- Discovery of a novel hybrid from finasteride and epristeride as 5α-reductase inhibitor
-
Finasteride and epristeride both inhibit 5α-reductase with high potency via competitive and non-competitive mechanism, respectively. A new hybrid of finasteride and epristeride was designed as a new 5α-reductase inhibitor based on combination principles in medicinal chemistry. Human 5β-reductase was chosen as a plausible surrogate of 5α-reductase type II and the results indicate that although the hybrid compound possesses the main bulk of epristeride, its inhibitory mechanism is same as of finasteride. The hybrid turned out to be a potent 5α-reductase inhibitor in low IC 50 ranges.
- Yao, Zhiyi,Xu, Yingjun,Zhang, Minmin,Jiang, Sheng,Nicklaus, Marc C.,Liao, Chenzhong
-
-
Read Online
- Temperature effects on the catalytic activity of the D38E mutant of 3-Oxo-Δ5-steroid isomerase: Favorable enthalpies and entropies of activation relative to the nonenzymatic reaction catalyzed by acetate ion
-
3-Oxo-Δ5-steroid isomerase (ketosteroid isomerase, KSI) catalyzes the isomerization of 5-androstene-3,17-dione (1) to 4-androstene-3,17-dione (3) via a dienolate intermediate (2-). KSI catalyzes this conversion about 13 orders of magnitude faster than the corresponding reaction catalyzed by acetate ion, a difference in activation energy (ΔG?) of ~18 kcal/mol. To evaluate whether the decrease in ΔG? by KSI is due to enthalpic or entropic effects, the activation parameters for the isomerization of 1 catalyzed by the D38E mutant of KSI were determined. A linear Arrhenius plot of k cat/KM versus 1/T gives the activation enthalpy (ΔH? = 5.9 kcal/mol) and activation entropy (TΔS? = -2.6 kcal/mol). Relative to catalysis by acetate, D38E reduces ΔH? by ~10 kcal/mol and increases TΔS? by ~5 kcal/mol. The activation parameters for the microscopic rate constants for D38E catalysis were also determined and compared to those for the acetate ion-catalyzed reaction. Enthalpic stabilization of 2- and favorable entropic effects in both chemical transition states by D38E result in an overall energetically more favorable enzymatic reaction relative to that catalyzed by acetate ion.
- Houck, Wendy J.,Pollack, Ralph M.
-
-
Read Online
- Silver-catalyzed vinylogous fluorination of vinyl diazoacetates
-
A silver-catalyzed vinylogous fluorination of vinyl diazoacetates to generate γ-fluoro-α,β-unsaturated carbonyls is presented. Application of this method to the fluorination of farnesol and steroid derivatives was achieved.
- Qin, Changming,Davies, Huw M. L.
-
-
Read Online
- Activation enthalpies and entropies for the microscopic rate constants of acetate-catalyzed isomerization of 5-androstene-3,17-dione
-
Both acetic acid and acetate catalyze the isomerization of 5-androstene-3,17-dione (1) to its conjugated isomer, 4-androstene-3,17-dione (3), through a dienol(ate) intermediate. The temperature dependence of the overall isomerization rate constants and of the microscopic rate constants for this isomerization was determined, and the Arrhenius plots give the activation enthalpy and entropy for each step. The source of the activation energy for the overall isomerization and for each of the individual steps is predominantly enthalpic, with a moderate to low entropic penalty. Additionally, the entropy and enthalpy for the keto - enol equilibrium of 1 and dienol were determined; this equilibrium is entirely controlled by enthalpy with no entropic contribution. The relevance of these results to the mechanism of the isomerization of 1 catalyzed by the enzyme 3-oxo-Δ5-steroid isomerase is discussed.
- Houck, Wendy J.,Pollack, Ralph M.
-
-
Read Online
- Selective oxidation of steroidal homoallylic alcohols using pyridinium chlorochromate (PCC)
-
Pyridinium chlorochromate (PCC), in the presence of anhydrous calcium carbonate, has been found to be an effective and convenient reagent for the selective oxidation of steroidal homoallylic alcohols to the corresponding β,δ-unsaturated ketones in good yield.
- Parish,Luo,Parish,Heidepriem
-
-
Read Online
- Method for preparing 4-androstenedione from dehydroepiandrosterone acetate
-
The invention provides a method for preparing 4-androstenedione from dehydroepiandrosterone acetate. The method comprises the following steps: carrying out a hydrolysis reaction on dehydroepiandrosterone acetate to obtain dehydroepiandrosterone, carrying out an oxidation reaction on the dehydroepiandrosterone to obtain crude 4-androstenedione, adding methanol and dichloroethane to the crude 4-androstenedione, and performing purification to obtain refined 4-androstenedione, wherein the obtained refined 4-androstenedione can be further reacted with potassium tert-butoxide to obtain 5-androstenedione. The method for preparing 4-androstenedione from dehydroepiandrosterone acetate has the following advantages: the preparation process is simple and feasible, and the production rate is improved,so the production values of enterprises are improved; and the cheap dehydroepiandrosterone acetate is used as the raw material to prepare the 4-androstenedione greatly demanded on the market, and the4-androstenedione is reacted to further prepare the 5-androstenedione, so the production cost of the enterprise is saved.
- -
-
-
- Development of a Chemoenzymatic Process for Dehydroepiandrosterone Acetate Synthesis
-
Dehydroepiandrosterone (DHEA, 2) is an important endogenous steroid hormone in mammals used in the treatment of a variety of dysfunctions in female and male health,1 as well as an intermediate in the synthesis of steroidal drugs, such as abiraterone acetate which is used for the treatment of prostate cancer.2-4 In this manuscript we describe a novel, concise, and cost-efficient route toward DHEA (2) and DHEA acetate (3) from 4-androstene-3,17-dione (4-AD, 1). Crucial to success was the identification of a ketoreductase from Sphingomonas wittichii for the highly regio- and stereoselective reduction of the C3-carbonyl group of 5-androstene-3,17-dione (5) to the required 3β-alcohol (2, >99% de). The enzyme displayed excellent robustness and solvent stability under high substrate concentrations (up to 150 g/L).
- Fryszkowska, Anna,Peterson, Justine,Davies, Nichola L.,Dewar, Colin,Evans, George,Bycroft, Matthew,Triggs, Neil,Fleming, Toni,Gorantla, Srikanth Sarat Chandra,Hoge, Garrett,Quirmbach, Michael,Timmanna, Upadhya,Reddy Poreddy, Srinivas,Kumar Reddy, D. Naresh,Dahanukar, Vilas,Holt-Tiffin, Karen E.
-
p. 1520 - 1528
(2016/08/30)
-
- Characterization of hamster NAD+-dependent 3(17)β-hydroxysteroid dehydrogenase belonging to the aldo-keto reductase 1C subfamily
-
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
-
p. 425 - 434
(2015/11/27)
-
- PROCESSES FOR THE PREPARATION OF DEHYDROEPIANDROSTERONE AND ITS INTERMEDIATES
-
The present application relates to a regioselective and stereoselective processes for the preparation of dehydroepiandrosterone (DHEA) and processes for its intermediates.
- -
-
Page/Page column 19; 20
(2014/12/12)
-
- Convenient method for the functionalization of the 4- and 6-positions of the androgen skeleton
-
The preparation and reactivity of steroidal vinyldiazo compounds is reported, providing a convenient, substituent tolerant, chemo- and stereoselective entry into 4- and 6-substituted androgen analogues from a common precursor. Under dirhodium catalysis, O-H insertion occurs at the carbenoid site, leading to 4-substituted steroids, but under silver catalysis, O-H insertion occurs at the vinylogous position, leading to 6-substituted steroids.
- Morton, Daniel,Dick, Allison R.,Ghosh, Debashis,Davies, Huw M. L.
-
supporting information; experimental part
p. 5838 - 5840
(2012/07/14)
-
- SUBSTITUTED ANDROST-4-ENE DIONES
-
The disclosure relates to novel C4 and C6 substituted androst-4-ene diones as well as andros-1,4-diene diones and derivatives thereof, their process of preparation, pharmaceutical compounds containing them, and the use of said compounds for the treatment of hormone-related disorders in mammals. This includes hormone-dependent cancers, particularly those caused by elevated levels of estrogen and its intermediates. These compounds can also be used in the treatment of other hormone-related disorders, inluding benign prostatic hyperplasia, cardiovascular disease, and neurodegenerative disorders.
- -
-
Page/Page column 63
(2011/10/31)
-
- AMINO DERIVATIVES OF ANDROSTANES AND ANDROSTENES AS MEDICAMENTS FOR CARDIOVASCULAR DISORDERS
-
Compounds of formula (I) wherein: the groups are as defined in the description, are useful for the preparation of medicaments for the treatment of cardiovascular disorders, in particular heart failure and hypertension. The compounds are inhibitors of the enzymatic activity of the Na+, K+-ATPase. Said compounds are used for the preparation of a medicament for the treatment of a disease caused by the hypertensive effects of endogenous ouabain, such as renal failure progression in autosomal dominant polycystic renal disease (ADPKD), preeclamptic hypertension and proteinuria and renal failure progression in patients with adducin polymorphisms.
- -
-
Page/Page column 32
(2011/04/14)
-
- AMINO DERIVATIVES OF ANDROSTANES AND ANDROSTENES AS MEDICAMENTS FOR CARDIOVASCULAR DISORDERS
-
Compounds of formula (I) wherein:the groups are as defined in the description, are useful for the preparation of medicaments for the treatment of cardiovascular disorders, in particular heart failure and hypertension. The compounds are inhibitors of the enzymatic activity of the Na+,K+-ATPase. Said compounds are used for the preparation of a medicament for the treatment of a disease caused by the hypertensive effects of endogenous ouabain, such as renal failure progression in autosomal dominant polycystic renal disease (ADPKD), preeclamptic hypertension and proteinuria and renal failure progression in patients with adducin polymorphisms.
- -
-
Page/Page column 106
(2008/06/13)
-
- Δ5-3β-hydroxysteroid dehydrogenase (3βHSD) from Digitalis lanata. Heterologous expression and characterisation of the recombinant enzyme
-
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
-
p. 704 - 710
(2008/03/12)
-
- Synthesis of [3α-3H]-Dehydroepiandrosterone and [3α-3H]-pregnenolone
-
[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
-
p. 221 - 226
(2007/10/03)
-
- Antenna-initiated photochemistry in polyfunctional steroids. Intramolecular singlet and triplet energy transfer between aryl, ketone, and alkene groups in 6β-(Dimethylphenylsiloxy)-5β-androstanes 1
-
Steroids have been prepared that bear a dimethylphenylsiloxy (DPSO) group and additional C3 and/or C17 ketone functionalities. The DPSO group has been used to harvest 266 nm photons and then activate the ketone functionalities through intramolecular singlet-singlet energy transfer (intra-SSET). Thus, the monoketones 3,3-(ethylenedioxy)-6β-(DPSO)-5β-androstan-17-one (6) and 6β-(DPSO)-5β-androstan-3-one (8) both exhibit DPSO-initiated photochemistry at the carbonyl groups. Irradiation of the diketone, 6β-(DPSO)-5β-androstane-3,17-dione (5), gives two ring D-derived photoproducta, an epimer (19) and an enal (18), both coming from the C17 ketone excited singlet state. Here Φintra-SSET from the aryl antenna to the carbonyl groups is ca. 88% efficients and occurs with a rate of ca. 6.5 × 109 s-1, with the chemistry indicative of facile intra-SSET between the C3 and C17 ketones. The alkylidene group at C3 (i.e., as in 6β-(DPSO)-3(E)-ethylidene-5β-androstan-17-one (33) and its Z isomer (34)) has no effect on the rate or efficiency of aryl activation of the C17 ketone.
- Jiang, S. Anna,Xiao, Changhe,Morrison, Harry
-
p. 7045 - 7055
(2007/10/03)
-
- A Mild Oxidizing Reagent for Alcohols and 1,2-Diols: o-Iodoxybenzoic Acid (IBX) in DMSO
-
o-Iodoxybenzoic acid (IBX) smoothly oxidizes primary and secondary alcohols to aldehydes and ketones, respectively. 1,2-Diols are converted to α-ketols or α-diketones without any oxidative cleavage of the glycol C-C bond.IBX oxidations are easily conducted in DMSO solution at room temperature, with yields ranging from good to quantitative.
- Frigerio, Marco,Santagostino, Marco
-
p. 8019 - 8022
(2007/10/02)
-
- Barium Permanganate, Ba(MnO4)2, a versatile and mild oxidizing agent for use under aprotic and non-aqueous conditions
-
Barium Permanganate is an easily prepared, stable, and a versatile oxidation reagent. With this reagent different types of primary and secondary hydroxy compounds are converted to their carbonyl derivatives. Aldehydes could be transformed to their carboxylic acids. Benzylic chloride and bromides are converted to their aldehydes and carboxylic acids. Semicarbazide and 2,4-dinitrophenylhydrazine derivatives of benzylic carbonyl compounds undergo carbon-nitrogen bond cleavage selectively and yield the expected carbonyl compounds. p-Hydroquinone is converted to p-benzoguinone and aromatic amines to their azo compounds. Anthracene and phenanthrene produce their 9,10-quinones. Diphenyl acetylene and trans stilbene give benzil, and styrene produces benzaldehyde. Selective oxidations of secondary benzylic carbon-hydrogen bonds occur and the corres- ponding carbonyl compounds are produced in good yields.
- Firouzabadi,Seddighi,Mottaghineiad,Bolourchian
-
p. 6869 - 6878
(2007/10/02)
-
- CHROMIUM(VI) BASED OXIDANTS-1. CHROMIUM PEROXIDE COMPLEXES AS VERSATILE, MILD, AND EFFICIENT OXIDANTS IN ORGANIC SYNTHESIS.
-
The preparation of 2,2'-bipyridylchromium peroxide, pyridinechromium peroxide, and chromium peroxide etherate is described. 2,2'-Bipyridylchromium peroxide converts different classes of alcohols to the carbonyl compounds.In 1,2-diols C-C bond cleavage occurs extensively. α-Hydroxy acids are decarboxylated quantitatively.Oximes are converted to their carbonyl compounds and thiols to their disulfides, dihydroxy phenolic compounds to quinones, benzyl amine to benzaldehyde, aromatic amines to their azo compounds, anthracene and phenanthrene to their quinones.Pyridinechromium peroxide converts different classes of alcohols efficiently to the carbonyl compounds, thiols to their disulfides, anthracene to anthraquinone.Mandelic and benzilic acids are decarboxylated very efficiently.Chromium peroxide etherate is an efficient reagent for the oxidation of different classes of alcohols to their carbonyl compounds.
- Firouzabadi, H.,Iranpoor, N.,Kiaeezadeh, F.,Toofan, J.
-
p. 719 - 726
(2007/10/02)
-
- DOUBLE BOND MIGRATION OVER SOLID KOH SUSPENDED IN APROTIC SOLVENTS
-
KOH suspended in DME is a good reagent to effect olefin double bond migration, especially deconjugation of α-enones.
- D'Incan, E.,Viout, P.
-
p. 3421 - 3424
(2007/10/02)
-