade, Yukio,Bunai, Yasuo,El-Kabbani, Ossama,Matsunaga, Toshiyuki
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p. 1514 - 1518
(2013/10/08)
-
- A practical solution for aqueous reactions of water-insoluble high-melting-point organic substrates
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A practical solution to the problem of performing aqueous reactions for very sparingly soluble high-melting-point (VSSHMP) organic substrates has been developed, which entails mechanically stirring a mixture of the substrate, the corresponding reagent(s), water, catalytic Aliquat 336 and sand. When the melting points of the substrates which include steroids, ketones, aldehydes, aromatics and alkaloids are around 200 °C, the reactions can be performed at 20 °C. The substrate solubility can be as low as 1 × 10-10 mol L-1. The Royal Society of Chemistry 2012.
- Cui, Xiaoxue,Li, Bo,Liu, Tianzhen,Li, Chunbao
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supporting information; experimental part
p. 668 - 672
(2012/06/01)
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- PROCESS FOR THE PREPARATION OF ESTRADIOL AND ITS DERIVATIVES
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The present invention provides a process for the preparation of a compound of formula I wherein R1 represents a hydrogen atom, halogen atom, cyano group, hydroxyl group, straight or branched C1-C10 alkyl group, straight or branched C2-C10 alkenyl group or C6- C10 aryl group; or a -OR2, -O(CO)R2, or -R2-OH group, wherein R2 is a straight or branched Ci-C6 alkyl group or a straight or branched C2-C6 alkenyl group, which process comprises treating a compound of formula II wherein R1 is as defined above, with a compound of formula III M(BH4) III wherein M is a monovalent metal ion, in a solvent at a temperature of from -10 to 10°C.
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Page/Page column 12-13
(2012/03/09)
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- Synthesis of 2-substituted 17β-hydroxy/17-methylene estratrienes and their in vitro cytotoxicity in human cancer cell cultures
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Synthesis of various types of 2-(alkylaminomethyl) and 2-(aroyl) 17β-estradiol analogs are reported. The synthesis of similar types of 2-substituted 17-methylene estratriene analogs was also achieved. Synthesis of chalcone derivatives of 17β-estradiol and 17-methylene estratriene were also realized. All these 2-substituted estratrienes were tested for their antiproliferative activity by using four different cell lines from colon, lung, glioma and breast cancers. Among the various 2-substituted estratrienes, the compounds 10d, 14a-h and 17e were found to have in vitro antiproliferative activity comparable to that of parent analogs 1-4. Comparison of the SAR pattern of these 2-susbtituted estratriene derivatives confirmed that relatively, 17-methylene estratrienes are more active than that of 17β-estradiol analogs.
- Panchapakesan, Ganapathy,Dhayalan, Vasudevan,Dhatchana Moorthy, Nachiappan,Saranya, Nidhyanandan,Mohanakrishnan, Arasambattu K.
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scheme or table
p. 1491 - 1504
(2011/11/06)
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- Chemical synthesis, characterisation and biological evaluation of furanic-estradiol derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1
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Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a series of epoxide and furanic E2 derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1. An intermediate epoxide was first obtained and then reduced to give a furanic steroid, which allowed us to introduce a molecular diversity like alcohol, bromide, ester, acid and amide. The inhibition of the transformation of [14C]-E1 (100 nM) into [14C]-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17β-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 μM. All furanic compounds showed a lower 17β-HSD1 inhibitory potency in intact T-47D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide, which gave 62% and 90% of inhibition of the [ 14C]-E1 (60 nM) into [14C]-E2 transformation at 1 and 10 μM, respectively.
- Farhane, Siham,Laplante, Yannick,Poirier, Donald
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-
- Simultaneously rapid deprotection of 3-acyloxy groups and reduction of D-ring ketones (nitrile) of steroids using DIBAL-H/NiCl2
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An efficient preparation of hydroxysteroids by a one-pot, simultaneously rapid deprotection of 3-acyloxy groups and reduction of D-ring ketones (nitrile) of steroids using DIBAL-H in the presence of NiCl2 (10 mol %) is described. The attractive features of this procedure for the preparation of the hydroxysteroid derivatives are the mild reaction conditions, short reaction time, excellent yields, clean reaction profiles, and an inexpensive catalyst system.
- Wang, Xingbin,Liu, Hui,Yan, Peiyun,Liu, Jinliang,Li, Yan,Sun, Qian,Wang, Cunde
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experimental part
p. 291 - 293
(2011/10/05)
-
- Improved arene fluorination methodology for I(III) salts
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(Equation Presented). The use of low polarity aromatic solvents (benzene or toluene) and/or the removal of inorganic salts results in dramatically improved yields of fluorinated arenes from diaryliodonium salts. This methodology is shown to "scale down" to the conditions used typically for radiotracer synthesis.
- Wang, Bijia,Qin, Linlin,Neumann, Kiel D.,Uppaluri, Shriharsha,Cerny, Ronald L.,DiMagno, Stephen G.
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supporting information; experimental part
p. 3352 - 3355
(2010/11/02)
-
- Improved and scalable synthetic route to the synthon 17-β-(2- Carboxyethyl)-1,3,5(10)-estratriene: An important intermediate in the synthesis of bone-targeting estrogens
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An improved, highly scalable methodology for the multigram-scale preparation of an important synthon, 17-β-(2-carboxyethyl)-1,3,5(10)- estratriene, is described. Previous approaches have failed to provide useful quantities of the analytically pure product because of facile retro-Michael breakdown of the-alkoxy carbonyl precursors during workup and isolation operations. The synthetic approach described herein has been designed specifically to sidestep this problematic breakdown process. This new scalable method of preparation overcomes a major hurdle in the exploration of structure-activity relationships centered around novel estradiol derivatives with bone-targeting properties and also provides a scalable process for subsequent developmental work.
- Nasim, Shama,Vartak, Ashish P.,Pierce, William M.,Grant Taylor,Crooks, Peter A.
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p. 772 - 781
(2011/03/20)
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- HEAT-LABILE PRODRUGS
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Disclosed herein are heat-labile prodrugs, their preparation and uses.
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Page/Page column 21
(2008/12/08)
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- Facile cleavage of ethers in ionic liquid
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Various alkyl ethers were efficiently cleaved by treating them with pyridinium halides in ionic liquid, and the desired products were obtained in excellent yields.
- Cheng, Lili,Aw, Carlin,Ong, Siew Siang,Lu, Yixin
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supporting information; experimental part
p. 2008 - 2010
(2009/08/14)
-
- First synthesis of a steroid containing an unstable 19-nor-androsta-1,5-dien-3-one system
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Mechanisms involved in the maintenance of human pregnancy and initiation of labour are poorly defined. A novel steroid hormone named estradienolone (ED), and having an unusual 19-nor-androsta-1,5-dien-3-one system, was previously reported. However, ED is scarcely available from urine, placenta and blood of pregnant women. For this reason, we have synthesized ED in order to verify its proposed structure. Although a 1,5-dien-3-one system had already been described for a C19-steroid (androstane) nucleus (no possible aromatization), the synthesis of the 19-nor-analogue is a major challenge because this system is very sensitive to aromatization. We now describe the successful construction and characterization of this unstable system. Starting from nortestosterone, the synthesis of 17β-hydroxy-19-nor-androsta-1,5-dien-3-one (1) is based on a protection of the 5,6-double bond, the introduction of the second 1,2-double bond, the careful recovery of the exo double bond and a final regioselective oxidation or reduction.
- Cadot, Christine,Poirier, Donald,Philip, Anie
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p. 4384 - 4392
(2007/10/03)
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- A simple, convenient and chemoselective formylation of sterols by Vilsmeier reagent
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Vilsmeier reagent (DMF-POCl3) was used as an efficient formylating agent. Several sterols having sec-hydroxyl group at 3/17-position have been modified into respective formate esters. The method is simple, mild, chemoselective and provides sec-alcoholic protection in good yields.
- Srivastava, Vandana,Negi, Arvind Singh,Kumar,Gupta
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p. 632 - 638
(2007/10/03)
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- Pharmaceutical composition with tumor necrosis factor A and 2-methoxyestrone-3-0-sulphamate for inhibition of estrone sulphatase
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A composition is described. The composition comprises i) a compound comprising a sulphamate group (“a sulphamate compound”); and ii) a biological response modifier.
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- Compound
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Disclosed and claimed are compounds suitable for use as an inhibitor of oestrone sulphatase in a subject in need thereof, as well as compositions containing such compounds and methods for using such compounds. Such compounds can be a sulphamate compound that has the Formula (X) and wherein X is a sulphamate group, and Y is CH2 and optionally any other H attached directly to the ring system is substituted by another group
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- Development of Odorless Thiols and Sulfides and Their Applications to Organic Synthesis
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Development of new odorless thiols (dodecanethiol, 4-n- heptylphenylmethanethiol, 4-trimethylsilylphenylmethanethiol, 4-trimethylsilylbenzenethiol) and an odorless sulfide (1-methylsulfanyldodecane) and their applications to dealkylation, Michael addition, Swern oxidation, and Corey-Kim oxidation are described.
- Nishide, Kiyoharu,Ohsugi, Shin-Ichi,Miyamoto, Tetsuo,Kumar, Kamal,Node, Manabu
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p. 189 - 200
(2007/10/03)
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- Hormone composition
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Twice weekly administration of an analog to a Vagifem tablet which only contains 10 μg of active material has a sufficient effect.
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- Halogenated sulphamate-, phosphonate-, thiophosphonate-, sulphonate- and sulphonamide- compounds as inhibitors of steroid sulphatase
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A compound is described. The compound has the formula (Ia) as presented in the FIG. 1; wherein: X is a ring having at least 4 atoms in the ring; K is hydrocarbyl group; Rh1 is an optional halo group; Rh2 is an optional halo group; at least one of Rh1 and Rh2 is present; Rs is any one of a sulphamate group, a phosphonate group, a thiophosphonate group, a sulphonate group or a sulphonamide group. The compound is capable of inhibiting steroid sulphatase (STS) activity.
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- 17-Aryl linker derivatised estrogen 3-sulphamates as inhibitors of steroid sulphatase
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There is provided a compound comprising a steroidal ring system and a group R1 selected from any one of a sulphamate group, a phosphonate group, a thiophosphonate group, a sulphonate group or a sulphonamide group; wherein the D ring of the steroidal ring system is substituted by a group R2 of the formula —L—R3, wherein L is an optional linker group and R3 is an aromatic hydrocarbyl group.
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- Composition
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There is provided a pharmaceutical composition comprising (i) a compound of the formula wherein: X is a hydrocarbyl ring having at least 4 atoms in the ring; K is a hydrocarbyl group; Rs is a sulphamate group; (ii) optionally admixed with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant, wherein the compound is present in an amount to provide a dosage of no greater than 200 μg/day.
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- OXIME-GROUP CONTAINING OESTRONE SULPHATASE INHIBITORS
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A sulphamate compound suitable for use as an inhibitor of oestrone sulphatase (E.C.3.1.6.2) is described. The compound is a polycyclic compound comprising at least two ring components, wherein the polycyclic compound comprises at least one sulphamate group attached to at least one of the ring components, and wherein at least one oxime group is attached to or is part of at least one of the ring components.
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- Use
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There is provided use of a material selected from (i) microtubule stabilizing agent; (ii) microtubule disrupter; (iii) a compound of the formula A-B wherein A is an oxyhydrocarbyl group and B is a cyclic group; and (iv) a compound of the formula C-D wherein C is an sulphamate group and D is a cyclic group, for the manufacture of a medicament for the inhibition of tumor necrosis factor α (TNFα) stimulated aromatase activity.
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- DERMATOLOGICAL COMPOSITIONS AND METHODS
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Disclosed are methods and compositions for regulating the melanin content of mammalian melanocytes; regulating pigmentation in mammalian skin, hair, wool or fur; treating or preventing various skin and proliferative disorders; by administration of various compounds, including alcohols, diols and/or triols and their analogues.
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- PACKAGING BAG FOR PLASTER AND PACKAGED PLASTER
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Packaged patch (10) according to the invention comprises patch (2) situated in space (4) inside patch package (3) composed of laminated packaging material (1), and its edges are sealed. Laminated packaging material (1) comprises hygroscopic material layer (13) made of LDPE containing 20-40 wt% of an inorganic filler, situated between moisture-permeable material layer (14) made of LDPE and having a moisture permeability of 40-120 g/m2/day and a screen material layer which blocks penetration of moisture, etc. and is composed of HDPE layer (12) and aluminum foil (11). The saturation hygroscopicity of laminated packaging material (1) is 2-30 g/m2under atmosphere conditions with a temperature of 25°C and a relative humidity of 75%. This construction sufficiently reduces the effect of moisture on a drug in patch (2) and allows patch (2) to be held in a stable state for prolonged periods, while also improving the economy and handleability of patch package (3).
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- Composition
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There is provided a pharmaceutical composition comprising (i) a compound of the formula wherein: X is a hydrocarbyl ring having at least 4 atoms in the ring; K is a hydrocarbyl group; Rs is a sulphamate group; (ii) optionally admixed with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant, wherein the compound is present in an amount to provide a dosage of no greater than 200 μg/day.
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- Odorless substitutes for foul-smelling thiols: Syntheses and applications
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Several alkanethiols and p-alkylphenylmethanethiols were synthesized, and their odors were compared with those of ethanethiol and benzyl mercaptan by human and instrumental sensors. Among the various thiols analyzed, 1-dodecanethiol (1) and p-heptylphenylmethanethiol (3) were revealed to be odorless. 1-Dodecanethiol (1) has been used instead of ethanethiol for dealkylation of ethers, and p-heptylphenylmethanethiol (3) can replace benzyl mercaptan in the preparation of a 1,3-mercapto alcohol from an α,β-unsaturated ketone. These odorless thiols will greatly improve the physical environment of the researcher working with these foul-smelling compounds.
- Node, Manabu,Kumar, Kamal,Nishide, Kiyoharu,Ohsugi, Shin-Ichi,Miyamoto, Tetsuo
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p. 9207 - 9210
(2007/10/03)
-
- Treatment of neurodegenerative diseases
-
Disclosed are methods for increasing the differentiation of mammalian neuronal cells for purposes of treating neurodegenerative diseases or nerve damage by administration of various compounds including alcohols, diols and/or triols and their analogues.
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-
- Synthesis of 2-alkoxyestradiols
-
Disclosed is a method of preparing a compound represented by the following structural formula: The method comprises reacting bromine (Br2) and an aliphatic organic acid with a compound represented by the following structural formula: R1 and R2 are each independently a hydroxyl protecting group.
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- Pharmaceutical combined preparation, kit and method for hormonal contraception
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PCT No. PCT/DE96/01192 Sec. 371 Date Jun. 3, 1998 Sec. 102(e) Date Jun. 3, 1998 PCT Filed Jun. 27, 1996 PCT Pub. No. WO97/01342 PCT Pub. Date Jan. 16, 1997The present invention describes a two-stage pharmaceutical combined preparation for hormonal contraception containing at least 30 daily unit doses, which preparation, in its first stage, comprises as hormonal active ingredient a combination of an oestrogen preparation and, in a dose that is at least sufficient to inhibit ovulation, a gestagen preparation, in single stage form and, in the second stage comprises as hormonal active ingredient an oestrogen preparation only, wherein the first stage comprises a minimum of 25 and a maximum of 77 daily discrete or continuous unit doses and the second stage comprises 5, 6 or 7 daily discrete or continuous unit doses, and wherein the total number of daily units is equal to the total number of days of the desired cycle of a minimum of 30 and a maximum of 84 days. This combined preparation, in the form of a monthly pack, which is used for female fertility control, permits as low as possible an oestrogen content in each individual unit dose and also has a low total hormone content per cycle of administration, with high contraceptive reliability, low incidence of follicle development, and satisfactory cycle control with reliable avoidance of intermediate bleeding as well as undesired side effects.
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- A new mild PTSA-catalyzed method for sulfate ester hydrolysis and acid-catalyzed rearrangement of 12-acetyl-diene-11-ol tetracyclic triterpenoids involving an angular methyl migration
-
Tetracyclic triterpenoids containing the 12-acetyl-Δ8,14-diene-ll-ol moiety undergo a series of acid-catalyzed rearrangements. The rearrangement products have been characterized, plausible mechanisms for the rearrangement have been elucidated and conditions have been developed to give high yields of the rearrangement products. A new and general PTSA·H2O and PPTS-catalyzed sulfate hydrolysis method has been developed. (C) 2000 Elsevier Science Ltd.
- Singh
-
p. 6973 - 6976
(2007/10/03)
-
- Obtainment of 17β-estradiol or 17β-estradiol-17 α-deuterium through stereoselective reduction of estrone, using NaBH4 and LiBD4 respectively in the presence of a crown ether
-
The present paper investigates the reduction of estrone 1 to estradiol 2, in methylene chloride in the presence of a crown ether (CE), with solid NaBH4 or LiBD4 in a solid/liquid diphase system. CEs involved in the study were 18-crown-6 (18C6), 15-crown-5 (15C5) and 12-crown-4 (12C4). Our results show that in the case of the reduction process using NaBH4, the 18C6 macrocyclic ligand was the most efficient. The process is stereoselective (leading to 17β-estradiol) being also applied in labelling through deuteration, yielding to 17β-estradiol-17α-deuterium (starting from estrone 1, in the presence of LiBD4 and crown ether 12C4).
- Nourescu, Dana,Luca, Constantin,Cǎproiu, Miron T.,Pencu, Gabriela I.,Constantinescu, Titus
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p. 531 - 535
(2007/10/03)
-
- 2-alkoxy estradiols and derivatives thereof
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Compounds represented by the following structural formula: wherein R1, R2 and R3 are as defined in the specification. The compounds are disclosed as useful in the treatment of various forms of cancer.
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