- Microbial transformation of dehydroepiandrosterone (DHEA) by some fungi
-
In this work, biotransformations of dehydroepiandrosterone (DHEA) 1 by Ulocladium chartarum MRC 72584, Cladosporium sphaerospermum MRC 70266 and Cladosporium cladosporioides MRC 70282 have been reported. U. chartarum MRC 72584 mainly hydroxylated 1 at C-7α and C-7β, accompanied by a minor hydroxylation at C-4β, a minor epoxidation from the β-face and a minor oxidation at C-7 subsequent to its hydroxylations. 3β,7β-Dihydroxy-5β,6β-epoxyandrostan-17-one 6, 3β,4β,7α-trihydroxyandrost-5-en-17-one 7 and 3β,4β,7β-trihydroxyandrost-5-en-17-one 8 from this incubation were identified as new metabolites. C. sphaerospermum MRC 70266 converted some of 1 into a 3-keto-4-ene steroid and then hydroxylated at C-6α, C-6β and C-7α, accompanied a minor 5α-reduction and a minor oxidation at C-6 following its hydroxylations. C. sphaerospermum MRC 70266 also hydroxylated some of 1 at C-7α and C-7β. C. cladosporioides MRC 70282 converted almost half of 1 into a 3-keto-4-ene steroid and then hydroxylated at C-6α and C-6β. C. cladosporioides MRC 70282 also reduced some of 1 at C-17.
- Yildirim, Kudret,Kuru, Ali,Y?lmazer Keskin, Semra,Ergin, Sinan
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p. 465 - 474
(2020/11/12)
-
- C-6α- vs C-7α-Substituted Steroidal Aromatase Inhibitors: Which Is Better? Synthesis, Biochemical Evaluation, Docking Studies, and Structure-Activity Relationships
-
C-6α and C-7α androstanes were studied to disclose which position among them is more convenient to functionalize to reach superior aromatase inhibition. In the first series, the study of C-6 versus C-7 methyl derivatives led to the very active compound 9 with IC50 of 0.06 μM and Ki = 0.025 μM (competitive inhibition). In the second series, the study of C-6 versus C-7 allyl derivatives led to the best aromatase inhibitor 13 of this work with IC50 of 0.055 μM and Ki = 0.0225 μM (irreversible inhibition). Beyond these findings, it was concluded that position C-6α is better to functionalize than C-7α, except when there is a C-4 substituent simultaneously. In addition, the methyl group was the best substituent, followed by the allyl group and next by the hydroxyl group. To rationalize the structure-activity relationship of the best inhibitor 13, molecular modeling studies were carried out.
- Roleira, Fernanda M. F.,Varela, Carla,Amaral, Cristina,Costa, Saul C.,Correia-Da-Silva, Georgina,Moraca, Federica,Costa, Giosuè,Alcaro, Stefano,Teixeira, Natércia A. A.,Tavares Da Silva, Elisiário J.
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p. 3636 - 3657
(2019/04/26)
-
- Sensitized Aliphatic Fluorination Directed by Terpenoidal Enones: A "visible Light" Approach
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In our continued effort to address the challenges of selective sp3 C-H fluorination on complex molecules, we report a sensitized aliphatic fluorination directed by terpenoidal enones using catalytic benzil and visible light (white LEDs). This sensitized approach is mild, simple to set up, and an economical alternative to our previous protocol based on direct excitation using UV light in a specialized apparatus. Additionally, the amenability of this protocol to photochemical flow conditions and preliminary evidence for electron-transfer processes are highlighted.
- Bume, Desta Doro,Harry, Stefan Andrew,Pitts, Cody Ross,Lectka, Thomas
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p. 1565 - 1575
(2018/02/09)
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- Multiple Enone-Directed Reactivity Modes Lead to the Selective Photochemical Fluorination of Polycyclic Terpenoid Derivatives
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In the realm of aliphatic fluorination, the problem of reactivity has been very successfully addressed in recent years. In contrast, the associated problem of selectivity, that is, directing fluorination to specific sites in complex molecules, remains a great, fundamental challenge. In this report, we show that the enone functional group, upon photoexcitation, provides a solution. Based solely on orientation of the oxygen atom, site-selective photochemical fluorination is achieved on steroids and bioactive polycycles with up to 65 different sp3 C-H bonds. We have also found that γ-, β-, homoallylic, and allylic fluorination are all possible and predictable through the theoretical modes reported herein. Lastly, we present a preliminary mechanistic hypothesis characterized by intramolecular hydrogen atom transfer, radical fluorination, and ultimate restoration of the enone. In all, these results provide a leap forward in the design of selective fluorination of complex substrates that should be relevant to drug discovery, where fluorine plays a prominent role.
- Pitts, Cody Ross,Bume, Desta Doro,Harry, Stefan Andrew,Siegler, Maxime A.,Lectka, Thomas
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supporting information
p. 2208 - 2211
(2017/02/23)
-
- Regio- and stereoselective reduction of 17-oxosteroids to 17β-hydroxysteroids by a yeast strain Zygowilliopsis sp. WY7905
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The reduction of 17-oxosteroids to 17β-hydroxysteroids is one of the important transformations for the preparation of many steroidal drugs and intermediates. The strain Zygowilliopsis sp. WY7905 was found to catalyze the reduction of C-17 carbonyl group of androst-4-ene-3,17-dione (AD) to give testosterone (TS) as the sole product by the constitutive 17β-hydroxysteroid dehydrogenase (17β-HSD). The optimal conditions for the reduction were pH 8.0 and 30 °C with supplementing 10 g/l glucose and 1% Tween 80 (w/v). Under the optimized transformation conditions, 0.75 g/l AD was reduced to a single product TS with >90% yield and >99% diastereomeric excess (de) within 24 h. This strain also reduced other 17-oxosteroids such as estrone, 3β-hydroxyandrost-5-en-17-one and norandrostenedione, to give the corresponding 17β-hydroxysteroids, while the C-3 and C-20 carbonyl groups were intact. The absence of by-products in this microbial 17β-reduction would facilitate the product purification. As such, the strain might serve as a useful biocatalyst for this important transformation.
- Liu, Yuanyuan,Wang, Yu,Chen, Xi,Wu, Qiaqing,Wang, Min,Zhu, Dunming,Ma, Yanhe
-
-
- Optimization of the 11α-hydroxylation of steroid DHEA by solvent-adapted Beauveria bassiana
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To extend the use of Beauveria bassiana for commercial applications, the optimization of reaction conditions and accurate prediction of biotransformation products are necessary. This work enhances the selective hydroxylation capacity of strain ATCC 7159, resulting in a cost effective and eco-friendly process for the synthesis of valuable 11α-hydroxy steroids. Our work establishes the biochemical pathway of DHEA to hydroxylated intermediates with strain ATCC 7159, and distinguishes the optimum conditions for reactor arrangements, substrate concentration, reaction temperature, and pH. Higher substrate conversion, selectivity, and yield of desired product was achieved with “resting cells.” Addition of higher volumes of growing medium relative to reaction buffer increases the reaction rate. When a diluted amount of substrate is used, a higher yield of 11α-hydroxy steroids is achieved. Also, reactions at 26 °C with pH ranges between 6.0 and 7.0 result in the highest conversion (70%) and the higher product yield (45.8%). B. bassiana has the capacity to metabolize DHEA and similar steroids in different reaction schemes, and has a promising future as biocatalyst to be used in the production of drug metabolites.
- Gonzalez, Richard,Nicolau, Felipe,Peeples, Tonya L.
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p. 103 - 109
(2017/03/21)
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- The generation of a steroid library using filamentous fungi immobilized in calcium alginate Dedicated to the memory of Professor Sir John W. Cornforth, University of Sussex (1917-2013).
-
Four fungi, namely, Rhizopus oryzae ATCC 11145, Mucor plumbeus ATCC 4740, Cunninghamella echinulata var. elegans ATCC 8688a, and Whetzelinia sclerotiorum ATCC 18687, were subjected to entrapment in calcium alginate, and the beads derived were used in the biotransformation of the steroids 3β,17β-dihydroxyandrost-5-ene (1) and 17β-hydroxyandrost-4-en-3-one (2). Incubations performed utilized beads from two different encapsulated fungi to explore their potential for the production of metabolites other than those derived from the individual fungi. The investigation showed that steroids from both single and crossover transformations were typically produced, some of which were hitherto unreported. The results indicated that this general technique can be exploited for the production of small libraries of compounds.
- Peart, Patrice C.,Reynolds, William F.,Reese, Paul B.
-
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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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- 5 α-chloro-androl -6β, 19-epoxy -3,17-dione method for the preparation of
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The invention provides a method for preparing 5 alpha-chlorine-androstane-6 beta, 19-epoxy-3,17-diketone. The method comprises the following steps: taking 4-AD as a raw material, carrying out 3-position enol esterification, reduction, 3,17-position double esterification, 5,6-position addition, 6,19-cyclization and 3,17-position double oxidation, and finally obtaining 5 alpha-chlorine-androstane-6 beta, 19-epoxy-3,17-diketone. The method has the advantages of being rich in raw material sources, environmentally-friendly, low in cost and high in yield of synthetic process, and the obtained 5 alpha-chlorine-androstane-6 beta, 19-epoxy-3,17-diketone can be applied to producing series of family planning drugs.
- -
-
Paragraph 0015; 0057-0058
(2018/01/19)
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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.
-
supporting information
p. 1520 - 1528
(2016/08/30)
-
- Synthesis and antiproliferative activity of some androstene oximes and their O-Alkylated derivatives
-
In order to study the structure-activity relationship with respect to the cytotoxicity of steroidal oximes, several 6E-hydroximino-4-ene steroids and their O-alkylated derivatives were synthesized. The oxime ethers were solidified and purified by preparing their corresponding oxalate salts. The new derivatives as well as some previously synthesized ones were evaluated for in vitro antineoplastic activity against a panel of 60 cancer cell lines at 10 μM. The oximes and oxime ethers were found to have moderate to good antiproliferative activity against various leukemia, colon, melanoma, and renal cancer cell lines. Several 6E-hydroximino-4-ene steroids and their O-alkylated derivatives were synthesized. Their structure-activity relationship with respect to the cytotoxicity of steroidal oximes was studied. The oximes and oxime ethers were found to have moderate-to-good antiproliferative activity against various leukemia, colon, melanoma, and renal cancer cell lines.
- Acharya, Pratap Chandra,Bansal, Ranju
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p. 193 - 199
(2014/03/21)
-
- Substrate specificity and inhibitor sensitivity of rabbit 20α-hydroxysteroid dehydrogenase
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In this study, we examined the substrate specificity and inhibitor sensitivity of rabbit 20α-hydroxysteroid dehydrogenase (AKR1C5), which plays a role in the termination of pregnancy by progesterone inactivation. AKR1C5 moderately reduced the 3-keto group of only 5α-dihydrosteroids with 17β- or 20α/β-hydroxy group among 3-ketosteroids. In contrast, the enzyme reversibly and efficiently catalyzed the reduction of various 17- and 20-ketosteroids, including estrogen precursors (dehydroepiandrosterone, estrone and 5α-androstan-3β- ol-17-one) and tocolytic 5β-pregnane-3,20- dione. In addition to the progesterone inactivation, the formation of estrogens and metabolism of the tocolytic steroid by AKR1C5 may be related to its role in rabbit parturition. AKR1C5 also reduced various non-steroidal carbonyl compounds, including isatin, an antagonist of the C-type natriuretic peptide receptor, and 4-oxo-2-nonenal, suggesting its roles in controlling the bioactive isatin and detoxification of cytotoxic aldehydes. AKR1C5 was potently and competitively inhibited by flavonoids such as kaempferol and quercetin, suggesting that its activity is affected by ingested flavonoids.
- Endo, Satoshi,Arai, Yuki,Hara, Akira,Kitade, Yukio,Bunai, Yasuo,El-Kabbani, Ossama,Matsunaga, Toshiyuki
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p. 1514 - 1518
(2013/10/08)
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- Potential of Azadirachta indica cell suspension culture to produce biologically active metabolites of dehydroepiandrosterone
-
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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- Biotransformation of some steroids by Mucor hiemalis MRC 70325
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In this work, incubations of testosterone, dehydroepiandrosterone and pregnenolone with Mucor hiemalis MRC 70325 have been reported. Incubation of testosterone afforded androst-4-en-3,17-dione (3%), 14a-hydroxyandrost- 4-en-3,17-dione (9%), 6β-hydroxyandrost-4-en-3,17-dione (2%) and 14a,17β-dihydroxyandrost-4-en-3-one (62%). Incubation of dehy droepiandrosterone afforded 3β,17β-dihydroxyandrost-5-ene (6%) and 3β,7α-dihydroxyandrost-5- en-17-one (72%). Incubation of pregnenolone afforded 3β,14a-dihydroxypregn-5-en-7,20-dione (3%), 3β,7α- dihydroxypregn- 5-en-20-one (64%) and 3β,7α,11α- trihydroxypregn-5-en-20-one (11%). 3β,14a-Dihydroxypregn-5-en-7,20-dione was identified as a new metabolite. Website
- Yildirim, Kudret,Saran, Hilal,Dolu, Omer Faruk,Kuru, Ali
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p. 566 - 569
(2013/10/22)
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- Synthesis and Antitumor Activity of Dehydroepiandrosterone Derivatives on Es-2, A549, and HepG2 Cells in vitro
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A series of dehydroepiandrosterone derivatives containing an acid ester was synthesized and evaluated for their antitumor activity on ES-2, A549, and HepG2 cells by the MTT assay. Most compounds showed antitumor activity, while compounds 1c, 2i, and 2o exhibited more potential inhibitory effects compared with dehydroepiandrosterone on ES-2 cells, A549 cells, and HepG2 cells, respectively.
- Liu, Xue-Kun,Ye, Bai-Jun,Wu, Yan,Nan, Ji-Xing,Lin, Zhen-Hua,Piao, Hu-Ri
-
experimental part
p. 523 - 529
(2012/06/15)
-
- NOVEL SERIES OF IMIDAZOLYL SUBSTITUTED STEROIDAL AND INDAN-1-ONE DERIVATIVES
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The present invention provides a novel series of imidazolyl substituted steroidal and indan-1-one derivatives and salts thereof having the following general structural formulae (A and B)
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Page/Page column 16-17
(2012/12/13)
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- Entrapment of mycelial fragments in calcium alginate: A general technique for the use of immobilized filamentous fungi in biocatalysis
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Transformation reactions on 3β,17β-dihydroxyandrost-5-ene using free fungal cells were compared with those carried out by macerated mycelia, immobilized in calcium alginate beads. Six fungi were utilized in this study, namely Rhizopus oryzae ATCC 11145, Mucor plumbeus ATCC 4740, Cunninghamella echinulata var. elegans ATCC 8688a, Aspergillus niger ATCC 9142, Phanerochaete chrysosporium ATCC 24725 and Whetzelinia sclerotiorum ATCC 18687. The results show, for the first time, that encapsulated mycelial fragments essentially carry out the same bioconversions as those observed with growing cells. As the immobilized cells were "resting", the products formed were free of contamination by natural products, and this greatly aided the purification of the metabolites. Conditions for bead preparation were optimized. Furthermore, it was noted that the beads could be reused, once they had been subjected to a rejuvenation process.
- Peart, Patrice C.,Chen, Avril R.M.,Reynolds, William F.,Reese, Paul B.
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experimental part
p. 85 - 90
(2012/02/04)
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- Microbial Baeyer-Villiger oxidation of steroidal ketones using Beauveria bassiana: Presence of an 11α-hydroxyl group essential to generation of D-homo lactones
-
This paper demonstrates for the first time transformation of a series of 17-oxo steroidal substrates (epiandrosterone, dehydroepiandrosterone, androstenedione) by the most frequently used whole cell biocatalyst, Beauveria bassiana, to 11α-hydroxy-17a-oxa-d-homo-androst-17-one products, in the following sequence of reactions: 11α-hydroxylation and subsequent Baeyer-Villiger oxidation to a ring-D lactone. 11α-Hydroxyprogesterone, the product of the first stage of the progesterone metabolism, was further converted along two routes: hydroxylation to 6β,11α- dihydroxyprogesterone or 17β-acetyl chain degradation leading to 11α-hydroxytestosterone, the main metabolite of the substrate. Part of 11α-hydroxytestosterone underwent a rare reduction to 11α-hydroxy- 5β-dihydrotestosterone. The experiments have demonstrated that the Baeyer-Villiger monooxygenase produced by the strain catalyzes solely oxidation of C-20 or C-17 ketones with 11α-hydroxyl group. 17-Oxo steroids, beside the 11α-hydroxylation and Baeyer-Villiger oxidation, also underwent reduction to 17β-alcohols; activity of 17β-hydroxysteroid dehydrogenase (17β-HSD) has significant impact on the amount of the formed ring-D δ-lactone.
- ?wizdor, Alina,Ko?ek, Teresa,Panek, Anna,Bia?on?ska, Agata
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experimental part
p. 253 - 262
(2012/03/10)
-
- Simultaneously rapid deprotection of 3-acyloxy groups and reduction of D-ring ketones (nitrile) of steroids using DIBAL-H/NiCl2
-
An efficient preparation of hydroxysteroids by a one-pot, simultaneously rapid deprotection of 3-acyloxy groups and reduction of D-ring ketones (nitrile) of steroids using DIBAL-H in the presence of NiCl2 (10 mol %) is described. The attractive features of this procedure for the preparation of the hydroxysteroid derivatives are the mild reaction conditions, short reaction time, excellent yields, clean reaction profiles, and an inexpensive catalyst system.
- Wang, Xingbin,Liu, Hui,Yan, Peiyun,Liu, Jinliang,Li, Yan,Sun, Qian,Wang, Cunde
-
experimental part
p. 291 - 293
(2011/10/05)
-
- Synthesis and antineoplastic activity of O-alkylated derivatives of 7-hydroximinoandrost-5-ene steroids
-
Varied positioning of the hydroximino group on the parental steroid skeleton results in remarkable changes in the antineoplastic activity profile of the compounds. Here, the compound 7-oximino-5-androstene and its O-alkylated derivatives have been prepared and screened for cytotoxic and aromatase inhibitory activity. The steroidal 7-oximino ether derivatives exhibited insignificant cytotoxic effects when screened against three cancer cell lines, MCF-7 (breast), NCl-H460 (lung), and SF-268 (CNS) at 100 μM. However, the imidazolyl-substituted steroidal oxime ethers displayed moderate inhibition of cytochrome P450 aromatase.
- Bansal, Ranju,Guleria, Sheetal,Ries, Christina,Hartmann, Rolf W.
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body text
p. 377 - 383
(2011/08/03)
-
- Hydroxylation of steroid compounds by Gelasinospora retispora
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Biotransformation of androst-4-ene-3,17-dione (1), 3β-hydroxypregnan- 5-en-20-one (pregnenolone, 2), 3β-hydroxyandrost-5-en-17-one (DHEA, 3) and estradiol (4) was investigated with fungus of Gelasinospora retispora. Biotransformation of 1 gave 11α-hydroxyandrost-4-ene-3,17-dione (5) in good yield. In the case of compound 2, three compounds, DHEA (3), 3β,17β-dihydroxyandrost-5-ene (6) and 3β,15β- dihydroxyandrost-5-en-17-one (7) were obtained. Moreover, DHEA (3) was converted to 3β,7α-dihydroxyandrost-5-en-17-one (8) and 3β,11α- dihydroxyandrost-5-ene-7,17-dione (9). And it was found that biotransformation of 4 affords 6β-hydroxyestradiol (10).
- Koshimura, Masahiro,Utsukihara, Takamitsu,Hara, Asako,Mizobuchi, Syuhei,Horiuchi, C. Akira,Kuniyoshi, Masayuki
-
experimental part
p. 72 - 77
(2010/12/20)
-
- NOVEL SERIES OF IMIDAZOLYL SUBSTITUTED STEROIDAL AND INDAN-1-ONE DERIVATIVES
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The present invention provides a novel series of imidazolyl substituted steroidal and indan-1-one derivatives and salts thereof having the following general structural formulae (A and B)
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Page/Page column 9
(2009/06/27)
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- Mild and selective deprotection method of acetylated steroids and diterpenes by dibutyltin oxide
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Dibutyltin oxide (DBTO) was first utilized for the deacetylation of steroid and diterpene esters. The results showed the deprotection of acetylated steroids and diterpenes separately with moderate catalysis dibutyltin oxide in methanol selectively removed part acetyl groups of these substrates, whereas several functional groups of the steroids and diterpenes were retained and neither isomerization nor degradation of these substrates was observed. It seems that the acetyl groups with lower steric hindrance or near carbonyl, alkoxy, or hydroxyl groups can be cleaved by the reaction, whereas the acetyl groups with higher steric hindrance or without carbonyl, alkoxy, or hydroxyl groups neighboring were retained under the same conditions. One of the interesting results obtained was the selective hydrolysis of the 3β-O-acetyl group in the presence of the 6β group in 3β,6β-Di-O-acetyl-5α-hydroxypregn-16-en-20-one. This allows for subsequent introduction of one unit at C-3 and the other unit at C-6. This procedure is useful for the synthesis of a series of closely related isomers of 3β,5α,6β-trihydroxypregn-16-en-20-one and other widespread polyhydroxysteroids in marine organisms and some terrestrial species.
- Wang, Shao-Min,Zhang, Yan-Bing,Liu, Hong-Min,Yu, Guo-Bin,Wang, Ke-Rang
-
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- C19-Steroids as androgen receptor modulators: Design, discovery, and structure-activity relationship of new steroidal androgen receptor antagonists
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Dehydroepiandrosterone (DHEA), the most abundant steroid in human circulating blood, is metabolized to sex hormones and other C19-steroids. Our previous collaborative study demonstrated that androst-5-ene-3β,17β-diol (Adiol) and androst-4-ene-3,17-dione (Adione), metabolites of DHEA, can activate androgen receptor (AR) target genes. Adiol is maintained at a high concentration in prostate cancer tissue; even after androgen deprivation therapy and its androgen activity is not inhibited by the antiandrogens currently used to treat prostate cancer patients. We have synthesized possible metabolites of DHEA and several synthetic analogues and evaluated their role in androgen receptor transactivation to identify AR modulators. Steroids with low androgenic potential in PC-3 cell lines were evaluated for anti-dihydrotestosterone (DHT) and anti-Adiol activity. We discovered three potent antiandrogens: 3β-acetoxyandrosta-1,5-diene-17-one 17-ethylene ketal (ADEK), androsta-1,4-diene-3,17-dione 17-ethylene ketal (OAK), and 3β-hydroxyandrosta-5,16-diene (HAD) that antagonized the effects of DHT as well as of Adiol on the growth of LNCaP cells and on the expression of prostate-specific antigen (PSA). In vivo tests of these compounds will reveal their potential as potent antiandrogens for the treatment of prostate cancer.
- Marwah, Padma,Marwah, Ashok,Lardy, Henry A.,Miyamoto, Hiroshi,Chang, Chawnshang
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p. 5933 - 5947
(2007/10/03)
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- ESTROGEN RECEPTOR MODULATORS
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The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget’s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, inflammation, inflammatory bowel disease, sexual dysfunction, hypertension, retinal degeneration and cancer, in particular of the breast, uterus and prostate.
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Page/Page column 27
(2008/06/13)
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- ESTROGEN RECEPTOR MODULATORS
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The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget’s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, inflammation, inflammatory bowel disease and cancer, in particular of the breast, uterus and prostate.
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Page/Page column 25
(2008/06/13)
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- ESTROGEN RECEPTOR MODULATORS
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The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget’s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, inflammation, inflammatory bowel disease, sexual dysfunction, hypertension, retinal degeneration and cancer, in particular of the breast, uterus and prostate.
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Page/Page column 26
(2008/06/13)
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- ESTROGEN RECEPTOR MODULATORS
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The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget’s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, inflammation, inflammatory bowel disease, sexual dysfunction, hypertension, retinal degeneration and cancer, in particular of the breast, uterus and prostate.
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Page/Page column 24-25
(2010/02/11)
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- ESTROGEN RECEPTOR MODULATORS
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The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget's disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, inflammation, inflammatory bowel disease, sexual dysfunction, hypertension, retinal degeneration and cancer, in particular of the breast, uterus and prostate.
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Page/Page column 27
(2010/02/14)
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- Titanyl Acetylacetonate as an Efficient Catalyst for a Mild and Convenient Reduction of Carbonyl Compounds with NaBH4 under Aprotic Condition
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Titanyl acetylacetonate, TiO(acac)2, is used as an efficient catalyst for the reduction of carbonyl compounds with sodium borohydride under aprotic condition. Reduction reactions are performed in CH3CN and THF. The corresponding alcohols are obtained in high to excellent yields and the chemoselective reduction of aldehydes over ketones is achieved successfully.
- Zeynizadeh, Behzad
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p. 1220 - 1226
(2007/10/03)
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- Novel stereoselective synthesis of 7β-methyl-substituted 5-androstene derivatives
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The 7β-methyl-5-androstene derivatives 11a-c were prepared in good yield with high stereoselectivities starting from 3β-acetoxyandrost-5-en-17-one 4. The addition of methylmagnesium iodide to the 7-carbonyl group of 7a-c gave, after hydrolysis, two isomers 9a-c and 10a-c, which were stereoselectively deoxygenated by means of an ionic hydrogenation to afford the compounds 11a-c.
- Zheng, Yunhong,Li, Yuanchao
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p. 1603 - 1606
(2007/10/03)
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- Imprinted polymers as protecting groups for regioselective modification of polyfunctional substrates
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Imprinted polymers were prepared using a functional monomer derived from boronophthalide and a number of steroid templates bearing spatially separated hydroxyl groups. The cooperative nature of the binding interaction was demonstrated in polymers imprinted with androst-5-ene-3β,17β-diol and its structural analogues. The stoichiometry and kinetics of binding were probed using IR spectroscopy, selective solvent extractions, and chemical modification experiments. The feasibility of using imprinted polymers as reusable protecting groups was established by the regioselective acylation of trihydroxysteroids bound to polymers imprinted with structurally related diols. In polymers prepared with tert-butyl ester templates "matched" to the substrate, regioselectivities as high as 23.1:1 (24-acetate:3-acetate) in the monoester products (65% of recovered material) were seen. In the "unmatched" case, the ratio fell to 5.4:1; however, in functionally identical control polymers, imprinted with ethylene glycol, the regioselectivity was completely reversed (1:100), and only poor yields of monoesters (13%) were obtained.
- Alexander, Cameron,Smith, Craig R.,Whitcombe, Michael J.,Vulfson, Evgeny N.
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p. 6640 - 6651
(2007/10/03)
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- Steroid transformations with Fusarium oxysporum var. cubense and Colletotrichum musae
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The utility of two locally isolated fungi, pathogenic to banana, for steroid biotransformation has been studied. The deuteromycetes Fusarium oxysporum var. cubense (IMI 326069, UAMH 9013) and Colletotrichum musae (IMI 374528, UAMH 8929) had not been examined previously for this potential. In general, F. oxysporum var. cubense effected 7α hydroxylation on 3β-hydroxy- Δ5-steroids, 6β, 12β, and 15α hydroxylation on steroidal-4-ene-3-ones, side-chain degradation on 17α,21-dihydroxypregnene-3,20-diones, and 15α hydroxylation on estrone. Both strains were shown to perform redox reactions on alcohols and ketones.
- Wilson, Maureen R.,Gallimore, Winklet A.,Reese, Paul B.
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p. 834 - 843
(2007/10/03)
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- Steroid transformations with Exophiala jeanselmei var. lecanii-corni and Ceratocystis paradoxa
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The fungi Exophiala jeanselmei var. lecanii-corni [IMI (International Mycological Institute) 312989, UAMH (University of Alberta Microfungus Collection and Herbarium) 8783] and Ceratocystis paradoxa (IMI 374529, UAMH 8784) have been examined for their potential in steroid biotransformation. The study has determined that E. jeanselmei var. lecanii-corni effected overall anti-Markovnikov hydration on dehydroisoandrosterone, and side-chain degradation on a variety of pregnanes. Both ascomycetes were found to carry out redox reactions of alcohols and ketones as well as 1,4 reduction of α,β-unsaturated carbonyl systems.
- Porter, Roy B.R.,Gallimore, Winklet A.,Reese, Paul B.
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p. 770 - 779
(2007/10/03)
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- Reductive cleavage of N,N,N',N'-tetramethylphosphorodiamidate with lithium naphthalenide. A convenient procedure for deoxygenation of alcohols
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A simple, effective alternative procedure has been developed for the reductive cleavage of the N,N,N,'N'-tetramethylphosphorodiamidate group, using lithium naphthalenide as the reagent.
- Liu, Hsing-Jang,Shang, Xiao
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p. 367 - 370
(2007/10/03)
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- Synthesis of 6&α,7&α- and 6&β,7&β-aziridinoandrost-4-ene-3,17-diones and related compounds: potential aromatase inhibitors
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The stereospecific synthesis of the novel 6β,7β- and 6α,7α-aziridinoandrost-4-ene-3,17-dione 21 and 23 has been accomplished by treatment of vicinal azidohydrins 19 and 20 respectively with triphenylphosphine.Several related compounds (fused steroidal oxiranes, azidohydrins and an azide) were also synthesized.Reaction of (E)-6-hydroxyiminoandrost-4-ene-3β,17β-diol 2 with lithium aluminium hydride (LAH) gave, respectively, 5β,6β- and 5α,6α-aziridineandrostane-3β,17β-diol 5 and 6.Although the 6,7-aziridines and their N-derivatives are poor inhibitors of human placental microsomal aromatase, most of the other compounds are modest inhibitors, while 7α-acetoxy-6β-azidoandrost-4-ene-3,17-dione 24 is a potent inhibitor of the enzyme (IC 50-value = 0.40 μ mol dm-3).
- Njar, Vincent C. O.,Hartmann, Rolf W.,Robinson, Cecil H.
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p. 985 - 992
(2007/10/02)
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- SYNTHESIS OF 19-HYDROXYSTEROIDS I. NEW SYNTHESIS OF 19-HYDROXYTESTOSTERONE
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For obtaining 19-hydroxytestosterone from dehydroepiandrosterone a new scheme of synthesis has been developed the key stages of which are the reduction of the 17-keto group to a 17-alcohol, the functionalization of the 19-methyl group via the bromohydrin with the formation of a 6β,19-epoxide, the selective hydrolysis of the free β-acetoxy group, the conversion of the 3β-hydroxy-5α-bromo derivative into the Δ4-3-ketone, and the reductive cleavage of the 6β,19-epoxide ring.
- Kovganko, N. V.,Kashkan, Zh. N.,Chernov, Yu. G.
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p. 584 - 588
(2007/10/02)
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- Photoinduced Molecular Transformations. Part 132. A Two-Step Intramolecular Transposition of the 17β-Acetyl Group of Pregnan-20-one to C-18 through the Formation of Cyclobutanols by the Reaction of the Excited Carbonyl, followed by a Selective β-Scission of Alkoxyl Radicals generated..
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New two-step transformations of a pregnan-20-one into 18-functionalized androstanes and 18a,18b-dihomoandrostanes are described; a type-II reaction of an excited pregnan-20-one protected in the A,B-ring gave the corresponding 20-hydroxy-18,20-cyclopregnane.Selective β-scission of the cyclobutanoxylradicals generated by irradiation of the nitrite or the hypoiodite gave a 5:4 ratio of the corresponding 18a,18b-dihomo-5α-androstane-18a-one and 18-iodoandrostan-17β-yl acetate in 89percent yield or 18a,18b-dihomo-5α-androstane-17,18a-dione 17-oxime in 83percent yield.The transformation involves a novel two-step intramolecular transposition of the 17β-acetyl group to C-18, and an oxygen insertion to the C-17-C-20 bond of pregnan-20 one.Several chemoselective transformations of the functional groups of the 18-iodoandrostan-17-one and 18a,18b-dihomo-5α-pregnan-18a-one, including the synthesis of 3β-hydroxy-18a,18b-dihomoandrost-5-ene-17,18a-dione, are reported.
- Suginome, Hiroshi,Nakayama, Yutaka
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p. 1843 - 1848
(2007/10/02)
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- Synthesis and NMR Studies of Some Steriodal Isoxazoles
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A short synthesis of 17α-pregna-2,4-dien-isoxazol-17β-ol (1) is described using mild reaction conditions and with a high overall yield.The equilibrium between keto-enolic forms has been studied by 1H NMR methods.Complete assignments of all the resonances in the 1H and 13C NMR spectra of Danazol have been made using a variety of one and two-dimensional correlation methods. 13C NMR spectra of all the intermediate and related model compounds were also assigned. Key words: Anabolic Agents, Isoxazolinic Steroids, 17α-Pregna-2,4-dien-isoxazol-17β-ol, Synthesis, NMR Spectra
- Giacopello, Sergio,Deluca, Monica E.,Seldes, Alicia M.
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p. 891 - 897
(2007/10/02)
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- The Mechanism of Cytochrome P-450 Dependent C-C Bond Cleavage: Studies on 17α-Hydroxylase-17,20-lyase
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It is shown that formation of 17α-hydroxyandrost-5-en-3β-ol from pregnenolone occurs solely at the expense of the cleavage of the C-17-C-20 bond of the precursor and is best rationalised by invoking the participation of an FeIII-OOH intermediate in the acyl-carbon fission process.
- Corina, David L.,Miller, Sharon L.,Wright, J. Neville,Akhtar, Muhammad
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p. 782 - 783
(2007/10/02)
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- EPIMERIC 17-HYDROXY DERIVATIVES OF 14β-ANDROST-5-EN-3β-YL ACETATE
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A new, six-step synthesis of 3β-hydroxy-14β-androst-5-en-17-one (IX) starting from 3β-hydroxyandrost-5-en-17-one has been elaborated.Reduction of acetate X with sodium borohydride afforded 17α-hydroxy-14β-androst-5-en-3β-yl acetate (XI).The corresponding 17β-derivative XIV was obtained by epimerization of 17α-O-tosyl derivative XIII with sodium nitrite in hexamethylphosphoramide.The 13C and 1H NMR spectra of 14β-androstane derivatives are discussed.
- Cerny, Ivan,Pouzar, Vladimir,Budesinsky, Milos,Drasar, Pavel,Havel, Miroslav
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p. 2510 - 2520
(2007/10/02)
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