- Structural Basis for Featuring of Steroid Isomerase Activity in Alpha Class Glutathione Transferases
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Glutathione transferases (GSTs) are abundant enzymes catalyzing the conjugation of hydrophobic toxic substrates with glutathione. In addition to detoxication, human GST A3-3 displays prominent steroid double-bond isomerase activity; e.g. transforming Δ5-androstene-3-17-dione into Δ4-androstene-3-17-dione (AD). This chemical transformation is a crucial step in the biosynthesis of steroids, such as testosterone and progesterone. In contrast to GST A3-3, the homologous GST A2-2 does not show significant steroid isomerase activity. We have solved the 3D structures of human GSTs A2-2 and A3-3 in complex with AD. In the GST A3-3 crystal structure, AD was bound in an orientation suitable for the glutathione (GSH)-mediated catalysis to occur. In GST A2-2, however, AD was bound in a completely different orientation with its reactive double bond distant from the GSH-binding site. The structures illustrate how a few amino acid substitutions in the active site spectacularly alter the binding mode of the steroid substrate in relation to the conserved catalytic groups and an essentially fixed polypeptide chain conformation. Furthermore, AD did not bind to the GST A2-2-GSH complex. Altogether, these results provide a first-time structural insight into the steroid isomerase activity of any GST and explain the 5000-fold difference in catalytic efficiency between GSTs A2-2 and A3-3. More generally, the structures illustrate how dramatic diversification of functional properties can arise via minimal structural alterations. We suggest a novel structure-based mechanism of the steroid isomerization reaction.
- Tars, Kaspars,Olin, Birgit,Mannervik, Bengt
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- Acid- and Base-Catalyzed Isomerization of Androst-5-ene-3,17-dione and 17α-Ethynyl-17β-hydroxy-5-estren-3-one
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Isomerization of androst-5-ene-3,17-dione (1) to androst-4-ene-3,17-dione (2) and of 17α-ethynyl-17β-hydroxy-5-estren-3-one (3) to 17α-ethynyl-17β-hydroxy-4-estren-3-one (4) is kinetically general acid-base catalyzed; 1 is more reactive than 3.Deuterium solvent kinetic isotope effects, k(H2O)/k(D2O), of ca.6 for tertiary amine catalyzed isomerization indicate rate-determining protonation of dienolate ions.The greater reactivity of 1 than 3, catalyzed by tertiary amines, is probably due to a greater concentration of the 1 dienolate ion than of the 3 dienolate ion.Ethanolamine, but not tris(hydroxymethyl)aminomethane, catalyzes isomerization of 1 and 3 via Schiff-base formation.Curvilinear pseudo-first-order plots for isomerization of 1 and 3 catalyzed by DCl/D2O indicate that partitioning of dienols is kinetically important.
- Perera, S. K.,Dunn, W. A.,Fedor, L. R.
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- Determination of the Microscopic Rate Constants for the Base-Catalyzed Conjugation of 5-Androstene-3,17-dione
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The hydroxide ion catalyzed isomerization of 5-androstene-3,17-dione (1) to 4-androstene-3,17-dione (2) proceeds through the formation of an intermediate dienolate ion (1-1).This dienolate ion has been observed in the ultraviolet spectrum (λmax ca. 256 nm) during the isomerization reaction.Rate constants for the formation of the dienolate ion and both its reversion to reactant (1) and its conversion to product (2) in aqueous solution were measured.In addition, the rate of exchange of the C-6 protons of 2 in D2O/MeOD was determined.These results enable a complete description of the reaction profile to be made, including all rate constants and the pKa values for 1 (12.7) and 2 (16.1).The possible relevance of these results to the mechanism of action of the enzyme 3-oxo-Δ5-steroid isomerase is briefly discussed.
- Pollack, Ralph M.,Zeng, Baifei,Mack, Joseph P. G.,Eldin, Sherif
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- Activity and inhibition of 3-beta-hydroxysteroid dehydrogenase/delta-5-4-isomerase in human skin
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Activity and inhibition of 3β-hydroxysteroid dehydrogenase/Δ5-4-isomerase, a key enzyme of biosynthesis of androgenic steroids, in human skin were studied. Whole-width dermal tissue specimens excised from various regions of the male and female body were investigated with an in vitro radioenzyme assay method using dehydroepiandrosterone as substrate. The Michaelis-Menten constant of the enzyme was found to be K(m) = 10 nM and the maximal velocity was V(max) = 0.625 pmol produced 4-androstene-3,17-dione/mg protein/20 min. Activity of 3β-hydroxysteroid dehydrogenase/Δ5-4-isomerase in male inguinal skin (n = 8) was 0.132-0.412, in female abdominal skin (n = 4) 0.140-0.255, in perineal skin (n = 4) 0.138-0.962 pmol/mg protein/20 min. The synthetic steroids cyproterone acetate, 4-MA and epostane proved to be potent inhibitors, IC50 values were 150, 6.2 and 1.45 nM, respectively.
- Toth,Szecsi,Julesz,Faredin
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- REGIO- AND STEREOSELECTIVE 1,4-REDUCTIONS OF METHYLATED, CROSS-CONJUGATED STEROIDAL CYCLOHEXADIENONES
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Regio- and stereoselectivities in conjugate reductions of steroidal 3-oxo-1,4-diene substrates, effected either directly by Fe(CO)5-NaOH-H2O in methanol solution or in two steps by NaBH4 reduction/Jones oxidation, depend on the substitution pattern of ring A.C(1) and C(2) methylated derivatives furnish Δ1-products with 5β-stereochemistry, whereas C(4) methylated and unsubstituted steroids both afford Δ4-derivatives.
- Kuenzer, H.,Stahnke, M.,Sauer, G.,Wiechert, R.
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Read Online
- Synthesis of Visible-Light–Activated Hypervalent Iodine and Photo-oxidation under Visible Light Irradiation via a Direct S0→Tn Transition
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Heavy atom-containing molecules cause a photoreaction by a direct S0→Tn transition. Therefore, even in a hypervalent iodine compound with a benzene ring as the main skeleton, the photoreaction proceeds under 365–400nm wavelength light, where UV-visible spectra are not observed by usual measurement method. Some studies, however, report hypervalent iodine compounds that strongly absorb visible light. Herein, we report the synthesis of two visible light-absorbing hypervalent iodines and their photooxidation properties under visible light irradiation. We also demonstrated that the S0→Tn transition causes the photoreaction to proceed under wavelengths in the blue and green light region.
- Matsuda, Yu,Matsumoto, Koki,Nagasawa, Sho,Nakajima, Masaya,Nemoto, Tetsuhiro
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p. 235 - 239
(2022/03/16)
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- Synthesis of Cardiotonic Steroids Oleandrigenin and Rhodexin B
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This article describes a concise synthesis of cardiotonic steroids oleandrigenin (7) and its subsequent elaboration into the natural product rhodexin B (2) from the readily available intermediate (8) that could be derived from the commercially available steroids testosterone or DHEA via three-step sequences. These studies feature an expedient installation of the β16-oxidation based on β14-hydroxyl-directed epoxidation and subsequent epoxide rearrangement. The following singlet oxygen oxidation of the C17 furan moiety provides access to oleandrigenin (7) in 12 steps (LLS) and a 3.1% overall yield from 8. The synthetic oleandrigenin (7) was successfully glycosylated with l-rhamnopyranoside-based donor 28 using a Pd(II)-catalyst, and the subsequent deprotection under acidic conditions provided cytotoxic natural product rhodexin B (2) in a 66% yield (two steps).
- Fejedelem, Zachary,Carney, Nolan,Nagorny, Pavel
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p. 10249 - 10262
(2021/07/31)
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- Electrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen Steroids
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The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto derivative. Conventional chemical reagents pose significant drawbacks for this synthetic strategy, as large amounts of waste are generated, and quenching of the reaction mixture and purification of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochemical strategies for the preparation of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidation has been developed, enabling several one-pot, multistep procedures for the synthesis of androgen steroids. In addition, simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of saturated androgens.
- Sommer, Florian,Kappe, C. Oliver,Cantillo, David
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supporting information
p. 6044 - 6049
(2021/03/15)
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- Platinum-Catalyzed α,β-Desaturation of Cyclic Ketones through Direct Metal–Enolate Formation
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The development of a platinum-catalyzed desaturation of cyclic ketones to their conjugated α,β-unsaturated counterparts is reported in this full article. A unique diene-platinum complex was identified to be an efficient catalyst, which enables direct metal-enolate formation. The reaction operates under mild conditions without using strong bases or acids. Good to excellent yields can be achieved for diverse and complex scaffolds. A wide range of functional groups, including those sensitive to acids, bases/nucleophiles, or palladium species, are tolerated, which represents a distinct feature from other known desaturation methods. Mechanistically, this platinum catalysis exhibits a fast and reversible α-deprotonation followed by a rate-determining β-hydrogen elimination process, which is different from the prior Pd-catalyzed desaturation method. Promising preliminary enantioselective desaturation using a chiral-diene-platinum complex has also been obtained.
- Chen, Ming,Dong, Guangbin
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supporting information
p. 7956 - 7961
(2021/03/01)
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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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- STEROID DERIVATIVE REGULATORS, METHOD FOR PREPARING THE SAME, AND USES THEREOF
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The present invention relates to steroid derivative regulators, a method for preparing the same, and uses thereof. Specifically, the present invention relates to a compound as shown in formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and uses thereof as a regulator of GABA A receptor for treating depression, convulsion, Parkinson's disease, and nervous system diseases, wherein the substituents of the formula (I) are as defined in the description.
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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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- Redetermination of the Structure of a Water-Soluble Hypervalent Iodine(V) Reagent AIBX and Its Synthetic Utility in the Oxidation of Alcohols and Synthesis of Isoxazoline N-Oxides
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The structure of a water-soluble hypervalent iodine(V) reagent AIBX is re-examined through its single-crystal X-ray analysis and theoretical calculations including Mayer bond order and localized orbital locator (LOL) and AIBX is believed to be a pseudocyclic iodylarene because of the strong electron-withdrawing nature of the trimethylammonium cation on its phenyl ring, which would decrease the electron density of carboxylic anion and make the ortho-carboxyl oxygen anion incapable to form hypervalent bond with iodine atom. However, the cyclic benziodoxole structure of AIBX could be obtained by adding a Br?nsted acid, which was supported by the calculation result including the increase of Mayer bond order and the shortening of the I-O bond length. Moreover, the fact that the system of AIBX and TFA could oxidize various alcohols to their corresponding carbonyl compounds would indicate that AIBX constitutes a cyclic benziodoxole structure under acidic conditions. In addition, an efficient method has been developed for the synthesis of isoxazoline N-oxides via AIBX-induced dehydrogenative cyclization using β-keto esters as substrates and methyl nitroacetate as a nucleophile.
- Shen, Hui-Jie,Duan, Ya-Nan,Zheng, Ke,Zhang, Chi
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p. 14381 - 14393
(2019/11/13)
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- Method for preparing 4-androstenedione from dehydroepiandrosterone acetate
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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.
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Paragraph 0026; 0029; 0030; 0032; 0035-0036; 0038; 0041-0042
(2019/07/04)
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- Dehydroepiandrosterone intermediate mother liquid recycling and use method
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The invention discloses a dehydroepiandrosterone intermediate mother liquid recycling and use method. According to the method, 4-AD is adopted as a raw material, a 5-AD intermediate mother liquid which is used in a process that DHEA (dehydroepiandrosterone) is synthesized through transposition and enzyme catalysis is subjected to alkali treatment, decoloring, purification and recycling to obtain 4-AD, and thus recycling and use of a 5-AD intermediate mother liquid are achieved. By adopting the method disclosed by the invention, 5-AD is recycled, so that the utilization rate of materials is increased, the purity of the obtained 4-AD is greater than or equal to 99%, the 4-AD can be reused to synthesize a steroid medicine, waste can be reduced, the cost can be reduced, and meanwhile, environment pollution can be reduced.
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Paragraph 0011-0012
(2020/01/03)
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- Synthesis of 3β-methyl ether of dehydroepiandrosterone by biotransformation of 3β-methyl ether of cholesterol with cells of mycobacteria Mycobacterium sp.
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3p-Methyl ether of dehydroepiandrosterone was obtained by microbiological transformation of 3?-methyl ether of cholesterol with Mycobacterium sp. Androstane-3,17-dione, androst-4-ene-3,17-dione, and androsta-1,4-diene-3,17-dione were minor transformation products.
- Andryushina,Stytsenko,Karpova,Yaderets,Zavarzin,Kurilov
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p. 2355 - 2358
(2020/02/18)
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- METHOD OF PRODUCING ORGANIC COMPOUND
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A method of producing an organic compound, which contains a step of performing a deodorization step using a flow reaction in a flow passage to remove, from a reaction liquid, a malodorous material generated or remaining in a reaction step, wherein the organic compound is an industrially useful compound.
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Paragraph 0232; 0238; 0243; 0245; 0247; 0253; 0256-0259
(2018/09/16)
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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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- Inherent steroid 17α,20-lyase activity in defunct cytochrome P450 17A enzymes
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Cytochrome P450 (P450) 17A1 catalyzes the oxidations of progesterone and pregnenolone and is the major source of androgens. The enzyme catalyzes both 17α-hydroxylation and a subsequent 17α,20-lyase reaction, and several mechanisms have been proposed for the latter step. Zebrafish P450 17A2 catalyzes only the 17α-hydroxylations. We previously reported high similarity of the crystal structures of zebrafish P450 17A1 and 17A2 and human P450 17A1. Five residues near the heme, which differed, were changed. We also crystallized this five-residue zebrafish P450 17A1 mutant, and the active site still resembled the structure in the other proteins, with some important differences. These P450 17A1 and 17A2 mutants had catalytic profiles more similar to each other than did the wildtype proteins. Docking with these structures can explain several minor products, which require multiple enzyme conformations. The 17α-hydroperoxy (OOH) derivatives of the steroids were used as oxygen surrogates. Human P450 17A1 and zebrafish P450s 17A1 and P450 17A2 readily converted these to the lyase products in the absence of other proteins or cofactors (with catalytically competent kinetics) plus hydroxylated 17α-hydroxysteroids. The 17α-OOH results indicate that a "Compound I" (FeO3+) intermediate is capable of formation and can be used to rationalize the products. We conclude that zebrafish P450 17A2 is capable of lyase activity with the 17α-OOH steroids because it can achieve an appropriate conformation for lyase catalysis in this system that is precluded in the conventional reaction.
- Gonzalez, Eric,Johnson, Kevin M.,Pallan, Pradeep S.,Phan, Thanh T.N.,Zhang, Wei,Lei, Li,Wawrzak, Zdzislaw,Yoshimoto, Francis K.,Egli, Martin,Peter Guengerich
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p. 541 - 556
(2018/02/14)
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- New product identification in the sterol metabolism by an industrial strain Mycobacterium neoaurum NRRL B-3805
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Mycobacterium neoaurum NRRL B-3805 metabolizes sterols to produce androst-4-en-3,17-dione (AD) as the main product, and androsta-1,4-dien-3,17-dione, 9α-hydroxy androst-4-en-3,17-dione and 22-hydroxy-23,24-bisnorchol-4-en-3-one have been identified as by-products. In this study, a new by-product was isolated from the metabolites of sterols and identified as methyl 3-oxo-23,24-bisnorchol-4-en-22-oate (BNC methyl ester), which was proposed to be produced via the esterification of BNC catalyzed by an O-methyltransferase using S-adenosyl-L-methionine as the methyl group donor. These results might open a new dimension for improvement of the efficiency of microbial AD production by eliminating this by-product via genetic manipulation of the strain.
- Li, Xuemei,Chen, Xi,Wang, Yu,Yao, Peiyuan,Zhang, Rui,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming,Ma, Yanhe
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supporting information
p. 40 - 45
(2018/02/21)
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- Biotransformation of testosterone by Ulocladium chartarum MRC 72584
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The incubation of testosterone 1 with Ulocladium chartarum MRC 72584 has been reported. U. chartarum MRC 72584 hydroxylated testosterone 1 at C-7β, C-6β, C-14α and C-12β, accompanied by a 5α-reduction and oxidations at C-6 and at C-17.
- Yildirim, Kudret,Kuru, Ali,Y?lmaz, ?engül
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p. 444 - 446
(2018/09/12)
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- Aliphatic C?C Bond Cleavage in α-Hydroxy Ketones by a Dioxygen-Derived Nucleophilic Iron–Oxygen Oxidant
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A nucleophilic iron–oxygen oxidant, formed in situ in the reaction between an iron(II)–benzilate complex and O2, oxidatively cleaves the aliphatic C?C bonds of α-hydroxy ketones. In the cleavage reaction, α-hydroxy ketones without any α-C?H bond afford a 1:1 mixture of carboxylic acid and ketone. Isotope labeling studies established that one of the oxygen atoms from dioxygen is incorporated into the carboxylic acid product. Furthermore, the iron(II) complex cleaves an aliphatic C?C bond of 17-α-hydroxyprogesterone affording androstenedione and acetic acid. The O2-dependent aliphatic C?C bond cleavage of α-hydroxy ketones containing no α-C?H bond bears similarity to the lyase activity of the heme enzyme, cytochrome P450 17A1 (CYP17A1).
- Bhattacharya, Shrabanti,Rahaman, Rubina,Chatterjee, Sayanti,Paine, Tapan K.
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supporting information
p. 3815 - 3818
(2017/03/27)
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- Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors
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In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-d-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [3H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p 50 being 15.6 nM as compared to clinically used drug finasteride (40 nM). There was also a significant inhibition of 5AR-1 with IC50 547 nM compared to finasteride (453 nM).
- Aggarwal, Saurabh,Mahapatra, Manoj Kumar,Kumar, Rajnish,Bhardwaj, Tilak R.,Hartmann, Rolf W.,Haupenthal, J?rg,Kumar, Manoj
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p. 779 - 788
(2016/02/09)
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- Biotransformation of dehydro-epi-androsterone by Aspergillus parasiticus: Metabolic evidences of BVMO activity
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The research on the synthesis of steroids and its derivatives is of high interest due to their clinical applications. A particular focus is given to molecules bearing a D-ring lactone like testolactone because of its bioactivity. The Aspergillus genus has been used to perform steroid biotransformations since it offers a toolbox of redox enzymes. In this work, the use of growing cells of Aspergillus parasiticus to study the bioconversion of dehydro-epi-androsterone (DHEA) is described, emphasizing the metabolic steps leading to D-ring lactonization products. It was observed that A. parasiticus is not only capable of transforming bicyclo[3.2.0]hept-2-en-6-one, the standard Baeyer-Villiger monooxygenase (BVMO) substrate, but also yielded testololactone and the homo-lactone 3β-hydroxy-17a-oxa-d-homoandrost-5-en-17-one from DHEA. Moreover, the biocatalyst degraded the lateral chain of cortisone by an oxidative route suggesting the action of a BVMO, thus providing enough metabolic evidences denoting the presence of BVMO activity in A. parasiticus. Furthermore, since excellent biotransformation rates were observed, A. parasiticus is a promising candidate for the production of bioactive lactone-based compounds of steroidal origin in larger scales.
- Mascotti, M. Laura,Palazzolo, Martín A.,Bisogno, Fabricio R.,Kurina-Sanz, Marcela
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- A method for processing of dehydrocostuslactone mother liquor epandrosterone
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The invention discloses a method for processing dehydroepiandrosterone mother liquor objects. DHEA, 3alpha-hydroxide radical-5-androstene-17-ketone and 3, 17-diketal objects can be obtained through column chromatography isolation; then the obtained 3alpha-hydroxide radical-5-androstene-17-ketone and the obtained 3, 17-diketal objects synthesize a starting material 4-AD. By means of the method, the purity of the dehydroepiandrosterone (DHEA) obtained through the column chromatography isolation is larger than or equal to 99.5%, and the DHEA total yield is larger than or equal to 75%; materials obtained through the column chromatography isolation can synthesize the 4-AD, reusing can be carried out, and the using rate is high; pollution of hormone waste to the environment is reduced.
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Paragraph 0033
(2017/02/24)
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- A by the 3,17-dione steroid preparing steroid the synthetic method of the compound of
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The invention discloses a synthetic method of steroid type drugs and intermediates, in particular relates to a synthetic method for preparing 17-hydroxy-20-ketone steroid compounds from 3,17-diketone steroids, and belongs to the field of synthesis of drugs. The method takes 3,17-diketone steroids as raw materials and adopts a conventional, environment-friendly, low-toxicity reagent, and the steroid type drugs such as cortisone, hydrocortisone, metacortandracin, or hydroprednisone, or intermediates 17alpha-hydroxy-20-ketone compounds are prepared simply and conveniently at high yield by selective protection of C3 or (and) C11-ketone group, Wittig reaction of C17, selective oxidization of 17(20)-position double bonds and halogenating replacement. The aftertreatment is simple, few three wastes are generated, the reaction selectivity is good, the yield is high, and byproducts anti-pregnancy steroidal drugs and steroidal compounds can be obtained. The raw materials are easy to get, the cost is low and the synthetic process is simple; the synthetic method is suitable for industrial production.
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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 0068
(2016/10/09)
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- A convenient alternative for the selective oxidation of alcohols by silica supported TEMPO using dioxygen as the final oxidant
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Various primary and secondary alcohols were selectively oxidized to the corresponding aldehydes and ketones using silica supported TEMPO as a heterogeneous catalyst and nitrosonium tetrafluoroborate as a cocatalyst. No over-oxidation of aldehydes to acids, nitration processes or oxidation of double bonds was observed. The reported procedure is very convenient, and uses mild experimental conditions (room temperature and dioxygen as the terminal oxidant). Furthermore, the reactions proceeded cleanly and the isolation of the desired compounds required minimal work-up. A mechanistic pathway has been proposed, in which nitrogen oxides and oxoammonium ions act as an electron transfer double bridge.
- Shakir, Ahmed Juwad,Paraschivescu, Codruta,Matache, Mihaela,Tudose, Madalina,Mischie, Alice,Spafiu, Felicia,Ionita, Petre
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supporting information
p. 6878 - 6881
(2015/11/27)
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- Aldo-keto Reductase 1B15 (AKR1B15): A mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates
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Alto-keto reductases (AKRs) comprise a superfamily of proteins involved in the reduction and oxidation of biogenic and xenobiotic carbonyls. In humans, at least 15 AKR superfamily members have been identified so far. One of these is a newly identified gene locus, AKR1B15, which clusters on chromosome 7 with the other human AKR1B subfamily members (i.e. AKR1B1 and AKR1B10). We show that alternative splicing of the AKR1B15 gene transcript gives rise to two protein isoforms with different N termini: AKR1B15.1 is a 316-amino acid protein with 91% amino acid identity to AKR1B10; AKR1B15.2 has a prolonged N terminus and consists of 344 amino acid residues. The two gene products differ in their expression level, subcellular localization, and activity. In contrast with other AKR enzymes, which are mostly cytosolic, AKR1B15.1 co-localizes with the mitochondria. Kinetic studies show that AKR1B15.1 is predominantly a reductive enzyme that catalyzes the reduction of androgens and estrogens with high positional selectivity (17β-hydroxysteroid dehydrogenase activity) as well as 3-ketoacyl-CoA conjugates and exhibits strong cofactor selectivity toward NADP(H). In accordance with its substrate spectrum, the enzyme is expressed at the highest levels in steroid-sensitive tissues, namely placenta, testis, and adipose tissue. Placental and adipose expression could be reproduced in the BeWo and SGBS cell lines, respectively. In contrast, AKR1B15.2 localizes to the cytosol and displays no enzymatic activity with the substrates tested. Collectively, these results demonstrate the existence of a novel catalytically active AKR, which is associated with mitochondria and expressed mainly in steroid-sensitive tissues.
- Weber, Susanne,Salabei, Joshua K.,M?ller, Gabriele,Kremmer, Elisabeth,Bhatnagar, Aruni,Adamski, Jerzy,Barski, Oleg A.
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p. 6531 - 6545
(2015/03/30)
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- 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)
-
- Biotransformation of testosterone and testosterone heptanoate by four filamentous fungi
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The microbial transformations of testosterone and testosterone heptanoate by four fungi: Absidia griseolla var. igachii PTCC 5260, Acremonium chrysogenu PTCC 5271, Fusarium fujikuroi PTCC 5144, and Fusarium solani complex PTCC 5285 were investigated for the first time. Incubation of testosterone heptanoate with F. fujikuroi and F. solani yielded three metabolites, which were isolated and characterized as testosterone, androst-4-ene-3,17-dione, and 6β-hydroxy testosterone. 6β-Hydroxy testosterone was the major metabolite obtained from testosterone heptanoate biotransformation by two fungal species. A. griseolla and A. chrysogenu produced 14α-hydroxy testosterone as major metabolite, together with testosterone and 6β-hydroxy testosterone in lower yields. The biotransformation of testosterone by F. fujikuroi and A. griseolla was also investigated in order to examine the influence of the ester group on the course of transformation. Androst-4-ene-3,17-dione was only identified in the biotransformation of testosterone by F. fujikuroi. The same product was observed in incubation of testosterone by A. griseolla, together with 14α-hydroxy testosterone in very low yield. Furthermore, time course study was also carried out in order to examine the formation of metabolites as a function of time, which was determined by HPLC. The structures of compounds were determined by their comprehensive spectroscopic analysis and comparison with literature data.
- Ghasemi, Sabrieh,Mohajeri, Maryam,Habibi, Zohreh
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supporting information
p. 7 - 12
(2014/12/11)
-
- Imitation of phase i oxidative metabolism of anabolic steroids by titanium dioxide photocatalysis
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The aim of this study was to investigate the feasibility of titanium dioxide (TiO2) photocatalysis for oxidation of anabolic steroids and for imitation of their phase I metabolism. The photocatalytic reaction products of five anabolic steroids were compared to their phase I in vitro metabolites produced by human liver microsomes (HLM). The same main reaction types - hydroxylation, dehydrogenation and combination of these two - were observed both in TiO2 photocatalysis and in microsomal incubations. Several isomers of each product type were formed in both systems. Based on the same mass, retention time and similarity of the product ion spectra, many of the products observed in HLM reactions were also formed in TiO2 photocatalytic reactions. However, products characteristic to only either one of the systems were also formed. In conclusion, TiO2 photocatalysis is a rapid, simple and inexpensive method for imitation of phase I metabolism of anabolic steroids and production of metabolite standards.
- Ruokolainen, Miina,Valkonen, Minna,Sikanen, Tiina,Kotiaho, Tapio,Kostiainen, Risto
-
-
- Regioselective dehydrogenation of 3-keto-steroids to form conjugated enones using o-iodoxybenzoic acid and trifluoroacetic acid catalysis
-
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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-
- Biotransformations of steroids to testololactone by a multifunctional strain Penicillium simplicissimum WY134-2
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The biotransformations of a range of steroidal compounds, including 17α-hydroxy progesterone, progesterone, testosterone, androst-4-ene-3,17- dione (AD), pregnenolone, and dehydroepiandrosterone (DHEA), by Penicillium simplicissimum WY134-2 have been investigated. In all the cases, testolic acid and testololactone were detected, and the acid was converted to the lactone when pH was adjusted to 1, leading to isolation of testololactone in 25%-96% yields. Especially for progesterone and testosterone, the isolated yields were 93% and 96% with substrate concentration being 3 g/L, suggesting that P. simplicissimum WY134-2 may be used for the synthesis of testololactone. The results revealed the multi-functional catalytic activity of P. simplicissimum WY134-2 toward steroids for the first time. The possible reaction pathways of steroids promoted by this strain were discussed.
- Yang, Beibei,Wang, Yu,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming,Ma, Yanhe
-
-
- Synthesis and bioconversions of formestane
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In an effort to generate new steroidal aromatase inhibitors, formestane (4-hydroxyandrost-4-ene-3,17-dione) (1) was biotransformed by Rhizopus oryzae to yield the known 4β,5α-dihydroxyandrostane-3,17-dione as the major product (5) and bioconverted by Beauveria bassiana to afford the known reduced 4,17β-dihydroxyandrost-4-en-3-one (6) and 3α,17β-dihydroxy- 5β-androstan-4-one (7) and the new 4,11α,17β-trihydroxyandrost- 4-en-3-one (8). All the metabolites showed more potent activities than their parent congener in the aromatase and MCF-7 breast cancer assays. The bioactivities and structural elucidation of these metabolites as well as the semisynthesis of formestane (1) from testosterone (2) are reported herein.
- Martin, Glenroy D. A.,Narvaez, Javier,Marti, Anne
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p. 1966 - 1969
(2013/11/19)
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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
-
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)
-
- Increased yield of biotransformation of exemestane with β-cyclodextrin complexation technique
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In this study, 6-methylenandrosta-4-ene-3,17-dione and Hydroxypropyl- β-cyclodextrin (HP-β-CD) were used to form a complex, which could be then biotransformed by Arthrobacter simplex ATCC6946 to obtain the antitumor drug exemestane. The complex was analyzed by UV, DSC and TG techniques, while the products were analyzed by HPLC, NMR and MS. These results confirmed that the β-cyclodextrin not only improved the water-solubility of 6-methylenandrosta-4-ene-3,17-dione, but also greatly enhanced the biocompatibility during the biotransformation process. This result may be applied to other precursors which have poor aqueous solubility in the biotransformation processes.
- Li, Guang,Li, Fushuang,Deng, Le,Fang, Xiaolan,Zou, Hui,Xu, Kangpin,Li, Tian,Tan, Guishan
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p. 1148 - 1151
(2013/10/08)
-
- 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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- Cloning, characterization, and expression analysis of a putative 17 beta-hydroxysteroid dehydrogenase 11 in the abalone, Haliotis diversicolor supertexta
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The 17-beta-hydroxysteroid dehydrogenases (17β-HSDs) are key enzymes for sex steroid biosynthesis. To date, relatively little is known about the presence and function of 17β-HSDs in marine gastropods. In the present study, a cDNA sequence encoding putative 17β-HSD type 11 (17β-HSD-11) was identified in marine abalone (Haliotis diversicolor supertexta). The full-length cDNA contains 1058 bp, including an open reading frame (ORF) of 900 bp that encodes a protein of 299 amino acids. Comparative structural analysis revealed that abalone 17β-HSD-11 shares relatively high homology with other 17b-HSD-11 hormologues, and a lesser degree of amino acid identity with other forms of 17b-HSD, especially in the functional domains, including the cofactor binding domain (TGxxxGxG) and catalytic site (YxxSK). Phylogenetic analysis showed that abalone 17β-HSD-11 belongs to the short-chain dehydrogenase/reductase (SDR) family. Functional analysis following transient transfection of the ORF into human embryonic kidney-293 (HEK-293) cells indicated that abalone 17β-HSD-11 has the ability to convert 5α-androstane-3α,17β-diol (3α-diol) to androsterone (A) and testosterone (T) to androstenedione (4A). Expression analysis in vivo demonstrated that abalone 17β-HSD-11 is differentially expressed during three stages (non-reproductive, reproductive, and post-reproductive). Taken together, these results indicate that ab-17β-HSD-11 is an SDR family member with a potential role in steroid regulation during the reproductive stage.
- Zhai, Hong-Ning,Zhou, Jin,Cai, Zhong-Hua
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experimental part
p. 57 - 63
(2012/08/27)
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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)
-
- New structure-activity relationships of A-and D-ring modified steroidal aromatase inhibitors: Design, synthesis, and biochemical evaluation
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A- and D-ring androstenedione derivatives were synthesized and tested for their abilities to inhibit aromatase. In one series, C-3 hydroxyl derivatives were studied leading to a very active compound, when the C-3 hydroxyl group assumes 3β stereochemistry (1, IC50 = 0.18 μM). In a second series, the influence of double bonds or epoxide functions in different positions along the A-ring was studied. Among epoxides, the 3,4-epoxide 15 showed the best activity (IC50 = 0.145 μM) revealing the possibility of the 3,4-oxiran oxygen resembling the C-3 carbonyl group of androstenedione. Among olefins, the 4,5-olefin 12 (IC50 = 0.135 μM) revealed the best activity, pointing out the importance of planarity in the A,B-ring junction near C-5. C-4 acetoxy and acetylsalicyloxy derivatives were also studied showing that bulky substituents in C-4 diminish the activity. In addition, IFD simulations helped to explain the recognition of the C-3 hydroxyl derivatives (1 and 2) as well as 15 within the enzyme.
- Varela, Carla,Tavares Da Silva, Elisiário J.,Amaral, Cristina,Correia Da Silva, Georgina,Baptista, Teresa,Alcaro, Stefano,Costa, Giosuè,Carvalho, Rui A.,Teixeira, Natércia A. A.,Roleira, Fernanda M. F.
-
scheme or table
p. 3992 - 4002
(2012/07/30)
-
- 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)
-
- METHODS FOR PREPARING SYNTHETIC BILE ACIDS AND COMPOSITIONS COMPRISING THE SAME
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This invention relates generally to methods for preparing certain bile acids from non-mammalian sourced starting materials as well as to synthetic bile acids and compositions comprising such acids wherein the acids are characterized by a different C14 population than naturally occurring bile acids as well as being free from any mammalian pathogens. This invention is also directed to the synthesis of intermediates useful in the synthesis of such bile acids. Accordingly, the C ring of the steroidal scaffold is oxidized to provide a synthetic route and intermediates to DCA. This invention also provides synthetic methods for preparing deoxycholic acid or a salt thereof starting from aromatic steroids such as estrogen, equilenin, and derivatives thereof. This invention is also directed to intermediates such as 12-oxo or delta-9,11-ene steroids as well as novel processes for their preparation. In preferred embodiments, bile acids are provided herein which have substituents on the B-ring and/or D-ring side chain and optionally on the hydroxy group of the A-ring.
- -
-
-
- Structure and catalytic mechanism of 3-ketosteroid-Δ4-(5α)- dehydrogenase from Rhodococcus jostii RHA1 genome
-
3-Ketosteroid Δ4-(5α)-dehydrogenases (Δ4-(5α)- KSTDs) are enzymes that introduce a double bond between the C4 and C5 atoms of 3-keto-(5α)-steroids. Here we show that the ro05698 gene from Rhodococcus jostii RHA1 codes for a flavoprotein with Δ4-(5α)-KSTD activity. The 1.6 A resolution crystal structure of the enzyme revealed three conserved residues (Tyr-319, Tyr-466, and Ser-468) in a pocket near the isoalloxazine ring system of the FAD co-factor. Site-directed mutagenesis of these residues confirmed that they are absolutely essential for catalytic activity. A crystal structure with bound product 4-androstene-3,17-dione showed that Ser-468 is in a position in which it can serve as the base abstracting the 4β-proton from the C4 atom of the substrate. Ser-468 is assisted by Tyr-319, which possibly is involved in shuttling the proton to the solvent. Tyr-466 is at hydrogen bonding distance to the C3 oxygen atom of the substrate and can stabilize the keto-enol intermediate occurring during the reaction. Finally, the FAD N5 atom is in a position to be able to abstract the 5α-hydrogen of the substrate as a hydride ion. These features fully explain the reaction catalyzed by Δ4-(5α)-KSTDs.
- Van Oosterwijk, Niels,Dijkstra, Bauke W.,Knol, Jan,Dijkhuizen, Lubbert,Van Der Geize, Robert
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p. 30975 - 30983,9
(2020/08/31)
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- COMPOUNDS AND METHODS FOR TREATING NEOPLASIA
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The invention features compounds, pharmaceutical compositions and methods useful for the treatment of neoplasia. In particular embodiments, the compounds of the invention are useful for the treatment of multidrug resistant neoplasia.
- -
-
Page/Page column 104-105
(2011/04/18)
-
- METHOD FOR CARRYING OUT OXIDATION REACTIONS USING INDUCTIVELY HEATED HEATING MEDIUM
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The invention relates to a method for carrying out an oxidation reaction for producing a product by heating a reaction medium containing a reactant and oxygen or an oxygen carrier in a reactor, wherein the reaction medium is brought into contact with a solid heating medium which may be heated by electromagnetic induction, which is surrounded by the reaction medium. The heating medium is heated by electromagnetic induction using an inductor, wherein an oxidation reaction is carried out on the first reactant to give a product and the product is separated from the heating medium. The inductor preferably generates an alternating field with a frequency in the range 1 to 100 kHz, preferably in the range 10 to 80 kHz and in particular up to 50 kHz.
- -
-
Page/Page column 6-7
(2011/12/14)
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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)
-
- Baeyer-villiger oxidation of some steroids by Aspergillus tamarii MRC 72400
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Biotransformations of epiandrosterone (1), dehydroepiandrosterone (2), testosterone (3), progesterone (4) and pregnenolone (5) by Aspergillus tamarii MRC 72400 for 5 days have been reported and the results of these incubations have been compared with previously published data obtained with Aspergillus tamarii QM 1223. A. tamarii MRC 72400 showed higher Bayer-Villiger monooxygenase activities than A. tamarii QM 1223 did. Apart from pregnenolone (5), A. tamarii MRC 72400 metabolized these steroids in different ways. Incubation of epiandrosterone (1) afforded 3β,11β-dihydroxy-5α-androstan-17- one (6) (3%) and 3β-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (7) (9.5%). Incubation of dehydroepiandrosterone (2) afforded 3β-hydroxy-17a- oxa-D-homoandrost-5-en-17-one (8) (28%), testolactone (9) (6%), 3β,7β-dihydroxyandrost-5-en-17-one (10) (13%) and 3β,7α- dihydroxyandrost- 5-en-17-one (11) (24%). Incubation of testosterone (3) afforded testolactone (9) (58%). Incubation of progesterone (4) also afforded testolactone (9), however in higher yield (86%). Incubation of pregnenolone (5) afforded 3β-hydroxy-17a-oxa-D-homoandrost- 5-en-17-one (8) (25%) and testolactone (9) (27%).
- Yildirim, Kudret,Uzuner, Ahmet,Gulcuoglu, Emine Yasemin
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scheme or table
p. 743 - 754
(2011/12/03)
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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
-
experimental part
p. 3474 - 3481
(2011/05/02)
-
- Inductively heated oxides inside microreactors - Facile oxidations under flow conditions
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Inductively heated iron oxides mixed with solid oxidants like CrO 2 and NiO2 efficiently oxidize organic substrates under flow conditions in fixed-bed reactors.
- Wegner, Jens,Ceylan, Sascha,Friese, Carsten,Kirschning, Andreas
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scheme or table
p. 4372 - 4375
(2010/09/20)
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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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- Contribution of arginine 13 to the catalytic activity of human class Pi glutathione transferase P1-1
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Arg13 is a conserved active-site residue in all known Pi class glutathione S-transferases (GSTs) and in most Alpha class GSTs. To evaluate its contribution to substrate binding and catalysis of this residue, three mutants (R13A, R13K, and R13L) were expressed in Escherichia coli and purified by GSH affinity chromatography. The substitutions of Arg13 significantly affected GSH-conjugation activity, while scarcely affecting glutathione peroxidase or steroid isomerase activities. Mutation of Arg13 into Ala largely reduced the GSH-conjugation activity by approximately 85-95%, whereas substitutions by Lys and Leu barely affected activity. These results suggest that, in the GSH-conjugation activity of hGST P1-1, the contribution of Arg13 toward catalytic activity is highly dependent on substrate specificities and the size of the side chain at position 13. From the kinetic parameters, introduction of larger side chains at position 13 results in stronger affinity (Leu > Lys, Arg > Ala) towards GSH. The substitutions of Arg13 with alanine and leucine significantly affected kcat, whereas substitution with Lys was similar to that of the wild type, indicating the significance of a positively charged residue at position 13. From the plots of log (kCat/K mCDNB) against pH, the pKa values of the thiol group of GSH bound in R13A, R13K, and R13L were estimated to be 1.8, 1.4, and 1.8 pK units higher than the pKa value of the wildtype enzyme, demonstrating the contribution of the Arg13 guanidinium group to the electrostatic field in the active site. From these results, we suggest that contribution of Arg13 in substrate binding is highly dependent on the nature of the electrophilic substrates, while in the catalytic mechanism, it stabilizes the GSH thiolate through hydrogen bonding.
- Kong, Ji-Na,Jo, Dong-Hyeon,Do, Hyun-Dong,Lee, Jin-Ju,Kong, Kwang-Hoon
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body text
p. 2497 - 2502
(2011/01/12)
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- The functions of key residues in the inhibitor, substrate and cofactor sites of human 3β-hydroxysteroid dehydrogenase type 1 are validated by mutagenesis
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In postmenopausal women, human 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1) is a critical enzyme in the conversion of DHEA to estradiol in breast tumors, while 3β-HSD2 participates in the production of cortisol and aldosterone in the human adrenal gland. The goals of this project are to determine if Arg195 in 3β-HSD1 vs. Pro195 in 3β-HSD2 in the substrate/inhibitor binding site is a critical structural difference responsible for the higher affinity of 3β-HSD1 for inhibitor and substrate steroids compared to 3β-HSD2 and whether Asp61, Glu192 and Thr8 are fingerprint residues for cofactor and substrate binding using site-directed mutagenesis. The R195P-1 mutant of 3β-HSD1 and the P195R-2 mutant of 3β-HSD2 have been created, expressed, purified and characterized kinetically. Dixon analyses of the inhibition of the R195P-1 mutant, P195R-2 mutant, wild-type 3β-HSD1 and wild-type 3β-HSD2 by trilostane has produced kinetic profiles that show inhibition of 3β-HSD1 by trilostane (Ki=0.10μM, competitive) with a 16-fold lower Ki and different mode than measured for 3β-HSD2 (Ki=1.60μM, noncompetitive). The R195P-1 mutation shifts the high-affinity, competitive inhibition profile of 3β-HSD1 to a low-affinity (trilostane Ki=2.56μM), noncompetitive inhibition profile similar to that of 3β-HSD2 containing Pro195. The P195R-2 mutation shifts the low-affinity, noncompetitive inhibition profile of 3β-HSD2 to a high-affinity (trilostane Ki=0.19μM), competitive inhibition profile similar to that of 3β-HSD1 containing Arg195. Michaelis-Menten kinetics for DHEA, 16β-hydroxy-DHEA and 16α-hydroxy-DHEA substrate utilization by the R195P-1 and P195R-2 enzymes provide further validation for higher affinity binding due to Arg195 in 3β-HSD1. Comparisons of the Michaelis-Menten values of cofactor and substrate for the targeted mutants of 3β-HSD1 (D61N, D61V, E192A, T8A) clarify the functions of these residues as well.
- Thomas, James L.,Mack, Vance L.,Sun, Jingping,Terrell, J. Ross,Bucholtz, Kevin M.
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scheme or table
p. 192 - 199
(2011/10/30)
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