- Thermodynamic analysis of remote substrate binding energy in 3α-hydroxysteroid dehydrogenase/carbonyl reductase catalysis
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The binding energy of enzyme and substrate is used to lower the activation energy for the catalytic reaction. 3α-HSD/CR uses remote binding interactions to accelerate the reaction of androsterone with NAD+. Here, we examine the enthalpic and entropic components of the remote binding energy in the 3α-HSD/CR-catalyzed reaction of NAD+ with androsterone versus the substrate analogs, 2-decalol and cyclohexanol, by analyzing the temperature-dependent kinetic parameters through steady-state kinetics. The effects of temperature on kcat/Km for 3α-HSD/CR acting on androsterone, 2-decalol, and cyclohexanol show the reactions are entropically favorable but enthalpically unfavorable. Thermodynamic analysis from the temperature-dependent values of Km and kcat shows the binding of the E-NAD+ complex with either 2-decalol or cyclohexanol to form the ternary complex is endothermic and entropy-driven, and the subsequent conversion to the transition state is both enthalpically and entropically unfavorable. Hence, solvation entropy may play an important role in the binding process through both the desolvation of the solute molecules and the release of bound water molecules from the active site into bulk solvent. As compared to the thermodynamic parameters of 3α-HSD/CR acting on cyclohexanol, the hydrophobic interaction of the B-ring of steroids with the active site of 3α-HSD/CR contributes to catalysis by increasing exclusively the entropy of activation (ΔTΔS? = 1.8 kcal/mol), while the BCD-ring of androsterone significantly lowers ΔΔH? by 10.4 kcal/mol with a slight entropic penalty of ?1.9 kcal/mol. Therefore, the remote non-reacting sites of androsterone may induce a conformational change of the substrate binding loop with an entropic cost for better interaction with the transition state to decrease the enthalpy of activation, significantly increasing catalytic efficiency.
- Hwang, Chi-Ching,Chang, Pei-Ru,Hsieh, Chia-Lin,Chou, Yun-Hao,Wang, Tzu-Pin
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- Kinetic analysis of androstenedione 5α-reductase in epithelium and stroma of human prostate
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In the human prostate, various androgen-metabolizing enzymes are present. Among these enzymes, testosterone 5α-reductase seems to be dominant. However androstenedione is also a potential substrate of the prostatic 5α-reductase. To address the question of to what extent the reduction of androstenedione to androstanedione occurs, the present study describes in detail the kinetic characteristics (K(m) and V(max)) and possible age-dependent alterations of this enzymatic step in epithelium and stroma of the human prostate. In normal prostate (NPR), the mean K(m) (nM) and V(max) (pmol/mg protein · h) were about twofold higher in stroma (K(m) 211; V(max), 130) than in epithelium (K(m), 120; V(max), 56), whereas in the benign prostatic hyperplasia (BPH), the mean K(m) (nM; mean ± SEM) and V(max) (pmol/mg protein · h: mean ± SEM) were about sixfold higher in stroma (K(m), 688 ± 121; V(max), 415 ± 73) than in epithelium (K(m), 120 ± 10; V(max), 73 ± 8). In BPH, those differences between epithelium and stroma were highly significant (p 0.001). However, the efficiency ratios (V(max)/K(m)) of neither BPH nor NPR showed any significant differences between epithelium (NPR, 0.47; BPH, 0.62 ± 0.06) and stroma (NPR, 0.70; BPH. 0.63 ± 0.05). With respect to age-related changes, only stroma showed a significant increase of K(m) (P 0.01) and V(max) (p 0.05) with age. In summary, in both epithelium and stroma of the human prostate, a 5α-reductase converts in measurable amounts androstenedione to androstanedione. The kinetic data were, in part, different between epithelium and stroma; the reason for this difference remains unclear. In comparison to other metabolic conversions, such as testosterone to dihydrotestosterone and androstenedione to testosterone, it is unlikely that, in the human prostate, the adrenal androgen androstenedione contributes significantly to the formation of testosterone and, further, of dihydrotestosterone.
- Weisser, Heike,Krieg, Michael
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- Preparation method 5α- androstane -3,17- diketone (by machine translation)
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The preparation method 5α - of, androstane - 333317-dione comprises the following steps: (4 -) preparing the compound, androstanone through 17-hydroxycyanidation, 3-hydroxycyanidation- 17-hydroxycyanidation of, 5,6-hydroxycyanidation to, 3-position ketal acid hydrolysis as the raw material 5α - and the method has the advantages. of low production cost, product purity. (by machine translation)
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- Unified Total Synthesis of Five Bufadienolides
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We report a unified total synthesis of five bufadienolides: bufalin (1), bufogenin B (2), bufotalin (3), vulgarobufotoxin (4), and 3-(N-succinyl argininyl) bufotalin (5). After the steroidal ABCD ring 8 was produced, the D ring was cross-coupled with a 2-pyrone moiety and stereoselectively epoxidized to generate 6. TMSOTf promoted a stereospecific 1,2-hydride shift from 6 to establish the β-oriented 2-pyrone of 19. Functional group manipulations from 19 furnished 1-5, which potently inhibited cancer cell growth.
- Hagiwara, Koichi,Inoue, Masayuki,Itoh, Hiroaki,Shimizu, Shinsuke
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supporting information
(2020/11/13)
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- A sodium trifluoromethanesulfinate-mediated photocatalytic strategy for aerobic oxidation of alcohols
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A sodium trifluoromethanesulfinate-mediated photocatalytic strategy for the aerobic oxidation of alcohols has been developed for the first time, and the photoredox aerobic oxidation of secondary and primary alcohols provided the corresponding ketones and carboxylic acids, respectively, in high to excellent yields.
- Zhu, Xianjin,Liu, Can,Liu, Yong,Yang, Haijun,Fu, Hua
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p. 12443 - 12446
(2020/10/30)
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- Photochemical Transformations with Iodine Azide after Release from an Ion-Exchange Resin
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This report discloses the photochemical homolytic cleavage of iodine azide after its formation following release from polymer-bound bisazido iodate(I) anions. A series of radical reactions are reported including the 1,2-functionlization of alkenes and the unprecedented chemoselective oxidation of secondary alcohols in the presence of primary alcohols.
- Dr?ger, Gerald,K?sel, Teresa,Kirschning, Andreas,Schulz, G?ran
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supporting information
p. 12376 - 12380
(2020/05/08)
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- Catalytic Acceptorless Dehydrogenation of Aliphatic Alcohols
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We developed the first acceptorless dehydrogenation of aliphatic secondary alcohols to ketones under visible light irradiation at room temperature by devising a ternary hybrid catalyst system comprising a photoredox catalyst, a thiophosphate organocatalyst, and a nickel catalyst. The reaction proceeded through three main steps: hydrogen atom transfer from the α-C-H bond of an alcohol substrate to the thiyl radical of the photo-oxidized organocatalyst, interception of the generated carbon-centered radical with a nickel catalyst, and β-hydride elimination. The reaction proceeded in high yield under mild conditions without producing side products (except H2 gas) from various alcohols, including sterically hindered alcohols, a steroid, and a pharmaceutical derivative. This catalyst system also promoted acceptorless cross-dehydrogenative esterification from aldehydes and alcohols through hemiacetal intermediates.
- Fuse, Hiromu,Mitsunuma, Harunobu,Kanai, Motomu
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supporting information
p. 4493 - 4499
(2020/03/05)
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- Microbial Modifications of Androstane and Androstene Steroids by Penicillium vinaceum
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The biotransformation of steroid compounds is a promising, environmentally friendly route to new pharmaceuticals and hormones. One of the reaction types common in the metabolic fate of steroids is Baeyer-Villiger oxidation, which in the case of cyclic ketones, such as steroids, leads to lactones. Fungal enzymes catalyzing this reaction, Baeyer-Villiger monooxygenases (BVMOs), have been shown to possess broad substrate scope, selectivity, and catalytic performance competitive to chemical oxidation, being far more environmentally green. This study covers the biotransformation of a series of androstane steroids (epiandrosterone and androsterone) and androstene steroids (progesterone, pregnenolone, dehydroepiandrosterone, androstenedione, 19-OH-androstenedione, testosterone, and 19-nortestosterone) by the cultures of filamentous fungus Penicillium vinaceum AM110. The transformation was monitored by GC and the resulting products were identified on the basis of chromatographic and spectral data. The investigated fungus carries out effective Baeyer-Villiger oxidation of the substrates. Interestingly, introduction of the 19-OH group into androstenedione skeleton has significant inhibitory effect on the BVMO activity, as the 10-day transformation leaves half of the 19-OH-androstenedione unreacted. The metabolic fate of epiandrosterone and androsterone, the only 5α-saturated substrates among the investigated compounds, is more complicated. The transformation of these two substrates combined with time course monitoring revealed that each substrate is converted into three products, corresponding to oxidation at C-3 and C-17, with different time profiles and yields.
- ?yczko, Paulina,Panek, Anna,Swizdor, Alina
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- Chemoselective Oxidation of p-Methoxybenzyl Ethers by an Electronically Tuned Nitroxyl Radical Catalyst
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The oxidation of p-methoxy benzyl (PMB) ethers was achieved using nitroxyl radical catalyst 1, which contains electron-withdrawing ester groups adjacent to the nitroxyl group. The oxidative deprotection of the PMB moieties on the hydroxy groups was observed upon treatment of 1 with 1 equiv of the co-oxidant phenyl iodonium bis(trifluoroacetate) (PIFA). The corresponding carbonyl compounds were obtained by treating the PMB-protected alcohols with 1 and an excess of PIFA.
- Hamada, Shohei,Sugimoto, Koichi,Elboray, Elghareeb E.,Kawabata, Takeo,Furuta, Takumi
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supporting information
p. 5486 - 5490
(2020/07/24)
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- Electrochemistry Broadens the Scope of Flavin Photocatalysis: Photoelectrocatalytic Oxidation of Unactivated Alcohols
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Riboflavin-derived photocatalysts have been extensively studied in the context of alcohol oxidation. However, to date, the scope of this catalytic methodology has been limited to benzyl alcohols. In this work, mechanistic understanding of flavin-catalyzed oxidation reactions, in either the absence or presence of thiourea as a cocatalyst, was obtained. The mechanistic insights enabled development of an electrochemically driven photochemical oxidation of primary and secondary aliphatic alcohols using a pair of flavin and dialkylthiourea catalysts. Electrochemistry makes it possible to avoid using O2 and an oxidant and generating H2O2 as a byproduct, both of which oxidatively degrade thiourea under the reaction conditions. This modification unlocks a new mechanistic pathway in which the oxidation of unactivated alcohols is achieved by thiyl radical mediated hydrogen-atom abstraction.
- Zhang, Wen,Carpenter, Keith L.,Lin, Song
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supporting information
p. 409 - 417
(2019/11/25)
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- A 5 α - androstane - 3, 17 - dione synthetic method
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A 5 α - androstane - 3, 17 - dione synthesis method, the method is to 4 - androstenedione as raw materials, the ketal reaction, hydrogenation reaction, hydrolysis reaction to obtain 5 α - androstane - 3, 17 - dione. The method of the invention has the process is simple, the production cost is low, the product has high purity, and suitability for industrial production.
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- Preparation method of 5alpha-androstane-3,17-dione
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The invention relates to a preparation method of 5alpha-androstane-3,17-dione. The method specifically comprises the following steps: 1, carrying out an etherification reaction on 4-androstenedione, triethyl orthoformate and anhydrous ethanol in the presence of an etherification catalyst, and performing post-treatment after the etherification reaction is completed in order to prepare a compoundwet 3-ethoxy-3,5-androstadien-17-one; 2, adding a the wet 3-ethoxy-3,5-androstadien-17-one into a methanol-dichloromethane mixed solvent, performing uniform stirring, adjusting the pH value of the obtained solution, carrying out a catalytic hydrogenation reaction under the action of a palladium-carbon catalyst, and filtering out the catalyst after the reaction is finished in order to obtain a 3-ethoxy-3-androstene-17-one solution; and 3, carrying out a hydrolysis reaction on the 3-ethoxy-3-androstene-17-tone solution and an acid, removing the solvent after the hydrolysis reaction is finished,and carrying out filtering, water washing and drying to obtain the 5alpha-androstane-3,17-dione. The method has the advantages of short process route, easily controlled production process, environmental friendliness, low production cost, and suitableness for industrial large-scale production.
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- Method for synthesizing stanozolol intermediate androstane-17alpha-methyl-17beta-hydroxyl-3-ketone
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The invention provides a method for synthesizing a stanozolol intermediate androstane-17alpha-methyl-17beta-hydroxyl-3-ketone. The method comprises the following steps: taking 4-androstenedione as a raw material, carrying out 3-site and 17-site keto-double-ketal, 5-site ethylenic bond catalytic hydrogenation and 3-site and 17-site double-ketal hydrolysis to prepare a compound 5alpha-androstane-3,17-diketone; then carrying out 3-site keto-double-etherification and 17-site Grignard addition, and finally carrying out hydrolysis to prepare the compound androstane-17alpha-methyl-17beta-hydroxyl-3-ketone, wherein the HPLC (High Performance Liquid Chromatography) purity of the compound is 99.0% or greater. The method provided by the invention is short in route, easy in production process control,environmentally-friendly, low in production cost and applicable to industrial large-scale production.
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- Electrochemical C-H oxygenation and alcohol dehydrogenation involving Fe-oxo species using water as the oxygen source
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High-valent iron-oxo complexes are key intermediates in C-H functionalization reactions. Herein, we report the generation of a (TAML)Fe-oxo species (TAML = tetraamido macrocyclic ligand) via electrochemical proton-coupled oxidation of the corresponding (TAML)FeIII-OH2 complex. Cyclic voltammetry (CV) and spectroelectrochemical studies are used to elucidate the relevant (TAML)Fe redox processes and determine the predominant (TAML)Fe species present in solution during bulk electrolysis. Evidence for iron(iv) and iron(v) species is presented, and these species are used in the electrochemical oxygenation of benzylic C-H bonds and dehydrogenation of alcohols to ketones.
- Das, Amit,Nutting, Jordan E.,Stahl, Shannon S.
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p. 7542 - 7548
(2019/08/20)
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- Metal-Free catalyst for visible-light-induced oxidation of unactivated alcohols using Air/Oxygen as an oxidant
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9-Fluorenone acts as a metal-free and additive-free photocatalyst for the selective oxidation of primary and secondary alcohols under visible light. With this photocatalyst, a plethora of alcohols such as aliphatic, heteroaromatic, aromatic, and alicyclic compounds has been converted to the corresponding carbonyl compounds using air/oxygen as an oxidant. In addition to these, several steroids have been oxidized to the corresponding carbonyl compounds. Detailed mechanistic studies have also been achieved to determine the role of the oxidant and the photocatalyst for this oxidation.
- Schilling, Waldemar,Riemer, Daniel,Zhang, Yu,Hatami, Nareh,Das, Shoubhik
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p. 5425 - 5430
(2018/05/15)
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- ATP3 and MTP3: Easily Prepared Stable Perruthenate Salts for Oxidation Applications in Synthesis
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The Ley–Griffith tetra-n-propylammonium perruthenate (TPAP) catalyst has been widely deployed by the synthesis community, mainly for the oxidation of alcohols to aldehydes and ketones, but also for a variety of other synthetic transformations (e.g. diol cleavage, isomerizations, imine formation and heterocyclic synthesis). Such popularity has been forged on broad reaction scope, functional group tolerance, mild conditions, and commercial catalyst supply. However, the mild instability of TPAP creates preparation, storage, and reaction reproducibility issues, due to unpreventable slow decomposition. In search of attributes conducive to catalyst longevity an extensive range of novel perruthenate salts were prepared. Subsequent evaluation unearthed a set of readily synthesized, bench stable, phosphonium perruthenates (ATP3 and MTP3) that mirror the reactivity of TPAP, but avoid storage decomposition issues.
- Moore, Peter W.,Read, Christopher D. G.,Bernhardt, Paul V.,Williams, Craig M.
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supporting information
p. 4556 - 4561
(2018/03/13)
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- 2-Iodoxybenzoic Acid Tosylates: the Alternative to Dess–Martin Periodinane Oxidizing Reagents
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Two powerful hypervalent iodine(V) oxidants, DMP-OTs (1-tosyloxy-1,1-diacetoxy-1H-1λ5-benzo[d][1,2]iodoxol-3-one) and IBX-OTs (1-tosyloxy-1-oxo-1H-1λ5-benzo[d][1,2]iodoxol-3-one) show high reactivity in the oxidation of structurally complex primary and secondary alcohols, which are highly functionalized polyketide or terpene fragments or steroids. The yields of the corresponding carbonyl compounds are even higher for the protocol that uses pyridine as additive. The oxidations proceed very rapidly at room temperature leaving the protective groups and π-systems intact and affording the corresponding carbonyl compounds in good to excellent yields. Moreover, IBX-OTs is an efficient reagent for the oxidative dehydrogenation of steroidal alcohols to the corresponding enones. (Figure presented.).
- Yusubov, Mekhman S.,Postnikov, Pavel S.,Yusubova, Roza Ya.,Yoshimura, Akira,Jürjens, Gerrit,Kirschning, Andreas,Zhdankin, Viktor V.
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p. 3207 - 3216
(2017/09/11)
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- Method for preparing epiandrosterone
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The invention discloses a method for preparing epiandrosterone. 4-androstenedione (I) is used as a raw material to prepare the epiandrosterone. The reaction formula is shown in the description. The low-cost 4-androstenedione is used as the raw material for the first time, and the epiandrosterone is obtained through synthesis on the mild reaction conditions, so that the production cost is greatly lowered, and the method is suitable for large-scale industrial production.
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- A 5 α- androstanedione method for the preparation of
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The invention discloses a preparation method of 5alpha-androstanedion. The method comprises steps of a reduction reaction, a hydrogenation reaction and an oxidation reaction. The chemical synthesis method for preparing 5alpha-androstanedion avoids the disadvantages of long middle route, high danger, low yield and serious environmental pollution of a traditional production method. Compared to the traditional production method, the method provided by the invention has easily controlled reaction conditions, simple operations, high yield and reduced cost, and the yield of refined product is more than 70% in weight. The raw materials used in the method can be obtained by fermentation of phytosterols, which have wide source and low price; therefore, the method has the characteristics of easily available raw materials and low cost.
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- COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS
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Described herein are neuroactive steroids of the Formula (II) : or a pharmaceutically acceptable salt thereof; wherein A, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5, R6 and ----- are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e. g., such for inducing sedation and/or anesthesia.
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Page/Page column 87
(2016/06/14)
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- COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS
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Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein (II), A, R1, R2, R3a, R4a, R4b, R5, R7a, and R7b are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.
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Page/Page column 144
(2016/05/24)
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- C-H Xanthylation: A Synthetic Platform for Alkane Functionalization
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Intermolecular functionalizations of aliphatic C-H bonds offer unique strategies for the synthesis and late-stage derivatization of complex molecules, but the chemical space accessible remains limited. Herein, we report a transformation significantly expanding the chemotypes accessible via C-H functionalization. The C-H xanthylation proceeds in useful chemical yields with the substrate as the limiting reagent using blue LEDs and an easily prepared N-xanthylamide. The late-stage functionalizations of complex molecules occur with high levels of site selectivity, and a variety of common functionality is tolerated in the reaction. This approach capitalizes on the versatility of the xanthate functional group via both polar and radical manifolds to unlock a wide array of C-H transformations previously inaccessible in synthesis.
- Czaplyski, William L.,Na, Christina G.,Alexanian, Erik J.
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supporting information
p. 13854 - 13857
(2016/11/06)
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- Photoinduced Oxidation of Secondary Alcohols Using 4-Benzoylpyridine as an Oxidant
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Photoinduced oxidation of secondary alcohols to ketones was achieved by utilizing an equimolar amount of 4-benzoylpyridine as an oxidant. This transformation proceeds at ambient temperature and exhibits high compatibility with polar functionalities including benzoyl, silyl, and methoxymethyl alcohol protecting groups as well as tosyloxy, bromo, sulfonyl, carbamate, ester, and carboxylic acid units. The present oxidation is solely promoted by the action of organic molecules without the aid of metallic reagents. (Chemical Equation Presented).
- Kamijo, Shin,Tao, Keisuke,Takao, Go,Tonoda, Hiroshi,Murafuji, Toshihiro
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supporting information
p. 3326 - 3329
(2015/07/15)
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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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- Effective and mild method for converting 3β-hydroxysteroids to 3-keto steroids via DDQ/TEMPO
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A mild and efficient oxidation of 3β-hydroxysteroids to the corresponding 3-keto steroids can be carried out at room temperature, using DDQ in the presence of catalytic TEMPO. Oxidation of saturated 3β-hydroxysteroids gave the corresponding ketones in excellent yield. The 5-unsaturated 3β-hydroxysteroids are oxidized selectively to 4-en-3-one or 4,6-diene-3-one derivatives according to the amount of DDQ in reaction. This is a good method for the synthesis of 4,6-diene-3-one from the corresponding 3β-hydroxy-5-ene steroids. Meanwhile, configurations of the oxidation compounds 2a, 2b, 3b, 2c, 2f and 2g were identified by X-ray diffraction. A possible mechanism is presented and discussed.
- Zhang, Wu,Pan, Dan,Wu, Aiqun,Shen, Liqun
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- Microbial Baeyer-Villiger oxidation of 5α-steroids using Beauveria bassiana. A stereochemical requirement for the 11α-hydroxylation and the lactonization pathway
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Beauveria bassiana KCH 1065, as was recently demonstrated, is unusual amongst fungal biocatalysts in that it converts C19 3-oxo-4-ene and 3β-hydroxy-5-ene as well as 3β-hydroxy-5α-saturated steroids to 11α-hydroxy ring-D lactones. The Baeyer-Villiger monooxygenase (BVMO) of this strain is distinguished from other enzymes catalyzing BVO of steroidal ketones by the fact that it oxidizes solely substrates with 11α-hydroxyl group. The current study using a series of 5α-saturated steroids (androsterone, 3α-androstanediol and androstanedione) has highlighted that a small change of the steroid structure can result in significant differences of the metabolic fate. It was found that the 3α-stereochemistry of hydroxyl group restricted "normal" binding orientation of the substrate within 11α-hydroxylase and, as a result, androsterone and 3α-androstanediol were converted into a mixture of 7β-, 11α- and 7α-hydroxy derivatives. Hydroxylation of androstanedione occurred only at the 11α-position, indicating that the 3-oxo group limits the alternative binding orientation of the substrate within the hydroxylase. Only androstanedione and 3α-androstanediol were metabolized to hydroxylactones. The study uniquely demonstrated preference for oxidation of equatorial (11α-, 7β-) hydroxyketones by BVMO from B. bassiana. The time course experiments suggested that the activity of 17β-HSD is a factor determining the amount of produced ring-D lactones. The obtained 11α-hydroxylactones underwent further transformations (oxy-red reactions) at C-3. During conversion of androstanedione, a minor dehydrogenation pathway was observed with generation of 11α,17β-dihydroxy-5α-androst-1-en-3-one. The introduction of C1C2 double bond has been recorded in B. bassiana for the first time.
- ?wizdor, Alina,Panek, Anna,Milecka-Tronina, Natalia
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- Regioselective dehydrogenation of 3-keto-steroids to form conjugated enones using o-iodoxybenzoic acid and trifluoroacetic acid catalysis
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Mild and regioselective conversion of 3-keto-5α- and 3-keto-5β-steroids (trans A/B- and cis A/B-ring juncture, respectively) to the corresponding enones (Δ1- and Δ4-3- ketones) by treatment with o-iodoxybenzoic acid (IBX) catalyzed by trifluoroacetic acid (TFA) in DMSO, is described. The IBX-mediated reaction involved dehydrogenation of the α- and β-hydrogen atoms of the 3-ketones to give the enones regioselectively in good isolated yields without concomitant formation of related dienones and trienones.
- Iida, Takashi,Omura, Kaoru,Sakiyama, Ryou,Kodomari, Mitsuo
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- Hydroxylation of DHEA and its analogues by Absidia coerulea AM93. Can an inducible microbial hydroxylase catalyze 7α- and 7β-hydroxylation of 5-ene and 5α-dihydro C19-steroids?
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In this paper we focus on the course of 7-hydroxylation of DHEA, androstenediol, epiandrosterone, and 5α-androstan-3,17-dione by Absidia coerulea AM93. Apart from that, we present a tentative analysis of the hydroxylation of steroids in A. coerulea AM93. DHEA and androstenediol were transformed to the mixture of allyl 7-hydroxy derivatives, while EpiA and 5α-androstan-3,17-dione were converted mainly to 7α- and 7β-alcohols accompanied by 9α- and 11α-hydroxy derivatives. On the basis of (i) time course analysis of hydroxylation of the abovementioned substrates, (ii) biotransformation with resting cells at different pH, (iii) enzyme inhibition analysis together with (iv) geometrical relationship between the C-H bond of the substrate undergoing hydroxylation and the cofactor-bound activated oxygen atom, it is postulated that the same enzyme can catalyze the oxidation of C7-Hα as well as C7-H β bonds in 5-ene and 5α-dihydro C19-steroids. Correlations observed between the structure of the substrate and the regioselectivity of hydroxylation suggest that 7β-hydroxylation may occur in the normal binding enzyme-substrate complex, while 7α-hydroxylation - in the reverse inverted binding complex.
- Milecka-Tronina, Natalia,Ko?ek, Teresa,?wizdor, Alina,Panek, Anna
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p. 883 - 891
(2014/01/23)
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- The iron(II) complex [Fe(CF3SO3)2(mcp)] as a convenient, readily available catalyst for the selective oxidation of methylenic sites in alkanes
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The efficient and selective oxidation of secondary C-H sites of alkanes is achieved by using low catalyst loadings of a non-expensive, readily available iron catalyst [Fe(II)(CF3SO3)2(mcp)], {Fe-mcp, [mcp=N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)cyclohexane-trans-1,2-diamine]}, and hydrogen peroxide (H2O2) as oxidant, via a simple reaction protocol. Natural products are selectively oxidized and isolated in synthetically amenable yields. The easy access to large quantities of the catalyst and the simplicity of the C-H oxidation procedure make this system a particularly convenient tool to carry out alkane C-H oxidation reactions on the preparative scale, and in short reaction times.
- Canta, Merce,Font, David,Gomez, Laura,Ribas, Xavi,Costas, Miquel
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supporting information
p. 818 - 830
(2014/04/03)
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- Rabbit 3-hydroxyhexobarbital dehydrogenase is a NADPH-preferring reductase with broad substrate specificity for ketosteroids, prostaglandin D2, and other endogenous and xenobiotic carbonyl compounds
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3-Hydroxyhexobarbital dehydrogenase (3HBD) catalyzes NAD(P) +-linked oxidation of 3-hydroxyhexobarbital into 3-oxohexobarbital. The enzyme has been thought to act as a dehydrogenase for xenobiotic alcohols and some hydroxysteroids, but its physiological function remains unknown. We have purified rabbit 3HBD, isolated its cDNA, and examined its specificity for coenzymes and substrates, reaction directionality and tissue distribution. 3HBD is a member (AKR1C29) of the aldo-keto reductase (AKR) superfamily, and exhibited high preference for NADP(H) over NAD(H) at a physiological pH of 7.4. In the NADPH-linked reduction, 3HBD showed broad substrate specificity for a variety of quinones, ketones and aldehydes, including 3-, 17- and 20-ketosteroids and prostaglandin D2, which were converted to 3α-, 17β- and 20α-hydroxysteroids and 9α,11β- prostaglandin F2, respectively. Especially, α-diketones (such as isatin and diacetyl) and lipid peroxidation-derived aldehydes (such as 4-oxo- and 4-hydroxy-2-nonenals) were excellent substrates showing low Km values (0.1-5.9 μM). In 3HBD-overexpressed cells, 3-oxohexobarbital and 5β-androstan-3α-ol-17-one were metabolized into 3-hydroxyhexobarbital and 5β-androstane-3α,17β-diol, respectively, but the reverse reactions did not proceed. The overexpression of the enzyme in the cells decreased the cytotoxicity of 4-oxo-2-nonenal. The mRNA for 3HBD was ubiquitously expressed in rabbit tissues. The results suggest that 3HBD is an NADPH-preferring reductase, and plays roles in the metabolisms of steroids, prostaglandin D2, carbohydrates and xenobiotics, as well as a defense system, protecting against reactive carbonyl compounds.
- Endo, Satoshi,Matsunaga, Toshiyuki,Matsumoto, Atsuko,Arai, Yuki,Ohno, Satoshi,El-Kabbani, Ossama,Tajima, Kazuo,Bunai, Yasuo,Yamano, Shigeru,Hara, Akira,Kitade, Yukio
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p. 1366 - 1375
(2013/11/19)
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- Direct organocatalytic stereoselective transfer hydrogenation of conjugated olefins of steroids
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Kinetically controlled and organocatalytic syn-selective transfer hydrogenation has been successfully demonstrated for the reduction of the enone functional group of various steroids. Herein, diastereoselective synthesis of many 5β-steroids have been reported through organocatalysis, which have broad medicinal and pharmaceutical applications. The mechanistic studies and the selectivity of the products clearly indicated that the catalyst 1b·d-CSA is mild enough to activate the various chiral cyclic enones through iminium ion formation during the organocatalytic transfer hydrogenations with Hantzsch ester 2a as a hydrogen source. Further, clear evidence for the selective formation of intermediate iminium species [I]+ have been characterized through on-line monitoring of controlled experiments by NMR and ESI-HRMS analyses.
- Ramachary, Dhevalapally B.,Sakthidevi, Rajasekar,Reddy, P. Srinivasa
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p. 13497 - 13506
(2013/09/02)
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- The regio- and stereo-selective reduction of steroidal 4-en-3-ones using Na2S2O4/NaHCO3 and CuCl/NaBH 4
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This paper describes the regio- and stereoselective reduction of a.
- Wang, Chunli,Chen, Xiaoyu,Huang, Yaoqing,Yang, Jesse,Chen, Ying
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p. 1339 - 1346
(2013/11/19)
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- Diastereoselective synthesis of C60/steroid conjugates
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The design and synthesis of fullerene-steroid hybrids by using Prato's protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five-membered ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C 60, thus ascertaining the proposed structures.
- Ruiz, Alberto,Coro, Julieta,Almagro, Luis,Ruiz, Jose A.,Molero, Dolores,Maroto, Enrique E.,Filippone, Salvatore,Herranz, Maria Angeles,Martinez-Alvarez, Roberto,Sancho-Garcia, Juan Carlos,Di Meo, Florent,Suarez, Margarita,Martin, Nazario
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p. 2819 - 2826
(2013/06/27)
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- Potential of Azadirachta indica cell suspension culture to produce biologically active metabolites of dehydroepiandrosterone
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Dehydroepiandrosterone (1) was investigated for biotransformation studies using the plant cell suspension culture of Azadirachta indica A. Juss. for the first time, yielding metabolites 2-6: 5α,3,17-androstanedione (2), 5-androstene-3β,17β-diol (3), 3β-hydroxyandrostan-17-one (4), 3β,11α-dihydroxy-5-androsten-17-one (5), and 3β,7α- dihydroxy-5-androsten-17-one (6), whose structures were solved through modern spectroscopic methods. All five compounds 2-6 have not been reported obtained by this way before. This is a new method to biosynthesize compounds 2-6 employing cultured cells of A. indica. Metabolites 2, 3, and 6 are important biologically active compounds, whereas 4 is a precursor for the production of the 7-hydroxylated compound having antiglucocorticoid and neuroprotective effects.
- Saifullah,Khan, Saifullah,Azizuddin,Choudhary, Muhammad Iqbal
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p. 671 - 676
(2013/11/06)
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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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- The Cephalostatins. 22. Synthesis of bis-steroidal pyrazine pyrones
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Cephalostatin 1 (1), a remarkably strong cancer cell growth inhibitory trisdecacyclic, bis-steroidal pyrazine isolated from the marine tube worm Cephalodiscus gilchristi, continues to be an important target for practical total syntheses and a model for the discovery of less complex structural modifications with promising antineoplastic activity. In the present study, the cephalostatin E and F rings were greatly simplified by replacement at C-17 with an α-pyrone (in 12), typical of the steroidal bufodienolides, and by a dihydro-γ- pyrone (in 16). The synthesis of pyrazine 12 from 5α- dihydrotestosterone (nine steps, 8% overall yield) provided the first route to a bis-bufadienolide pyrazine. Dihydro-γ-pyrone 16 was synthesized in eight steps from ketone 13. While only insignificant cancer cell growth inhibitory activity was found for pyrones 12 and 16, the results provided further support for the necessity of more closely approximating the natural D-F ring system of cephalostatin 1 in order to obtain potent antineoplastic activity.
- Pettit, George R.,Moser, Bryan R.,Mendonca, Ricardo F.,Knight, John C.,Hogan, Fiona
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p. 1063 - 1069
(2012/10/29)
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- Synthesis and antituberculosis activity of several steroids from 3αacetoxy-5βpregn-16-En-20-one
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The semicarbazone and isonicotinoylhydrazone of 5βpregn-2-en-20-one, which was prepared from 3βacetoxy-5βpregn-16-en-20-one, were synthesized for the first time. The antituberculosis activity of these and semicarbazones and isonicotinoylhydrazones of saturated, unsaturated, and adamantane-modified ketosteroids synthesized by us earlier was studied in vitro experiments.
- Sikharulidze,Nadaraia,Kakhabrishvili
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p. 423 - 425
(2012/11/06)
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- MEDICINAL APPLICATIONS OF BENZOIC ACID HYDRAZONES SYNTHESIZED ON THE BASIS OF STEROIDAL TIGOGENIN
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Novel benzoic acid hydrazones of 5α-androstan-3,17-dione have been prepared on the basis of steroidal tigogenin of the plant Yucca gloriosa. The hydrazones of the General Formula (I), General Formula (II) and General Formula (III) as shown in the accompanying FIGURE of the drawing are synthesized. The hydrazones have shown promising anti-T.B., anti-cancer and anti-HIV activity revealing immense potential as more efficacious, less toxic drugs with fewer undesirable side effects. They could also prove valuable in correcting hormonal abnormalities that cause severe health problems.
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Page/Page column 2
(2011/08/04)
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- Hydroxylation of steroids by Fusarium oxysporum, Exophiala jeanselmei and Ceratocystis paradoxa
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The potential of Fusarium oxysporum var. cubense UAMH 9013 to perform steroid biotransformations was reinvestigated using single phase and pulse feed conditions. The following natural steroids served as substrates: dehydroepiandrosterone (1), pregnenolone (2), testosterone (3), progesterone (4), cortisone (5), prednisone (6), estrone (7) and sarsasapogenin (8). The results showed the possible presence of C-7 and C-15 hydroxylase enzymes. This hypothesis was explored using three synthetic androstanes: androstane-3,17-dione (9), androsta-4,6-diene-3,17-dione (10) and 3α,5α-cycloandrost-6- en-17-one (11). These fermentations of non-natural steroids showed that C-7 hydroxylation was as a result of that position being allylic. The evidence also pointed towards the presence of a C-15 hydroxylase enzyme. The eleven steroids were also fed to Exophiala jeanselmei var. lecanii-corni UAMH 8783. The results showed that the fungus appears to have very active 5α and 14α-hydroxylase enzymes, and is also capable of carrying out allylic oxidations. Ceratocystis paradoxa UAMH 8784 was grown in the presence of the above-mentioned steroids. The results showed that monooxygenases which effect allylic hydroxylation and Baeyer-Villiger rearrangement were active. However, redox reactions predominated.
- Peart, Patrice C.,McCook, Kayanne P.,Russell, Floyd A.,Reynolds, William F.,Reese, Paul B.
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experimental part
p. 1317 - 1330
(2011/11/06)
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- Cineole biodegradation: Molecular cloning, expression and characterisation of (1R)-6β-hydroxycineole dehydrogenase from Citrobacter braakii
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The first steps in the biodegradation of 1,8-cineole involve the introduction of an alcohol and its subsequent oxidation to a ketone. In Citrobacter braakii, cytochrome P450cin has previously been demonstrated to perform the first oxidation to produce (1R)-6β-hydroxycineole. In this study, we have cloned cinD from C. braakii and expressed the gene product, which displays significant homology to a number of short-chain alcohol dehydrogenases. It was demonstrated that the gene product of cinD exhibits (1R)-6β-hydroxycineole dehydrogenase activity, the second step in the degradation of 1,8-cineole. All four isomers of 6-hydroxycineole were examined but only (1R)-6β-hydroxycineole was converted to (1R)-6-ketocineole. The (1R)-6β-hydroxycineole dehydrogenase exhibited a strict requirement for NAD(H), with no reaction observed in the presence of NADP(H). The enzyme also catalyses the reverse reaction, reducing (1R)-6-ketocineole to (1R)-6β-hydroxycineole. During this study the N-terminal His-tag used to assist protein purification was found to interfere with NAD(H) binding and lower enzyme activity. This could be recovered by the addition of Ni2+ ions or proteolytic removal of the His-tag.
- Slessor, Kate E.,Stok, Jeanette E.,Cavaignac, Sonia M.,Hawkes, David B.,Ghasemi, Younes,De Voss, James J.
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experimental part
p. 81 - 86
(2010/05/17)
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- Platinum supported on TiO2 as a new selective catalyst on heterogeneous hydrogenation of α,β-unsaturated oxosteroids
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This paper describes the photochemical deposition of platinum onto TiO 2 surface and the full characterization of the catalysts using BET, XPS and TEM techniques. The 1 and 3 wt. % Pt/TiO2 catalysts reveal high activity with 70% and 96% of α-diastereoselectivity in the hydrogenation of the carbon-carbon double bond of the α,β-unsaturated oxosteroids 4-androstene-3,17-dione, and 3β-acetoxypregna-5,16-dien-20- one, respectively. Using higher temperature and pressure, the catalysts promote the further reduction of C-3 carbonyl group. Catalyst recovering and recycling is easily achieved with no appreciable lost of catalytic activity after five subsequent runs.
- Nunes, Rui M.D.,MacHado, Bruno F.,Pereira, Mariette M.,Moreno, Maria José S.M.,Faria, Joaquim L.
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experimental part
p. 1 - 5
(2011/02/24)
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- Biotransformation of testosterone and progesterone by Penicillium digitatum MRC 500787
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The biotransformation of testosterone and progesterone by Penicillium digitatum MRC 500787 for 5 days is described. The biotransformation of testosterone afforded 5α-androstane-3,17-dione, 3α-hydroxy-5α- androstan-17-one, 3β-liydroxy-5α-androstan-17-one and androst-4-ene-3,17-dione. The biotransformation of progesterone afforded 5α-pregnane- 3,20-dione.
- Yildirim, Kudret,Gulsan, Fatih,Kupcu, Ilknur
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experimental part
p. 675 - 683
(2011/08/03)
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- Significant steroids: Effective and general synthesis of 4α- and 4β-amino-5α-androstanes
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4α-Aminosteroids were synthesized by the substitution of a 2α-bromo ketone using K2CO3 as an activator; 4β-aminosteroids were synthesized in excellent yields by a highly regioselective and trans-stereospecific ring opening of a steroidal 3,4α-epoxide using ZnCl2-H2O as a catalyst. The Royal Society of Chemistry 2009.
- Ke, Xianbing,Hu, Hao,Zhang, Keda,Xu, Wenjin,Zhu, Qifeng,Wu, Lamei,Hu, Xianming
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supporting information; experimental part
p. 1037 - 1039
(2009/07/10)
-
- MEDICINAL APPLICATIONS OF BENZOIC ACID HYDRAZONES SYNTHESIZED ON THE BASIS OF STEROIDAL TIGOGENIN
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Novel benzoic acid hydrazones of 5α-androstan-3, 17-dione have been prepared on the basis of steroidal tigogenin of the plant Yucca gloriosa. The hvdrazones of the General Formula (I), General Formula (II) and General Formula (III) as shown in the accompanying Figure of the drawing are synthesized. The hydrazones have shown promising anti-T.B., anti-cancer and anti-HIV activity revealing immense potential as more efficacious, less toxic drugs with fewer undesirable side effects. They could also prove valuable in correcting hormonal abnormalities that cause severe health problems.
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Page/Page column 7
(2009/12/27)
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- Facile synthesis of steroidal vicinal hydroxysulfides via the reaction of steroidal epoxides with thiols in the presence of an ionic liquid
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Ring-opening of steroidal 2,3-epoxides with thiols can be carried out effectively in the Bronsted acidic ionic liquid [Hmim] +[BF4]- as a recyclable solvent and catalyst. The use of other ionic liquids/molten salts resulte
- Horvath, Anita,Frigyes, David,Maho, Sandor,Berente, Zoltan,Kollar, Laszlo,Skoda-Foeldes, Rita
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body text
p. 4037 - 4041
(2010/03/26)
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- 3,3-Diphenylpentane skeleton as a steroid skeleton substitute: Novel inhibitors of human 5α-reductase 1
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We designed and synthesized novel type 1 5α-reductase inhibitors by using 3,3-diphenylpentane skeleton as a substitute for the usual steroid skeleton. 4-(3-(4-(N-Methylacetamido)phenyl)pentan-3-yl)phenyl dibenzylcarbamate (11k) is a competitive 5α-reductase inhibitor with the IC50 value of 0.84 μM.
- Hosoda, Shinnosuke,Hashimoto, Yuichi
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p. 5414 - 5418
(2008/02/13)
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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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- Synthetic scope of alcohol transfer dehydrogenation catalyzed by Cu/Al 2O3: A new metallic catalyst with unusual selectivity
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A method for the anaerobic oxidation of a wide series of alcohols including cyclohexanols and steroidal alcohols, has been set up. It relies on a transfer dehydrogenation reaction from the substrate alcohol to styrene catalyzed by a heterogeneous, reusable copper catalyst under very mild liquid phase experimental conditions (90°C, N2) and shows unusual selectivity. Thus, the method is selective for the oxidation of secondary and allylic alcohols even in the presence of unprotected primary and benzylic alcohols. Electronic effects and the choice of the hydrogen acceptor account for the selectivity observed.
- Zaccheria, Federica,Ravasio, Nicoletta,Psaro, Rinaldo,Fusi, Achille
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p. 6426 - 6431
(2008/09/20)
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- Highly efficient chemoselective deprotection of O,O-acetals and O,O-ketals catalyzed by molecular iodine in acetone
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An extremely convenient method for deprotection of acetals and ketals catalyzed by molecular iodine (10 mol %) in acetone is reported. The protocol achieved the deprotection of acyclic or cyclic O,O-acetals and O,O-ketals in excellent yields within a few minutes under neutral conditions. The double bond, hydroxyl group, and acetate group remained unchanged, and the highly acid-sensitive furyl, tert-butyl ethers, and ketone-oxime stayed intact under these conditions.
- Sun, Jianwei,Dong, Yanmei,Cao, Liya,Wang, Xinyan,Wang, Shaozhong,Hu, Yuefei
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p. 8932 - 8934
(2007/10/03)
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- Investigation on the regioselectivities of intramolecular oxidation of unactivated C-H bonds by dioxiranes generated in Situ
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We found that dioxiranes generated in situ from ketones 1-6 and Oxone underwent intramolecular oxidation of unactivated C-H bonds at δ sites of ketones to yield tetrahydropyrans. From the trans/cis ratio of oxidation products 1a and 2a as well as the retention of the configuration at the δ site of ketone 5, we proposed that the oxidation reaction proceeds through a concerted pathway under a spiro transition state. The intramolecular oxidation of ketone 6 showed the preference for a tertiary δ C-H bond over a secondary one. This intramolecular oxidation method can be extended to the oxidation of the tertiary γ′ C-H bond of ketones 9 and 10. For ketone 11 with two δ C-H bonds and one γ′ C-H bond linked respectively by a sp3 hydrocarbon tether and a sp2 ester tether, the oxidation took place exclusively at the δ C-H bonds. Finally, by introducing proper tethers, regioselective hydroxylation of steroid ketones 12-14 have been achieved at the C-17, C-16, C-3, and C-5 positions.
- Wong, Man-Kin,Chung, Nga-Wai,He, Lan,Wang, Xue-Chao,Yan, Zheng,Tang, Yeung-Chiu,Yang, Dan
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p. 6321 - 6328
(2007/10/03)
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- N-tert-Butylbenzenesulfenamide-catalyzed oxidation of alcohols to the corresponding carbonyl compounds with N-chlorosuccinimide
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N-tert-Butylbenzenesulfenamide (1)-catalyzed oxidation of various primary and secondary alcohols to the corresponding aldehydes and ketones was efficiently carried out by using N-chlorosuccinimide (NCS) in the coexistence of potassium carbonate and molecular sieves 4? at easy-to-control temperatures ranging from 0°C to room temperature. The present catalytic oxidation was performed without giving any damage to the functional groups in alcohols, and was particularly effective in the oxidation of alcohols that formed labile aldehydes because of its mild reaction conditions. Further, selective oxidation of primary hydroxy groups took place in 1-catalyzed oxidation of several diols. Mechanistic investigation suggested that the chlorination of the sulfenamide 1 by NCS led to the formation of a key species, N-tert-butylbenzenesulfinimidoyl chloride (2), which in turn oxidized alcohols in the presence of potassium carbonate to afford carbonyl products by accompanying regeneration of the catalyst 1.
- Matsuo, Jun-Ichi,Iida, Daisuke,Yamanaka, Hiroyuki,Mukaiyama, Teruaki
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p. 6739 - 6750
(2007/10/03)
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