- Regulation of steroidogenesis in the ovine corpus luteum
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To examine the factor affecting LH-induced progesterone production in vitro in ovine luteal slices, an experimental procedure was employed wherein each slice served as its own control. The role of microfilaments in steroidogenesis was studied in luteal slices treated with cytochalasin B (an inhibitor of microfilament function). Cytochalasin B treatment resulted in significant reduction of progesterone production by luteal slices in response to LH and the addition of serum to the medium did not alter this effect. The ability of luteal slices to respond to LH with increased progesterone secretion was restored when cytochalasin B was removed from the medium. Further studies indicated that inhibition of LH-induced progesterone production by treatment with cytochalasin B was not a result of a change in: 1) cyclic adenosine 3'-5'-monophosphate production in response to LH; 2) mitochondrial membrane permeability to cholesterol; or 3) activity of 3β-hydroxysteroid dehydrogenase, Δ5, Δ4-isomerase enzyme complex. The possibility existed that microfilaments were necessary for cholesterol transport to mitochondria in response to LH stimulation. However, mitochondrial cholesterol content was unchanged in response to LH in the presence or absence of aminoglutethimide (an inhibitor of cholesterol side-chain cleavage enzyme activity) as determined by uptake of 3H-cholesterol or total content determined by gas-liquid chormatography. Further, treatment with cytochalasin B had no effect on mitochondrial cholesterol content. These results suggest a role for microfilaments in LH-induced progesterone production at a point prior to the conversion of cholesterol to pregnenolone.
- Silavin,Moss,Niswender
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- Development of a quantitative assay method for 3 beta-hydroxy-delta 5-steroid dehydrogenase in the rat testis.
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We investigated the first step of the sex steroid hormone biosynthesis pathway by assaying the activities of 3 beta-hydroxy-delta 5-steroid dehydrogenase, the rate-limiting enzyme in this pathway. We have developed a simple and rapid colorimetric assay for 3 beta-hydroxy-delta 5-steroid dehydrogenase in rat testis. The supernatant from rat testis tissue homogenates were used for the enzyme assay. The enzyme activity was determined by measuring the absorbance at 570nm which indicates the rate of conversion of pregnenolone into progesterone in the presence of NAD, using phenazine methosulfate and nitro blue tetrazolium as the color reagent. The activity of this enzyme ranged from 4.57+/-1.34 to 10.56+/-2.13 nmol/mg protein/min with a mean activity of 8.96+/-1.27 nmol/mg protein/min. The K(m) of the enzyme at an optimum pH of 7.25 was about 4.7+/-0.12 nM.
- Qujeq, Durdi
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- IDENTIFICATION OF A UNIQUE SERTOLI CELL STEROID AS 3α-HYDROXY-4-PREGNEN-20-ONE (3α-DIHYDROPROGESTERONE: 3α-DHP)
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An allylic steroid produced from progesterone by rat Sertoli cells and which does not appear to have been described previously as a product of gonadal or adrenal tissues has been isolated and identified as 3α-hydroxy-4-pregnen-20-one (3α-dihydroprogesterone; 3α-DHP). 3α-DHP appears to be a reactive molecule which is easily oxidized or dehydrated and its identification was possible by a combination of microchemical procedures, derivative formation, specific enzyme reaction, TLC, GC, HPLC, spectrophotometry and mass spectrometry.The biological functions of this Sertoli cell steroid are not known, but it is suggested that 3α-DHP is more than a metabolic waste product because (a) its production rate varies with age and is highest at the onset of meiosis, and (b) there appear to be specific receptors for it in the testis.
- Wiebe, J. P.
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- Soft drugs: Thiazolidine-type derivatives of progesterone and testosterone
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Progesterone and testosterone are natural soft drugs, but to be used as drugs, their fast and facile metabolism must be prevented and their delivery controlled. A prodrug-soft drug combination can serve this purpose. Thiazolidines of testosterone, testosterone 17-proprionate and progesterone were synthesized from the reaction of cysteine alkyl esters, N-methylaminoethanethiol, and mercaptamine and their hydrochlorides with the appropriate steroids. The thiazolidines function as bioreversible derivatives of the parent steroids.
- Bodor,Sloan
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- 3β-HYDROXYSTEROID DEHYDROGENASE/Δ5-4ISOMERASE ACTIVITY IN THE RHESUS MONKEY PLACENTA AND FETAL ADRENAL, TESTIS AND OVARY DURING LATE GESTATION
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3β-Hydroxysteroid dehydrogenase/Δ5-4isomerase (3β-HSDH) was measured in the rhesus monkey (Macaca mulatta) placenta, fetal adrenal (whole organ minus medulla), testis and ovary during late gestation (Days 145-162).Activities were evaluated from the conversion of -pregnenolone to progesterone.The maximum enzyme velocity (Vm) in adrenal microsomes (100,000 g pellet) was significantly higher (146 nmoles progesterone/h x mg-1 protein) than in microsomes from the other tissues.Testicular Vm was greater than either ovarian or placental Vm which were not different from one another (11.5 versus 1.9, 1.2 nmoles progesterone/h x mg-1 protein, respectively).Apparent Michaelis-Menten constants in the adrenal, placenta, testis and ovary averaged 1.8, 2.5, 0.27 and 0.16 μM, respectively.In some cases, substrate inhibition was noted.Estimated dissociation constants for pregnenolone were 2.3 μM (adrenal), 2.1 μM (placenta), 0.74 μM (testis) and 0.13 μM (ovary). 3β-HSDH was less active in a crude mitochondrial preparation from the fetal adrenal (10,000 g pellet) than in microsomes, whereas activity in the placenta and testis appeared to be equally distributed between mitochrondria and microsomes.Rate measurements were consistent with the apparent potentials of these organs to synthesize their characteristic hormones.Thus, 3β-HSDH activity may be an important rate determining step in hormone synthesis.The importance of substrate inhibition in progesterone formation remains to be assessed.
- Sholl, Samuel A.
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- The catalytic mechanism of the 3-ketosteroid isomerase of Digitalis lanata involves an intramolecular proton transfer and the activity is not associated with the 3β-hydroxysteroid dehydrogenase activity
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The isomerization of the Δ5-3-ketosteroid isoprogesterone into the Δ4-3-ketosteroid progesterone has been examined with recombinant 3β-hydroxysteroid dehydrogenase from Digitalis lanata (rDl3βHSD), partially purified 3-ketosteroid isomerase from Digitalis lanata (Dl3KSI) and under non-enzymatic conditions in deuterium oxide (D2O). Studies indicate that the isomerization catalyzed by the Dl3KSI proceeds without significant isotope exchange between the medium and the steroid and thus involves an intramolecular proton transfer consistent with the mechanism of the bacterial 3-ketosteroid isomerase of Pseudomonas testosteroni. For the rDl3βHSD as well as under non-enzymatic conditions deuterium was incorporated from the incubation buffer during isomerization. Together with a comparison of the rate of isomerization under the different conditions, it was demonstrated that rDl3βHSD does not possess 3-ketosteroid isomerase activity.
- Meitinger, Nadine,Munkert, Jennifer,Maia de Pádua, Rodrigo,de Souza Filho, José Dias,Maid, Harald,Bauer, Walter,Braga, Fern?o Castro,Kreis, Wolfgang
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- A Dual Role Reductase from Phytosterols Catabolism Enables the Efficient Production of Valuable Steroid Precursors
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4-Androstenedione (4-AD) and progesterone (PG) are two of the most important precursors for synthesis of steroid drugs, however their current manufacturing processes suffer from low efficiency and severe environmental issues. In this study, we decipher a dual-role reductase (mnOpccR) in the phytosterols catabolism, which engages in two different metabolic branches to produce the key intermediate 20-hydroxymethyl pregn-4-ene-3-one (4-HBC) through a 4-e reduction of 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) and 2-e reduction of 3-oxo-4-pregnene-20-carboxyl aldehyde (3-OPA), respectively. Inactivation or overexpression of mnOpccR in the Mycobacterium neoaurum can achieve exclusive production of either 4-AD or 4-HBC from phytosterols. By utilizing a two-step synthesis, 4-HBC can be efficiently converted into PG in a scalable manner (100 gram scale). This study deciphers a pivotal biosynthetic mechanism of phytosterol catabolism and provides very efficient production routes of 4-AD and PG.
- Peng, Haidong,Wang, Yaya,Jiang, Kai,Chen, Xinru,Zhang, Wenlu,Zhang, Yanan,Deng, Zixin,Qu, Xudong
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p. 5414 - 5420
(2021/02/05)
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- One-Pot Deoxygenation and Substitution of Alcohols Mediated by Sulfuryl Fluoride
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Sulfuryl fluoride is a valuable reagent for the one-pot activation and derivatization of aliphatic alcohols, but the highly reactive alkyl fluorosulfate intermediates limit both the types of reactions that can be accessed as well as the scope. Herein, we report the SO2F2-mediated alcohol substitution and deoxygenation method that relies on the conversion of fluorosulfates to alkyl halide intermediates. This strategy allows the expansion of SO2F2-mediated one-pot processes to include radical reactions, where the alkyl halides can also be exploited in the one-pot deoxygenation of primary alcohols under mild conditions (52-95% yield). This strategy can also enhance the scope of substitutions to nucleophiles that are previously incompatible with one-pot SO2F2-mediated alcohol activation and enables substitution of primary and secondary alcohols in 54-95% yield. Chiral secondary alcohols undergo a highly stereospecific (90-98% ee) double nucleophilic displacement with an overall retention of configuration.
- Epifanov, Maxim,Mo, Jia Yi,Dubois, Rudy,Yu, Hao,Sammis, Glenn M.
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p. 3768 - 3777
(2021/03/01)
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- Preparation method of progesterone
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The invention discloses a preparation method of progesterone, which comprises the following steps of taking (20S)-20-hydroxymethyl pregna-4-ene-3-ketone as a raw material, and an acidic ionic liquid-based catalyst as a catalyst to react in a solvent, after the reaction is finished, separating the catalyst to obtain a reaction solution, sequentially concentrating the obtained reaction solution under normal pressure, adding water to separate out solid, filtering to obtain a progesterone crude product, and recrystallizing to obtain a progesterone fine product. The catalyst is prepared through catalysis of the acid controllable ionic liquid catalyst, the acid controllable ionic liquid catalyst has the characteristics of being high in designability, small in green pollution and the like, and when the acid controllable ionic liquid catalyst serves as the catalyst, the catalyst and a product are automatically layered after reaction; the catalyst can realize acidity controllability and regeneration through simple treatment after multiple cycles, so that the catalyst has a good application prospect.
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Paragraph 0052-0081
(2021/04/26)
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- Zn-Mediated Hydrodeoxygenation of Tertiary Alkyl Oxalates
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Herein we describe a general, mild, and scalable method for hydrodeoxygenation of readily accessible tertiary alkyl oxalates by Zn/silane under Ni-catalyzed conditions. The reduction method is suitable for an array of structural motifs derived from tertiary alcohols that bear diverse functional groups, including the synthesis of a key intermediate en route to estrone.
- Ye, Yang,Ma, Guobin,Yao, Ken,Gong, Hegui
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p. 1625 - 1628
(2021/01/18)
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- Discovery of novel steroidal-chalcone hybrids with potent and selective activity against triple-negative breast cancer
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A series of novel steroidal-chalcone derivates were designed and synthesized based on the molecular hybridization strategy and further evaluated for their growth inhibitory activity against three human cancer cell lines. The MTT results indicated that most compounds were apparently more sensitive to human breast cancer cells MDA-MB-231. Compounds 8 and 18 exerted the best cytotoxic activity against triple-negative MDA-MB-231 cells with the IC50 values of 0.42 μM and 0.52 μM respectively, which were 23-fold increase or more compared with 5-Fu. Further mechanism studies demonstrated that compound 8 could induce cells apoptosis through regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. Moreover, compound 8 could upregulate the cellular ROS levels which accelerated the apoptosis of MDA-MB-231 cells. In addition, interestingly, cell cycle assay showed that compound 8 could arrest MDA-MB-231 cells at S phase but not commonly anticipated G2/M phase. These evidences fully confirmed that compound 8 could be a potential candidate that deserves further development as an antitumor agent against triple-negative breast cancer.
- Bai, Chengfeng,Hou, Qiangqiang,Lin, Xin,Lu, Xiang,Luo, Guoshun,Wei, Hanlin,Xiang, Hua
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- Steroid compound as well as preparation method and application thereof (by machine translation)
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The compounds have the structure shown in the general formula (I) or the general formula (II); and experiments prove that the compounds can treat three-negative breast cancer by promoting apoptosis. (by machine translation)
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- ENABLING CHOLESTEROL CATABOLISM IN HUMAN CELLS
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Compositions, methods, and systems for modifying sterol metabolism in a subject is disclosed. In some embodiments, the subjects may be administered one or more mammalian cells modified to express at least one sterol degrading enzyme derived from a bacterium. In many embodiments, the cell is a macrophage or monocyte stably expressing three or more enzymes that aid in opening the β ring of cholesterol. The disclosed compositions and methods may be useful in lowering cholesterol levels in a subject in need thereof. In some embodiments, the subject may have a genetic predisposition to atherosclerosis.
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Paragraph 0029; 0037
(2020/07/05)
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- Preparation method of progesterone
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The invention discloses a preparation method of progesterone, and belongs to the technical field of preparation and processing of steroid hormone drugs. The preparation method comprises the steps that21-hydroxy-20-methylprogesterone-4-ene-3-ketone (1) is used as a starting material, 20-formylprogesterone-4-ene-3-ketone (2) is obtained through an oxidation reaction step, then an oxidative decarburization reaction step is performed under the action of a catalyst, and the product progesterone (3) is obtained. Compared with the prior art, the preparation method of the progesterone is shorter in reaction route and higher in yield, the adopted raw materials are low in cost and easy to obtain, less pollution is generated in the reaction process, the industrial development trend of green chemistry is met, and good social benefits and broader market prospects are achieved.
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Paragraph 0028-0035
(2020/02/29)
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- Direct Access to Isotopically Labeled Aliphatic Ketones Mediated by Nickel(I) Activation
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An extensive range of functionalized aliphatic ketones with good functional-group tolerance has been prepared by a NiI-promoted coupling of either primary or secondary alkyl iodides with NN2 pincer NiII-acyl complexes. The latter were easily accessed from the corresponding NiII-alkyl complexes with stoichiometric CO. This Ni-mediated carbonylative coupling is adaptable to late-stage carbon isotope labeling, as illustrated by the preparation of isotopically labelled pharmaceuticals. Preliminary investigations suggest the intermediacy of carbon-centered radicals.
- Donslund, Aske S.,Pedersen, Simon S.,Gaardbo, Cecilie,Neumann, Karoline T.,Kingston, Lee,Elmore, Charles S.,Skrydstrup, Troels
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p. 8099 - 8103
(2020/03/16)
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- Kinetics of Electrophilic Fluorination of Steroids and Epimerisation of Fluorosteroids
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Fluorinated steroids, which are synthesised by electrophilic fluorination, form a significant proportion of marketed pharmaceuticals. To gain quantitative information on fluorination at the 6-position of steroids, kinetics studies were conducted on enol ester derivatives of progesterone, testosterone, cholestenone and hydrocortisone with a series of electrophilic N?F reagents. The stereoselectivities of fluorination reactions of progesterone enol acetate and the kinetic effects of additives, including methanol and water, were investigated. The kinetics of epimerisation of 6β-fluoroprogesterone to the more pharmacologically active 6α-fluoroprogesterone isomer in HCl/acetic acid solutions are detailed.
- Rozatian, Neshat,Harsanyi, Antal,Murray, Ben J.,Hampton, Alexander S.,Chin, Emily J.,Cook, Alexander S.,Hodgson, David R. W.,Sandford, Graham
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supporting information
p. 12027 - 12035
(2020/08/28)
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- Base-free oxidation of alcohols enabled by nickel(ii)-catalyzed transfer dehydrogenation
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An efficient nickel(ii)-catalyzed transfer dehydrogenation oxidation of alcohols is reported that relies on cyclohexanone as the formal oxidant and does not require the use of an external base. The synthetic utility of this protocol is demonstratedviathe facile oxidation of structurally complicated natural products.
- Ye, Danfeng,Liu, Zhiyuan,Sessler, Jonathan L.,Lei, Chuanhu
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supporting information
p. 11811 - 11814
(2020/10/13)
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- Transfer-dehydrogenation of secondary alcohols catalyzed by manganese NNN-pincer complexes
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Novel catalytic systems based on pentacarbonylmanganese bromide and stable NNN-pincer ligands are presented for the transfer-dehydrogenation of secondary alcohols to give the corresponding ketones in good to excellent isolated yields. Best results are obtained using di-picolylamine derivatives as ligands and acetone as an inexpensive hydrogen acceptor. Besides high activity for benzylic substrates, aliphatic alcohols, as well as steroid derivatives, are readily oxidized in the presence of the optimal phosphorus-free catalyst.
- Budweg, Svenja,Junge, Kathrin,Beller, Matthias
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supporting information
p. 14143 - 14146
(2019/12/02)
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- A progesterone synthesis method
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The invention belongs to the steroid hormone pharmaceutical preparation technology field, in particular to [...] hormone drug progesterone synthesis method, the present invention provides synthetic method, in formula (II) as shown in the compound as a raw material, of formula (II) first compound of boron trifluoride ether pure reaction in formula (III) as shown in the; then the type (III) as shown in the in acetone with potassium permanganate, high sodium iodate reaction, as shown in formula (I) progesterone crude product, progesterone crude product by ethanol are refined to progesterone. The method of the present invention radically change the synthetic route, the adoption of the starting material, reducing reaction steps, more simple, economic, environmental protection, the total yield of synthesis in 80% or more, the content of the HPLC 99.35% or more, the industrial implementation, and improves the economic benefit.
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Paragraph 0011; 0035; 0040-0044; 0048-0052; 0053-0061; 0065
(2019/06/07)
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- Preparation method of progesterone and progesterone intermediate
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The invention relates to a method for preparing progesterone and a progesterone intermediate. According to the method, a cyano compound 2 is used as a substrate; reaction is carried out in an aproticorganic solvent at a temperature of -20 DEG C to 5 DEG C by taking trimethylhalosilane as a hydroxyl-removing reagent, so that a progesterone intermediate 3 is obtained; and a methylation reaction isconducted on the progesterone intermediate 3, so that progesterone is obtained. The reaction route is shown in the specification.
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- Method for synthesizing progesterone
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The invention relates to a method for synthesizing progesterone. The method is characterized in that Dinorcholenaldehyde used as a starting material sequentially undergo amination, oxidation and hydrolysis reactions to obtain progesterone. The method has the advantages of simple process, good product quality, high yield, and low preparation cost of the raw material Dinorcholenaldehyde. The overalldesign of the process route is rationally optimized, the quality of the synthesized product is good, the HPLC purity is greater than 99.5%, the yield is high, the total weight yield can reach 88%, and every reaction is simple to operate and easy to control, so the method is suitable for industrial production.
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Paragraph 0013; 0036; 0041-0042; 0043; 0048-0049; 0050
(2019/10/01)
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- Method for synthesizing progesterone (by machine translation)
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The process is simple, the preparation cost is low, 20 - the product yield is high, the yield of the product, is high, the, yield of the product is high, the yield of the, product is high, and. the purity of, the product, is more, than or equal, to more than, the product, and the method 90% is, HPLC suitable for 99.5%, industrial production. (by machine translation)
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Paragraph 0031-0041
(2019/12/25)
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- Method for preparing high quality progesterone
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The invention discloses a preparation method of high-quality progesterone, which comprises the following steps: by using pregnenolone as the raw material, sequentially carrying out ketal protection, Oppenauer oxidation and hydrolysis to obtain a progesterone crude product, and recrystalizing to obtain the high-quality progesterone of which the purity is greater than or equal to 99.7% and the single impurity content is less than 0.1%. In the ketal protection process, the pregnenolone and ethylene glycol react in the presence of an organic solvent, triethyl orthoformate and a catalyst; and in the Oppenauer oxidation process, the ketal product obtained by ketal protection reacts with cyclohexanone under reflux conditions in the presence of anhydrous toluene and aluminum isopropoxide. The purity of the prepared progesterone is greater than or equal to 99.7%, the single impurity content is less than 0.1%, and the total weight yield is greater than or equal to 82%, so the method is suitable for industrialized mass production.
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- Design, synthesis and biological evaluation of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives as dual 5α-reductase inhibitors and androgen receptor antagonists
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Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities. It is obvious that the androgen-dependent cell line LNCaP was much more sensitive than the androgen-independent cell line PC-3. Among all the synthesized compounds, 11d and 11k displayed the best inhibition activity with 4-fold more sensitive toward LNCaP than PC-3, which was consistent with their high affinities observed in AR binding assay. Molecular modeling studies suggested that 11k could bind to AR in a manner similar to the binding of dihydrotestosterone to AR. Compared to the finasteride, 11k showed a longer plasma half-life (4 h) and a better bioavailability. Overall, based on biological activities data, compound 11d and 11k can be identified as potential dual 5α-reductase inhibitors and AR antagonists which might be of therapeutic importance for prostate cancer treatment.
- Lao, Kejing,Sun, Jie,Wang, Chong,Wang, Ying,You, Qidong,Xiao, Hong,Xiang, Hua
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p. 4212 - 4217
(2017/08/23)
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- Design, synthesis and biological evaluation of novel androst-3,5-diene-3-carboxylic acid derivatives as inhibitors of 5α-reductase type 1 and 2
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5α-Reductase is a key enzyme responsible for dihydrotestosterone biosynthesis and has been recognized as an important target for discovering new drugs against benign prostatic hyperplasia (BPH). In this study, a series of novel steroidal androst-3,5-diene-3-carboxylic acids have been designed and synthesized. Biological evaluations were performed on their 5α-reductase inhibitory activities by both in vitro enzyme inhibition assay and in vivo by prostate weighing method. Results showed that most of them displayed excellent 5α-reductase inhibitory potency. Detailed evaluation indicated that most of the compounds displayed slightly higher inhibition potency towards type 2 isozyme. Among all the compounds, 16a was found to be the most potential inhibitor with the IC50 of 0.25?μM and 0.13?μM against type 1 and 2 isozymes respectively. In vivo 5a-reductase inhibitory evaluation of 16a also showed a more significant reduction effect (p??0.001) in rat prostate weight than epristeride. Furthermore, the results of in silico ADME study indicated that compound 16a exhibited good pharmacokinetic properties. Thus, 16a could serve as promising lead candidates for further study.
- Lao, Kejing,Sun, Jie,Wang, Chong,Lyu, Weiting,Zhou, Boshen,Zhao, Ruheng,Xu, Qian,You, Qidong,Xiang, Hua
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- Method for preparing progesterone
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The invention discloses a completely novel process route for preparing progesterone. The route adopts an initial raw material, namely 4-androstenedione (4AD) which is relatively cheap and easy to obtain, is relatively good in reaction independence of different steps, concise in procedure, simple and convenient to operate, applicable to industrial production and high in yield, and the accumulative yield of 5 steps is 55% or greater, or even up to 60%. In the situation that the price of a conventional raw material, namely 16-dehydropregnenolone acetate, soars, the process route has very high production application and economic values, and more importantly, a highly toxic reagent, namely acetone cyanohydrins, which is used in a conventional method, is not used in the method disclosed by the invention, so that the method is both economic and environmentally friendly, and is beneficial to industrial production.
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Paragraph 0047-0048
(2017/08/31)
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- Preparation method of progesterone
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The invention discloses a preparation method of progesterone. The method comprises the following steps: introducing pure oxygen or air into a mixture composed of a compound (2), a copper catalyst, TEMPO, NMP, N,N-dialkylaniline and a solvent to perform reaction, and collecting the progesterone from the reaction product. The method avoids using the heavy metal agent, greatly increases the reaction yield, and greatly lowers the production cost. The progesterone prepared by the method has high stereoselectivity, and the purity can reach 99% or above after simple purification; and thus, the method is convenient for industrialized implementation. The reaction equation is disclosed in the specification.
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Paragraph 0030; 0031; 0032; 0033; 0034; 0035; 0036-0044
(2017/09/18)
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- Selective reduction of 4,6- conjugate diene -3-one steroid compound method
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Belonging to the field of chemical pharmacy, the invention relates to a method for selective reduction of 4, 6-conjugated diene-3-one steroid, and solves the problem of low yield in hydrogen reduction. The method mainly includes the steps of: 1) adding the 4, 6-conjugated diene-3-one steroid, a liquid solvent, a catalyst, and a reducing agent hydrogen donor into a reaction kettle, performing nitrogen protection, and carrying out stirring heating till reflux; 2) carry out reflux reaction for 3-10h; 3) at the end of reaction, filtering out the catalyst; 4) distilling the solvent; 5) adding purified water after distillation; and 6) conducting cooling, pumping filtering, washing and drying to obtain a 4-ene-3-steroid crystal.
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Paragraph 0050-0057
(2019/11/21)
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- Method for preparing progesterone
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The invention discloses a method for preparing progesterone. 4-androstenedione (I) is taken as a raw material, a 17-position branch chain is introduced through cyanation and other reactions, and progesterone (VI) is prepared. The reaction formula is shown in the specification. The invention discloses a novel process for preparing progesterone. 4-androstenedione (I) with low price is initially taken as a starting raw material, progesterone with the total yield as high as 80% or higher by weight is obtained after five steps of reactions, the cost is low, and the method is suitable for industrial production.
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- Synthetic method of progesterone
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The invention belongs to the field of organic chemistry, and provides a synthetic method of progesterone. The method comprises the following steps: 1, slowing adding 2-chloroethyl propanoate to a 3beta-ether-3,5-androstadien-17-one solvent dissolved with a strong alkali, and carrying out an addition and cyclization reaction to obtain ethyl 3beta-ether-2,5- androstadien-17,20-epoxy-20-methyl-20-carboxylate; and 2, carrying out a high temperature decarboxylation and hydrolysis reaction on ethyl 3beta-ether-2,5-androstadien-17,20-epoxy-20-methyl-20-carboxylate in a lithium chloride-containing solvent under the protection of nitrogen or an inert gas to obtain progesterone. The method provided by the invention has the advantages of fundamental changing of the synthesis route, adoption of cheap initial raw materials, reaction step reduction, simplicity, economy, and environmental protection, allows the synthesis mole yield to reach 90% or above, benefits industrial enforcement, and has very high economic benefits.
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Paragraph 0034; 0035
(2016/10/31)
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- Preparation method for progesterone
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The invention discloses a preparation method for progesterone. The method comprises the following steps: with the compound 3-(2,2-dimethyl-1,3-dioxopropyl)-5-en-17-one (II) as a starting raw material, subjecting the starting raw material and a sulfonylmethyl isocyanide compound (III) to a condensation reaction under the action of alkali so as to prepare a formamido-sulfonylmethylene compound (IV); subjecting the compound (IV) to dehydration so as to obtain an isocyano-sulfonylmethylene compound (V); carrying out a reduction reaction on the compound (V) so as to prepare an isocyano-sulfonylmethyl compound (VI); subjecting the compound (VI) to methylation so as to obtain an isocyano-sulfonylethyl compound (VII); and carrying out hydrolysis on the compound (VII) so as to obtain the target products progesterone (I). The preparation method is simple in integral process, easy to operate, low in cost and suitable for large-scale production.
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Paragraph 0043; 0044
(2016/10/10)
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- New process for synthesizing steroid 3-one-4-ene
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The invention discloses a new process for synthesizing steroid 3-one-4-ene. The method comprises the steps: with steroid 3-hydroxy-5-ene as a starting material, in a nonprotic organic solvent, with air or oxygen as an oxidant and with a transition metal nitrate and a 2,2,6,6-tetramethylpiperidine-1-oxyl free radical or an analogue thereof as catalysts, oxidizing to obtain the steroid 3-one-4-ene. The method has the advantages of high yield, mild reaction conditions, easily controlled operation, low energy consumption, low cost, and safety; and the whole process is friendly to the environment, and is suitable for industrialization.
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Paragraph 0067; 0068
(2016/10/09)
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- Alternative synthetic approaches to rac-progesterone by way of the classic Johnson cationic polycyclization strategy
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Three alternative synthetic entries into Johnson's classic synthesis of rac-progesterone are presented in this manuscript. ent-Progesterone, the non-natural enantiomer of progesterone, has recently been identified as a potential alternative to progesterone for investigations into possible prevention and treatment of traumatic brain injury (TBI). Difficulties in accessing ent-progesterone in large quantities prevent it from being studied more thoroughly. Strategies for producing synthetic rac-progesterone are described and discussed herein.
- Slegeris, Rimantas,Dudley, Gregory B.
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p. 3666 - 3672
(2016/06/06)
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- Characterization of hamster NAD+-dependent 3(17)β-hydroxysteroid dehydrogenase belonging to the aldo-keto reductase 1C subfamily
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The cDNAs for morphine 6-dehydrogenase (AKR1C34) and its homologous aldo-keto reductase (AKR1C35) were cloned from golden hamster liver, and their enzymatic properties and tissue distribution were compared. AKR1C34 and AKR1C35 similarly oxidized various xenobiotic alicyclic alcohols using NAD+, but differed in their substrate specificity for hydroxysteroids and inhibitor sensitivity. While AKR1C34 showed 3α/17β/20α-hydroxysteroid dehydrogenase activities, AKR1C35 efficiently oxidized various 3β- and 17β-hydroxysteroids, including biologically active 3β-hydroxy-5α/β-dihydro-C19/C21-steroids, dehydroepiandrosterone and 17β-estradiol. AKR1C35 also differed from AKR1C34 in its high sensitivity to flavonoids, which inhibited competitively with respect to 17β-estradiol (Ki 0.11-0.69 μM). The mRNA for AKR1C35 was expressed liver-specific in male hamsters and ubiquitously in female hamsters, whereas the expression of the mRNA for AKR1C34 displayed opposite sexual dimorphism. Because AKR1C35 is the first 3(17)β-hydroxysteroid dehydrogenase in the AKR superfamily, we also investigated the molecular determinants for the 3β-hydroxysteroid dehydrogenase activity by replacement of Val54 and Cys310 in AKR1C35 with the corresponding residues in AKR1C34, Ala and Phe, respectively. The mutation of Val54Ala, but not Cys310Phe, significantly impaired this activity, suggesting that Val54 plays a critical role in recognition of the steroidal substrate.
- Endo, Satoshi,Noda, Misato,Ikari, Akira,Tatematsu, Kenjiro,El-Kabbani, Ossama,Hara, Akira,Kitade, Yukio,Matsunaga, Toshiyuki
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p. 425 - 434
(2015/11/27)
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- Cooperative catalysis by iridium complexes with a bipyridonate ligand: Versatile dehydrogenative oxidation of alcohols and reversible dehydrogenation-hydrogenation between 2-propanol and acetone
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Going into reverse: An efficient and versatile catalytic system for the dehydrogenative oxidation of alcohols under extremely mild conditions has been developed using a Cp*Ir complex with bipyridonate ligand as catalyst (see scheme, Cp=pentamethylcyclopentadienyl). Reversible and repetitive transformation between 2-propanol and acetone by catalytic dehydrogenation- hydrogenation is also achieved. Copyright
- Kawahara, Ryoko,Fujita, Ken-Ichi,Yamaguchi, Ryohei
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supporting information
p. 12790 - 12794
(2013/02/22)
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- Conversion of human steroid 5β-reductase (AKR1D1) into 3β-hydroxysteroid dehydrogenase by single point mutation E120H: Example of perfect enzyme engineering
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Human aldo-keto reductase 1D1 (AKR1D1) and AKR1C enzymes are essential for bile acid biosynthesis and steroid hormone metabolism. AKR1D1 catalyzes the 5β-reduction of Δ4-3- ketosteroids, whereas AKR1C enzymes are hydroxysteroid dehydrogenases (HSDs). These enzymes share high sequence identity and catalyze 4-pro-(R)-hydride transfer from NADPH to an electrophilic carbon but differ in that one residue in the conserved AKR catalytic tetrad, His120 (AKR1D1 numbering), is substituted by a glutamate in AKR1D1. We find that the AKR1D1 E120H mutant abolishes 5β-reductase activity and introduces HSD activity. However, the E120H mutant unexpectedly favors dihydrosteroids with the 5α-configuration and, unlike most of the AKR1C enzymes, shows a dominant stereochemical preference to act as a 3β-HSD as opposed to a 3α-HSD. The catalytic efficiency achieved for 3β-HSD activity is higher than that observed for any AKR to date. High resolution crystal structures of the E120H mutant in complex with epiandrosterone, 5β-dihydrotestosterone, and Δ4-androstene-3,17-dione elucidated the structural basis for this functional change. The glutamate-histidine substitution prevents a 3-ketosteroid from penetrating the active site so that hydride transfer is directed toward the C3 carbonyl group rather than the Δ4-double bond and confers 3β-HSD activity on the 5β-reductase. Structures indicate that stereospecificity of HSD activity is achieved because the steroid flips over to present its α-face to the A-face of NADPH. This is in contrast to the AKR1C enzymes, which can invert stereochemistry when the steroid swings across the binding pocket. These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference.
- Chen, Mo,Drury, Jason E.,Christianson, David W.,Penning, Trevor M.
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experimental part
p. 16609 - 16622
(2012/07/30)
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- Pincer and diamine Ru and Os diphosphane complexes as efficient catalysts for the dehydrogenation of alcohols to ketones
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The ruthenium and osmium complexes [MCl2(diphosphane)(L)] (M=Ru, Os; L=bidentate amino ligand) and [MCl(CNN)(dppb)] (CNN=pincer ligand; dppb=1,4-bis- (diphenylphosphino)butane), containing the N-H moiety, have been found to catalyze the acceptorless dehydrogenation of alcohols in tBuOH and in the presence of KOtBu. The compounds trans-[MCl2(dppf)(en)] (M=Ru 7, Os 13; dppf=1,1′-bis(diphenylphosphino)ferrocene; en=ethylenediamine) display very high activity and different substrates, including cyclic and linear alcohols, are efficiently oxidized to ketones by using 0.8-0.04mol% of catalyst. The effect of the base and the comparison of the catalytic activity of the Ru versus Os complexes are reported. The ruthenium complex 7 generally leads to a faster conversion into ketones with respect to the osmium complex 13, which displays better activity in the dehydrogenation of 5-en-3β-hydroxy steroids. The synthesis of new Ru and Os complexes [MCl2(PP)(L)] (PP=dppb, dppf; L=(±)-trans-1,2-diaminocyclohexane, 2-(aminomethyl) pyridine, and 2-aminoethanol) of trans and cis configuration is also reported. Alcohol breakdown: Ruthenium and osmium phosphane complexes containing nitrogen ligands with the N-H functionality efficiently catalyze the acceptorless dehydrogenation of alcohols. With [MCl2(dppf)(en)] (M=Ru, Os; dppf=1,1′-bis(diphenylphosphino)ferrocene; en=ethylenediamine) in the presence of KOtBu several alcohols have been converted into ketones (see scheme), including sterols for which Os displays a better activity than Ru. Copyright
- Baratta, Walter,Bossi, Gianluca,Putignano, Elisabetta,Rigo, Pierluigi
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experimental part
p. 3474 - 3481
(2011/05/02)
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- Studies on Baeyer-Villiger oxidation of steroids: DHEA and pregnenolone d-lactonization pathways in Penicillium camemberti AM83
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Penicillium camemberti AM83 strain is able to carry out effective Baeyer-Villiger type oxidation of DHEA, pregnenolone, androstenedione and progesterone to testololactone. Pregnenolone and DHEA underwent oxidation to testololactone via two routes: through
- Kolek, Teresa,Szpineter, Anna,Swizdor, Alina
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scheme or table
p. 859 - 862
(2009/12/01)
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- Baeyer-Villiger oxidation of DHEA, pregnenolone, and androstenedione by Penicillium lilacinum AM111
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The Baeyer-Villiger monooxygenase (BVMO) produced by Penicillium lilacinum AM111, in contrast to other enzymes of this group known in the literature, is able to process 3β-hydroxy-5-ene steroid substrates. Transformation of DHEA and pregnenolone yielded, as a sole or main product, 3β-hydroxy-17a-oxa-d-homo-androst-5-en-17-one, a new metabolite of these substrates; pregnenolone was transformed also to testololactone. Testololactone was the only product of oxidation of androstenedione by P. lilacinum AM111. Investigations of the time evolution of reaction progress have indicated that the substrates stimulate activity of BVMO(s) of P. lilacinum AM111.
- Kolek, Teresa,Szpineter, Anna,Swizdor, Alina
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experimental part
p. 1441 - 1445
(2009/04/06)
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- Δ5-3β-hydroxysteroid dehydrogenase (3βHSD) from Digitalis lanata. Heterologous expression and characterisation of the recombinant enzyme
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During the biosynthesis of cardiac glycosides, Δ5-3β- hydroxysteroid dehydrogenase (3βHSD, EC 1.1.1.51) converts pregnenolone (5-pregnen-3β-ol-20-one) to isoprogesterone (5-pregnene-3,20-dione). A 3βHSD gene was isolated from leaves of Digitalis lanata. It consisted of 870 nucleotides containing a 90 nucleotide long intron. A full-length cDNA clone that encodes 3βHSD was isolated by RT-PCR from the same source. A Sph I/Kpn I 3βHSD cDNA was cloned into the pQE30 vector and then transferred into E. coli strain M15[pREP4]. 3βHSD cDNA was functionally expressed as a His-tagged fusion protein (pQ3βHSD) composed of 273 amino acids (calculated molecular mass 28,561 Da). PQ3βHSD was purified by metal chelate affinity chromatography on Ni-NTA. Pregnenolone and other 3β-hydroxypregnanes but not cholesterol were 3β-oxidised by pQ3βHSD when NAD was used as the co-substrate. Testosterone (4-androsten-17β-ol-3-one) was converted to 4-androstene-3,17-dione indicating that the pQ3βHSD has also 17β-dehydrogenase activity. pQ3βHSD was able to reduce 3-keto steroids to their corresponding 3β-hydroxy derivatives when NADH was used as the co-substrate. For comparison, 3βHSD genes were isolated and sequenced from another 6 species of the genus Digitalis. Gene structure and the deduced 3βHSD proteins share a high degree of similarity. Georg Thieme Verlag KG Stuttgart.
- Herl, Vanessa,Frankenstein, Joerdis,Meitinger, Nadine,Mueller-Uri, Frieder,Kreis, Wolfgang
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p. 704 - 710
(2008/03/12)
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- Substrate specificity of a mouse aldo-keto reductase (AKR1C12)
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AKR1C12, a mouse member of the aldo-keto reductase (AKR) superfamily, is highly expressed in the stomach and is identical to a protein encoded in an interleukin-3-regulated gene in mouse myeloid cells, but its function remains unknown. In this study, the recombinant AKR1C12 was purified to homogeneity and the specificity for coenzymes and substrates was examined at a physiological pH of 7.4. The enzyme reduced various α-dicarbonyl compounds, several ketosteroids, aldehydes and some ketones using NADH as the preferred coenzyme. In the reverse reaction, the enzyme showed coenzyme preference for NAD +, and oxidized 3α-, 17β- and 20α-hydroxysteroids, and non-steroidal aliphatic and alicyclic alcohols, of which many hydroxysteroids and geranylgeraniol were good substrates, exhibiting low K m and high kcat/Km values. The results, together with the intracellular high ratio of NAD+/NADH, suggest that AKR1C12 functions as a dehydrogenase for the endogenous hydroxysteroids and geranylgeraniol in mouse stomach and myeloid cells.
- Endo, Satoshi,Matsumoto, Kengo,Matsunaga, Toshiyuki,Ishikura, Shuhei,Tajima, Kazuo,El-Kabbani, Ossama,Hara, Akira
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p. 2488 - 2492
(2007/10/03)
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- Smilagenin and its use
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The invention discloses the use of a smilagenin in the treatment of cognitive disfunction and similar conditions. Methods of treatment, and pharmaceutical compositions are also disclosed.
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- Conjugate reduction of α,β-unsaturated ketones using an Mn(III) catalyst, phenylsilane and isopropyl alcohol
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Treatment of a variety of α,β-unsaturated ketones with Mn(dpm)3 (3 mol%)/PhSiH3 (1.3 equiv.)/isopropyl alcohol with the exclusion of air resulted in the formation of the saturated ketone. (C) 2000 Elsevier Science Ltd.
- Magnus,Waring,Scott
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p. 9731 - 9733
(2007/10/03)
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- Synthesis of [3α-3H]-Dehydroepiandrosterone and [3α-3H]-pregnenolone
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[3α-3h]-dehydroepiandrosterone ([3α-3h]-3β-hydroxy-5-androsten-17- one) and [3α-3h]-pregnenolone ([3α-3h]-3β-hydroxy-5-pregnen-20-one) were prepared by selective reduction of 3-keto-5-ene intermediates with tritiated sodium borohydride. These were used as substrates to set up a tritium release assay for 3β-hydroxysteroid oxido-reductase and 5→4-ene isomerase (3β- HSD) which is a key enzyme in steroidogenesis.
- Tait
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p. 221 - 226
(2007/10/03)
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- On the Mechanism of Cleavage of Thioacetals Promoted by Copper(II) Sulphate Adsorbed on Silica Gel
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A probable mechanism of the cleavage reaction of thioacetals by copper(II) sulphate adsorbed on silica gel involves: formation of a chelate between sulphur atoms and copper(II), previously coordinated with hydroxyl groups on the silica surface, and the subsequent hydrolysis promoted by hydroxyl groups on the silica gel surface.
- Caballero, Gerardo M.,Gros, Eduardo G.
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p. 1147 - 1151
(2007/10/03)
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- Ruthenium-catalyzed Oppenauer-type oxidation of 3β-hydroxy steroids. A highly efficient entry into the steroidal hormones with 4-en-3-one functionality
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Oxidation of 5-unsaturated 3β-hydroxy steroids 1 to the corresponding 4-en-3-one derivatives 2 can be performed efficiently by acetone at reflux in the presence of a catalytic system consisting of either (PPh3)3RuCl2 (3) and K2CO3 or [(C4Ph4COHOCC4Ph4)(μ-H)][(CO)4Ru2] (4). The reaction proceeds via a ruthenium-catalyzed dehydrogenation of 1 and subsequent hydrogen transfer to acetone with concomitant double bond migration.
- Almeida, Maria L. S.,Kocǒvsky, Pavel,Báckvall, Jan-E?.
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p. 6587 - 6590
(2007/10/03)
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- Stereospecific oxidation of 3β-hydroxysteroids by persolvent fermentation with Pseudomonas sp. ST-200
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Pseudomonas sp. strain ST-200 isolated from a humus soil effectively oxidizes cholesterol dissolved in organic solvents but not that suspended in the growth medium. The organism does not assimilate cholesterol. This organism oxidized a variety of 5α- or 5-ene-steroids dissolved in organic solvent. First, the 3β-OH group was oxidized to a ketone group. The 3α-OH group was scarcely oxidized. Successively, C-6 position of 5-ene-steroids was hydroxylated, and a double bond of 5-ene-steroids was transferred from Δ5 to Δ4. Then, the 6-OH group was oxidized to a ketone group. Persolvent fermentation with ST-200 would provide an effective, convenient, and stereospecific method to oxidize the C-3 and C-6 positions of steroids.
- Aono, Rikizo,Doukyu, Noriyuki
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p. 1146 - 1151
(2007/10/03)
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- Cleavage of acetals promoted by copper (II) sulphate adsorbed on silica gel
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Copper sulphate supported on silica gel promotes the easy removal of cyclic acetals and tetrahydropyranyl ethers to give the respective parent carbonyl and hydroxyl compounds.
- Cabellero,Gros
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p. 395 - 404
(2007/10/02)
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- Formation of 5α steroids by biotranformation involving the 5 α-reductase activity of Penicillium decumbens
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The biotransformation of a series of Δ4-3-ketosteroids by the Penicillium decumbens ATCC 10436 has been investigated. Conversion to the 5α-dihydrosteroid was observed substrates of the androsterone and pregne series: the reaction is tolerant of non-polar substituents (Cl and CH3) at C-4 of the substrate, but does not occur in the presence of a 4-hydroxyl group, or with additional unsaturation at the Δ1 or Δ6 positions. A-nor, B-nor, 3-deoxy-, and 3,5-cycloandrostanes are not reduced, but 6-methylenestestosterone is converted to a 6-methylene-5α-dihydro derivative. Several biotransformations are reported which involve oxidoreductase activity at C-3 and/or C-17, either concomitant or independent of Δ4 reduction: the substrate specificity of the oxidoreductase processes has been examined and defined by the use of 3α-hydroxy, 3β-hydroxy, 3-keto, 17β-keto substituted steroids. In this way, the existence in P. decumbens of 3β-hydroxy-3-keto and 17β-hydroxy-17-keto oxidoreductases has been demonstrated.
- Holland, Herbert L.,Dore, Sophia,Xu, Weili,Brown, Frances M.
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p. 642 - 647
(2007/10/02)
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- Tetrapropylammonium perruthenate as a mild and efficient oxidant for sensitive steroidal alcohols
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Tetrapropylammonium perruthenate N-methylmorpholine N-oxide oxidation of steroidal alcohols is described. The reagent combination is mild and gave good yields of the corresponding ketones. Although the oxidation can generate ketones from 3-, 11-, 15-, 17-, and 20-hydroxy steroids, the oxidation of homoallylic alcohols proceeds in low yields. Finally, we observed that the oxidation reagents will convert 17α-hydroxy-2-keto steroids to 17-keto systems in excellent yields.
- Acosta, C. Kirk,Rao, Pemmaraju N.,Kim, Hyun K.
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p. 205 - 208
(2007/10/02)
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- 5 α-pregnan-20-ones and 5-pregnen-20-ones and related compounds
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Compounds of the formulae: STR1 useful as anti-obesity, anti-diabetic, anti-coronary and hypolipidemic agents.
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