- An efficient one-pot synthesis generating 4-ene-3,6-dione functionalised steroids from steroidal 5-en-3β-ols using a modified Jones oxidation methodology
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Steroids with 4-ene-3,6-dione functionality have application in natural product chemistry, as synthetic intermediates and as aromatase inhibitors. Here, we report a two-phase oxidation of a range of steroidal 5-en-3β-ols into corresponding 4-ene-3,6-diones using a modified Jones oxidation. The new reaction affords high yields (77-89%) of product in relatively short reaction times (1-2 h). The simplicity of this reaction gives significant advantages over previously reported methodologies.
- Hunter, A. Christy,Priest, Shelley-Marie
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- A novel synthesis of steroidal Δ4,3,6-diones using pyridinium chlorochromate (PCC)
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Pyridinium chlorochromate (PCC), in refluxing benzene, has been found to be an effective and convenient reagent for the oxidation of steroidal Δ5-3β-tetrahydropyranyl ethers to the corresponding Δ4-3,6-diones in high yield.
- Parish,Kizito,Heidepriem
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- Oxidation of steroidal 5-en-3β-ols with Jones reagent in ether
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The two-phase oxidation of steroidal 5-en-3β-ol (via 5-en-3-ones) into corresponding 4-en-3,6-diones in diethyl ether with Jones reagent was investigated. It was found that the system Jones reagent/diethyl ether enables short reaction times and easy isolation of the obtained products. The exclusive abstraction of 4α-hydrogen during oxidation, together with molecular mechanics (MM2), and semiempirical (PM3) calculations, suggest that boat conformation of ring A precedes the formation of corresponding radicals (or cations).
- Solaja, Bogdan A.,Mili, Dragana R.,Do, Ljiljana I.
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- Oxidation of homoallylic steroidal alcohols with pyridinium chlorochromate. The synthesis of steroidal 4-en-3,6-diones
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Prolonged oxidation of steroidal homoallylic Δ5-3-alcohols with pyridinium chlorochromate (PCC) in dichloromethane affords the corresponding Δ4-3,6-diones via the intermediate Δ5-3-one and not a Δ4-3-one.
- Blaszczyk,Paryzek
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- A novel oxidation of homoallylic alcohols under sonochemical conditions
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The oxidation of 3β-hydroxy-Δ5-cholestenes, -pregnenes and -androstenes to the corresponding Δ4-3,6-diones has been achieved in high yields by a new one-step process, using tetra-n-propylammonium perruthenate with 4-methylmorpholine N-oxide as co-oxidant, under sonochemical conditions.
- Miranda Moreno,Sa E Melo,Campos Neves
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- OXIDATION WITH SODIUM PEROXIDE. DIRECT INTRODUCTION OF A γ CARBONYL GROUP INTO α,β UNSATURATED KETOSTEROIDS
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Aqueous sodium peroxide oxidises the conjugated Δ4-3-ketosteroids 1a-1d to the corresponding Δ4-3,6-diones in good yield.Saturated carbonyl and alcohol groups are not affected by the reaction.
- Holland, Herbert L.,Daum, Ulrich,Riemland, Elly
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- Pyridinium dichromate: A novel reagent for the oxidation of steroidal Δ5-3β-alcohols to the corresponding Δ4-3,6-diketones
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A novel procedure for the direct conversion of steroidal Δ5-3β-alcohols to the corresponding Δ4-3,6-diketones in high yield (66-85%) has been achieved using pyridinium dichromate (PDC) in dimethylformamide (DMF) at room temperature.
- Hector, Markus,Hartmann, Rolf W.,Njar, Vincent C. O.
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- Facile synthesis of steroidal Δ4-3,6-diones from Δ5-3-ols using pyridinium chlorochromate
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Pyridinium chlorochromate (PCC) in dichloromethane under ambient conditions is found to oxidise steroidal Δ5-3-alcohols to Δ4-3,6-diketones in high yield.
- Nangia,Anthony
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- Synthesis and biological evaluation of steroidal derivatives as selective inhibitors of AKR1B10
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AKR1B10 is a member of human aldo-keto reductase superfamily, and a promising anti-cancer therapeutic target. In this paper, androst-5-ene-3β- ol, dehydroepiandrosterone, pregnenolone and cholesterol were used as reactants, sixteen products were obtained through Jones reaction and reduction reaction using NaBH4. Their inhibitory activities against AKR1B10 and AKR1B1 were measured. The most active compound (3a) has the IC50 of 0.50 μM for AKR1B10, and the most AKR1B10 selective compound (2a) has the IC 50 of 0.81 μM with AKR1B1/AKR1B10 selectivity of 195. In addition, the binding modes of 2a and 3a in the active site of human AKR1B10 were identified by docking.
- Zhang, Wei,Wang, Ling,Zhang, Liping,Chen, Wenli,Chen, Xinying,Xie, Minyu,Yan, Guangmei,Hu, Xiaopeng,Xu, Jun,Zhang, Jingxia
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- Improved syntheses of aromatase inhibitors and neuroactive steroids efficient oxidations and reductions at key positions for bioactivity
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An Henbest reduction, followed by the preparation of a silyl enol ether and oxidation in situ with m-CPBA has led to the neurosteroids 3α-hydroxy- and 3α,21-dihydroxy-5α-pregnanolones. Using testosterone as starting material, a new short synthesis of an aromatase inhibitor, 4-OHA, has been achieved through hydroboration/oxidation followed by a Swern type oxidation and epimerization. Another aromatase inhibitor, androst-4-ene-3,6,17-trione, has been efficiently prepared using PCC on montmorillonite K10, under ultrasonic irradiation.
- Campos Neves, Andre S.,Sa E Melo, Maria Luisa,Moreno, Maria Jose S. M.,Tavares Da Silva, Elisiario J.,Salvador, Jorge A. R.,Da Costa, Saul P.,Martins, Rosa Maria L. M.
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- Novel approach to the synthesis of istaroxime
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Istaroxime 1, a novel cardiotonic agent with high efficiency and low toxicity was synthesized from dehydroepiandrosterone 2 using a novel approach that included epoxidation, ring-opening, substitution, and oximation. The new protocol without gas protection was milder than the reported approaches. The overall yield of the method was 24.1%.
- Liang,Guo,Jiang
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p. 2643 - 2647
(2017/12/26)
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- Novel synthesis method of Istaroxime
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The invention belongs to the field of pharmaceutical chemistry, and discloses a novel synthesis method of Istaroxime. The method comprises the following steps: by using dehydrogenated epiandrosterone as an initial raw material, carrying out epoxidation, ring opening, reduction, oxidation and other reactions to prepare an intermediate M-06; by using ethyl benzoate as an initial raw material, reacting the ethyl benzoate with hydroxylamine hydrochloride to obtain phenyl hydroximic acid, carrying out hydrochlorination and chlorination by using ethanolamine as a raw material to obtain dichloroacetate, and carrying out substitution, hydrolysis and other reactions on the dichloroacetate and the phenyl hydroximic acid to obtain an intermediate M-11; and finally, reacting the M-06 with the M-11 to obtain the end product Istaroxime. According to the method, in the intermediate M-06 synthesis process, the polarity of all the intermediates has great differences from that of the impurities and reaction reagents; and in the intermediate 11 synthesis process, the active spots capable of participating in the chemical reaction in the reaction substrate are simple. Therefore, the method can achieve the requirements without carrying out column chromatography purification, thereby simplifying the synthesis after-treatment process.
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Paragraph 0091; 0092; 0093; 0094; 0095; 0096-0098
(2016/10/10)
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- Development of a Chemoenzymatic Process for Dehydroepiandrosterone Acetate Synthesis
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Dehydroepiandrosterone (DHEA, 2) is an important endogenous steroid hormone in mammals used in the treatment of a variety of dysfunctions in female and male health,1 as well as an intermediate in the synthesis of steroidal drugs, such as abiraterone acetate which is used for the treatment of prostate cancer.2-4 In this manuscript we describe a novel, concise, and cost-efficient route toward DHEA (2) and DHEA acetate (3) from 4-androstene-3,17-dione (4-AD, 1). Crucial to success was the identification of a ketoreductase from Sphingomonas wittichii for the highly regio- and stereoselective reduction of the C3-carbonyl group of 5-androstene-3,17-dione (5) to the required 3β-alcohol (2, >99% de). The enzyme displayed excellent robustness and solvent stability under high substrate concentrations (up to 150 g/L).
- Fryszkowska, Anna,Peterson, Justine,Davies, Nichola L.,Dewar, Colin,Evans, George,Bycroft, Matthew,Triggs, Neil,Fleming, Toni,Gorantla, Srikanth Sarat Chandra,Hoge, Garrett,Quirmbach, Michael,Timmanna, Upadhya,Reddy Poreddy, Srinivas,Kumar Reddy, D. Naresh,Dahanukar, Vilas,Holt-Tiffin, Karen E.
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p. 1520 - 1528
(2016/08/30)
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- Allylic Oxidations Catalyzed by Dirhodium Catalysts under Aqueous Conditions
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The present invention relates to compositions and methods for achieving the efficient allylic oxidation of organic molecules, especially olefins and steroids, under aqueous conditions. The invention concerns the use of dirhodium (II,II) “paddlewheel complexes, and in particular, dirhodium carboximate and tert-butyl hydroperoxide as catalysts for the reaction. The use of aqueous conditions is particularly advantageous in the allylic oxidation of 7-keto steroids, which could not be effectively oxidized using anhydrous methods, and in extending allylic oxidation to enamides and enol ethers.
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Page/Page column 18-19
(2009/04/24)
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- Allylic oxidations catalyzed by dirhodium caprolactamate via aqueous tert-butyl hydroperoxide: The role of the tert-butylperoxy radical
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Dirhodium(II) caprolactamate exhibits optimal efficiency for the production of the tert-butylperoxy radical, which is a selective reagent for hydrogen atom abstraction. These oxidation reactions occur with aqueous tert-butyl hydroperoxide (TBHP) without rapid hydrolysis of the caprolactamate ligands on dirhodium. Allylic oxidations of enones yield the corresponding enedione in moderate to high yields, and applications include allylic oxidations of steroidal enones. Although methylene oxidation to a ketone is more effective, methyl oxidation to a carboxylic acid can also be achieved. The superior efficiency of dirhodium(II) caprolactamate as a catalyst for allylic oxidations by TBHP (mol % of catalyst, % conversion) is described in comparative studies with other metal catalysts that are also reported to be effective for allylic oxidations. That different catalysts produce essentially the same mixture of products with the same relative yields suggests that the catalyst is not involved in product-forming steps. Mechanistic implications arising from studies of allylic oxidation with enones provide new insights into factors that control product formation. A previously undisclosed disproportionation pathway, catalyzed by the tert-butoxy radical, of mixed peroxides for the formation of ketone products via allylic oxidation has been uncovered.
- McLaughlin, Emily C.,Choi, Hojae,Wang, Kan,Chiou, Grace,Doyle, Michael P.
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supporting information; experimental part
p. 730 - 738
(2009/07/04)
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- Structure-activity relationship study of androstene steroids with respect to local anti-inflammatory activity
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A sex hormone, 37β-acetoxy-17β-hydroxy-androst-5-ene (1) (CAS 1639-43-6), was isolated from aerial parts of Acacia nilotica. This compound is reported to have anti-inflammatory activity. In view of this, considering this molecule as a lead molecule different androstene compounds were synthesized to study their potency and structure-activity relationship with respect to local anti-inflammatory activity. The experiments indicated that 17 ketonic compounds were more active towards inflammation than their oxime analogues. Similarly, for the compounds containing an acetyl group fixed at C-3 position a decreasing trend of activity was observed in the order of ketonic, hydroxyl, oxime and acetyl group, respectively, when these groups are at C-17 position. ECV · Editio Cantor Verlag, Aulendorf.
- Chaubal, Rohini,Mujumdar, Arvind M.,Misar, Ashwini,Deshpande, Vishnu H.,Deshpande, Nirmala R.
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p. 394 - 398
(2007/10/03)
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- Regioselective hydroperoxygenation of aralkanes and α,β- unsaturated carbonyl compounds catalyzed by N-hydroxyphthalimide and 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile)
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Aerobic oxidation of aralkanes and α,β-unsaturated carbonyl compounds in the presence of a catalytic amount of N-hydroxyphthalimide (NHPI) and 2,2′-Azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) under 1 atmos. of oxygen at 30°C gave α-hydroperoxyaralkanes and γ-hydroperoxy-α,β-unsaturated carbonyl compounds, respectively. Copyright Taylor & Francis, Inc.
- Sugamoto, Kazuhiro,Matsushita, Yoh-Ichi,Yamamoto, Takashi,Matsui, Takanao
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p. 1865 - 1874
(2007/10/03)
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- An alternative preparation of steroidal Δ4-3,6-diones
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The oxidation of readily available steroidal 3-chloro-3,5-dienes with chromic acid is shown to give the corresponding 4-ene-3,6-diones.
- Kiran, Ismail,Hanson, James R.
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p. 208 - 209
(2007/10/03)
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- Topical treatment for mastalgia
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A composition for medicinal treatment by means of topical administration is described, which contains an aromatase inhibitor, in addition to conventional constituents of topical forms of administration. The active ingredient or the composition containing this active ingredient is especially suitable for the prophylaxis and for the treatment of mastalgia.
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- The Oxidation of Some Steroidal Dienes and Trienes with Chromic Acid
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The chromic acid oxidation of steroidal 2,4- and 3,5-dienes and 2,4,6-trienes has been shown to take place at the secondary termini of the alkenes rather than at the allylic positions and has been rationalized in terms of a sequence of 1:4-additions of chromic acid.
- Hanson, James R.,Kiran, Ismail
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p. 2532 - 2545
(2007/10/03)
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- Syntheses of Androst-5-ene-4,7,17-trione and A-Norandrost-5-ene-3,7,17-trione
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Syntheses are described of the aromatase inhibitor, androst-5-ene-4,7,17-trione, its 17β-acetate and A-nor analogue, A-norandrost-5-ene-3,7,17-trione, starting from dehydroisoandrosterone and testosterone.
- Hanson, James R.,Kiran, Ismail,Masarwah, Natheer F.,Uyanik, Cavit
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p. 2420 - 2434
(2007/10/03)
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- OXIDATIONS OF ENONE SYSTEMS IN STEROIDS BY OXIDIZERS WITH REVERSIBLE REDOX POTENTIAL
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The oxidation of steroid enones by oxidizers with reversible redox potentials (mostly tetrazolium salts) is described.Products containing an oxo or hydroxy group at the position γ with respect to the oxo of the enone group were isolated in relatively high yields.The results of kinetic studies on the redox processes are reported and a reaction mechanism is proposed.
- Jasiczak, Jan
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p. 2687 - 2692
(2007/10/02)
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- Studies Directed towards a Mechanistic Evaluation of Aromatase Inhibition with 4-Androstene-3,6,17-trione: Its Reactions with Thiols
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Reactions of 4-androstene-3,6,17-trione (1) with thiols under various conditions are described.Treatment of (1) with ethanedithiol in MeOH in the presence or absence of BF3*Et2O gave principally a 3,3-dithioacetal (2) or a 3α,4α-ethylenedithio adduct (5), respectively.The reaction of (1) with EtSH in MeOH gave a 5α-reduced compound (9), a 3,3-diethyldithioacetal (10), a 6-methoxy-4,6-diene-3,17-dione (11), and a 4α-ethylthio adduct (12).Under p-TsOH-acidic conditions, (10) and (11) were obtained in modest yields.In contrast, (12) was isolated as the sole product under NaHCO3-basic conditions.Furthermore, (1) reacted with N-acetyl-L-cysteine uner basic conditions to yield a 1,4-adduct, sodium N-acetyl-S-(3,6,17-trioxo-5α-androstan-4α-yl)-L-cysteinate (17) along with (9).
- Numazawa, Mitsuteru,Tsuji, Masachika,Osada, Ryoko
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p. 718 - 734
(2007/10/02)
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- Aromatase Inhibitors. Synthesis and Biological Activity of Androstenedione Derivatives
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The synthesis and biological evaluation of androstenedione derivatives as inhibitors of estrogen biosynthesis are described.The results show that 4-hydroxy analogues are among the most potent in vitro inhibitors of the series.Esterification of the 4-hydroxy steroids generally reduced activity.Further conjugation of the 3-keto 4-ene system to give 4-hydroxy-4,6-androstadiene-3,17-dione caused more rapid inactivation of aromatase in rat ovarian microsomes than 4-hydroxyandrostenedione.Some compounds exhibited differences in activity when tested for inhibition of human placental microsomes vs. rat ovarian microsomes.The 4-hydroxyandrostenedione derivatives and their nonbulky esters were generally more potent in vitro and in vivo inhibitors than other substituted steroids in the series.Several of the synthesized compounds markedly reduce (50-81percent) estrogen levels in rats on proestrus and/or had antifertility action.To date, none of the compounds surpassed the in vivo inhibitory action of 4-hydroxy-4-androstene-3,17-dione or its 4-acetate derivative.
- Marsh, David A.,Brodie, Harry J.,Garrett, Wesley,Tsai-Morris, Chon-Hwa,Brodie, Angela M. H.
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p. 788 - 795
(2007/10/02)
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- Peroxide oxidation of Δ4-3-ketosteroids
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Treatment of Δ4-3-ketosteroids with tert-butyl hydroperoxide in the presence of lithium hydroxide leads to the formation of the corresponding 4β,5β epoxides stereospecifically and in good yield.The stereospecificity of this reaction is explicable in terms of the accepted mechanism for the hydrogen peroxide epoxidation of Δ4-3-ketosteroids.The use of aqueous sodium peroxide as oxidant leads to the production of the corresponding Δ4-3,6-diones.A mechanism for this reaction is proposed in which the key step is autooxidation of the corresponding deconjugated Δ5-3-ketone, produced from the starting material in situ by the action of the reagents.Lithium peroxide does not oxidize androst-4-ene-3,17-dione at C-6, but produces the 4,5-epoxides in low yield together with an A-nor-3,5-secoacid.
- Holland, Herbert L.,Riemland, Elly,Ulrich, Daum
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p. 1919 - 1923
(2007/10/02)
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- Hydroxylation of Δ5-Steroids with N-Bromosuccinimide to 5α,6β-Diols
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The reaction of N-bromosuccinimide with Δ5-steroids such as, diosgenin, cholesterol, stigmasterol and dehydroisoandrosterone were studied.It was found that NBS in a solvent mixture of acetone, water and acetic acid (8:1:0.1) oxidises the olefinic bond of all the previous steroidal compounds to the corresponding transglycollic, 5α,6β-dihydroxylic products in about 60percent yield at room temperature. - Keywords: N-Bromosuccinimide, Δ5-Steroids, Diosgenin, Cholesterol, Stigmastane, Dihydroisoandrosterone
- Dawidar, A. M.,Saleh, A. A.,Abdel-Malek, M. M.
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p. 102 - 106
(2007/10/02)
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