PL214910B1 - Process for simultaneous preparation of 3ß, 7alpha-dihydroxyandrost-5-en-17-one and 3ß, 7ß-dihydroxyandrost-5-en-17-one - Google Patents
Process for simultaneous preparation of 3ß, 7alpha-dihydroxyandrost-5-en-17-one and 3ß, 7ß-dihydroxyandrost-5-en-17-oneInfo
- Publication number
- PL214910B1 PL214910B1 PL392488A PL39248810A PL214910B1 PL 214910 B1 PL214910 B1 PL 214910B1 PL 392488 A PL392488 A PL 392488A PL 39248810 A PL39248810 A PL 39248810A PL 214910 B1 PL214910 B1 PL 214910B1
- Authority
- PL
- Poland
- Prior art keywords
- dihydroxyandrost
- dhea
- formula
- hydroxy
- substrate
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- OLPSAOWBSPXZEA-JIEICEMKSA-N 7alpha-hydroxydehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3[C@H](O)C=C21 OLPSAOWBSPXZEA-JIEICEMKSA-N 0.000 title claims description 10
- OLPSAOWBSPXZEA-GCNMQWDSSA-N 7beta-hydroxydehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3[C@@H](O)C=C21 OLPSAOWBSPXZEA-GCNMQWDSSA-N 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 5
- 230000009466 transformation Effects 0.000 claims description 6
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 claims description 5
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical group C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- 241000306282 Umbelopsis isabellina Species 0.000 claims description 4
- 230000000813 microbial effect Effects 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 2
- 230000036983 biotransformation Effects 0.000 claims 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000033444 hydroxylation Effects 0.000 description 4
- 238000005805 hydroxylation reaction Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 241000233866 Fungi Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 241000235526 Mucor racemosus Species 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229940094957 androgens and estrogen Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 239000011942 biocatalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 230000001067 neuroprotector Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Steroid Compounds (AREA)
Description
Przedmiotem wynalazku jest sposób jednoczesnego wytwarzania 33,7a-dihydroksyandrost-5-en-17-onu, o wzorze 2, i 33,73-dihydroksyandrost-5-en-17-onu, o wzorze 3, przedstawionych na rysunku.The present invention relates to a process for the simultaneous preparation of 33.7a-dihydroxyandrost-5-en-17-one of the formula 2 and 33.73-dihydroxyandrost-5-en-17-one of the formula 3 shown in the drawing.
Związki te mogą znaleźć zastosowanie w przemyśle farmaceutycznym.These compounds can find application in the pharmaceutical industry.
Dehydroepiandrosteron (DHEA, 33-hydroksyandrost-5-en-17-on), syntetyzowany w warstwie siateczkowej kory nadnerczy oraz tkankach mózgu ssaków, jest prekursorem męskich i żeńskich hormonów płciowych, a także odgrywa ważną rolę w funkcjonowaniu centralnego układu nerwowego i układu immunologicznego (R. C. Bron, C. Jasio, V. Papadopoulos, J. Neurochem. 2000, 74, ss. 847-59). Wyniki wielu badań wskazują, że neuroprotektorowe działanie wykazuje nie DHEA, a jego metabolity, głównie hydroksypochodne przy C-7: 3β,7α-dihydroksyandrost-5-en-17-on ^α-hydroksy-DHEA) i 33,73-dihydroksyandrost-5-en-17-on (73-hydroksy-DHEA). Wymienione metabolity są też aktywnymi immunomodulatorami (A. Pringle, W. Schmidt, J. Deans, E. Wulfert, K. Reymann, L. Sundstrom, Eur. J. Neurosci, 2003, 18, ss. 117-24; D. L. Auci, C. L. Reading, J. M. Frincke, Autoimmunity Rev., 2009, 8, ss. 369-72).Dehydroepiandrosterone (DHEA, 33-hydroxyandrost-5-en-17-one), synthesized in the reticular layer of the adrenal cortex and in mammalian brain tissues, is a precursor of male and female sex hormones, and also plays an important role in the functioning of the central nervous system and the immune system ( RC Bron, C. Jasio, V. Papadopoulos, J. Neurochem. 2000, 74, pp. 847-59). The results of many studies show that the neuroprotector effect is not shown by DHEA, but its metabolites, mainly hydroxy derivatives at C-7: 3β, 7α-dihydroxyandrost-5-en-17-one ^ α-hydroxy-DHEA) and 33.73-dihydroxyandrost- 5-en-17-one (73-hydroxy-DHEA). These metabolites are also active immunomodulators (A. Pringle, W. Schmidt, J. Deans, E. Wulfert, K. Reymann, L. Sundstrom, Eur. J. Neurosci, 2003, 18, pp. 117-24; DL Auci, CL Reading, JM Frincke, Autoimmunity Rev., 2009, 8, pp. 369-72).
Enzymatyczna hydroksylacja, w której utleniaczem jest tlen atmosferyczny, to efektywna, przyjazna dla środowiska metoda utleniania wiązania C-H. Jako biokatalizatory najczęściej stosowane są grzyby strzępkowe, ze względu na różnorodność produkowanych przez nie hydroksylaz, jak i ich wysoką aktywność katalityczną (P. Fernandes, A. Gruz, B. Angelova, H. M. Pinheiro, J. M. S. Carbal, Enzyme Microbial Technology, 2003, 32, ss. 688-705).Enzymatic hydroxylation, in which the oxidant is atmospheric oxygen, is an effective, environmentally friendly method of oxidizing the C-H bond. Filamentous fungi are most often used as biocatalysts due to the variety of hydroxylases they produce and their high catalytic activity (P. Fernandes, A. Gruz, B. Angelova, HM Pinheiro, JMS Carbal, Enzyme Microbial Technology, 2003, 32, pp. 688-705).
Znane są z doniesień literaturowych, głównie z ostatnich lat, liczne przykłady enzymatycznej hydroksylacji DHEA. W wielu tkankach ssaków (wątroby, mózgu, skóry) identyfikowano obecność 7α-hydroksy-DHEA i 73-hydroksy-DHEA (S. B. Kim, S. Chalbot, D. Pompon, D. H. Jo, R. Morfin,Numerous examples of enzymatic hydroxylation of DHEA are known from literature reports, mainly from recent years. The presence of 7α-hydroxy-DHEA and 73-hydroxy-DHEA (S. B. Kim, S. Chalbot, D. Pompon, D. H. Jo, R. Morfin,
J. Steroid. Biochem. Mol. Biol., 2004, 92, ss. 383-389; S. Chalbot, R. Morfin, Drug Metabolism and Disposition, 2005, 33, ss. 363-69). Te metabolity wykazują wyższą aktywność immunologiczną i antyglukokortykoidową niż DHEA. Ponadto nie wpływają one na wzrost poziomu androgenów i estrogenów. W badaniach przesiewowych nad hydroksylacją mikrobiologiczną, mieszaninę 7α- i 73-hydroksyDHEA identyfikowano po transformacji przez trzydzieści siedem, spośród sześćdziesięciu czterech szczepów zdolnych do hydroksylacji DHEA (T. G. Lobastova, S. A. Gulevskaya, G. V. Sukhodolskaya,J. Steroid. Biochem. Moth. Biol., 2004, 92, pp. 383-389; S. Chalbot, R. Morfin, Drug Metabolism and Disposition, 2005, 33, pp. 363-69). These metabolites show higher immune and antiglucocorticoid activity than DHEA. Moreover, they do not increase the level of androgens and estrogens. In screening for microbial hydroxylation, a mixture of 7α- and 73-hydroxyDHEA was identified after transformation by thirty-seven of the sixty-four strains capable of hydroxylating DHEA (T. G. Lobastova, S. A. Gulevskaya, G. V. Sukhodolskaya,
K. F. Turchin, M. V. Donora, Biocatal. Biotransform, 2007, 25; ss. 434-42). Po czterodniowej transformacji DHEA przez szczep Mucor racemosus uzyskano 40,9% 7α-hydroksy-DHEA i 18% 73-hydroksyDHEA (H. Li, H-M Liu, W. Ge, L. Huang, L. Shan, Steroids, 2005, 70, ss. 970-73).K. F. Turchin, M. V. Donor, Biocatal. Biotransform, 2007,25; pp. 434-42). After a four-day transformation of DHEA by the Mucor racemosus strain, 40.9% 7α-hydroxy-DHEA and 18% 73-hydroxyDHEA were obtained (H. Li, HM Liu, W. Ge, L. Huang, L. Shan, Steroids, 2005, 70, pp. 970-73).
Wynalazek dotyczy sposobu jednoczesnego wytwarzania 3β,7α-dihydroksyandrost-5-en-17-onu ^-hydroksy-DHEA), o wzorze 2, i 3β,7β-dihydroksyandrost-5-en-17-onu ^-hydroksy-DHEA), o wzorze 3, na drodze mikrobiologicznej hydroksylacji 3β-hydroksyandrost-5-en-17-on (DHEA), o wzorze 1.The invention relates to a process for the simultaneous preparation of 3β, 7α-dihydroxyandrost-5-en-17-one [beta] -hydroxy-DHEA), of the formula 2, and 3β, 7β-dihydroxyandrost-5-en-17-one [beta] -hydroxy-DHEA), of formula 3 by microbial hydroxylation of 3β-hydroxyandrost-5-en-17-one (DHEA) of formula 1.
Istota wynalazku polega na tym, że 3β-hydroksyandrost-5-en-17-on (DHEA) przekształca się do 3β,7α-dihydroksyandrost-5-en-17-onu ^α-hydroksy-DHEA) i 3β,7β-dihydroksyandrost-5-en-17-onu ^β-hydroksy-DHEA) za pomocą kultury szczepu Mortierella isabellina AM212.The essence of the invention is that 3β-hydroxyandrost-5-en-17-one (DHEA) is transformed into 3β, 7α-dihydroxyandrost-5-en-17-one (α-hydroxy-DHEA) and 3β, 7β-dihydroxyandrost -5-en-17-one ^ β-hydroxy-DHEA) with the culture of the strain Mortierella isabellina AM212.
Korzystne jest, gdy proces transformacji prowadzi się wodną kulturą szczepu, przy wstrząsaniu reagentów, w temperaturze 293-300K.It is advantageous if the transformation process is carried out with an aqueous strain culture, with agitation of the reactants, at a temperature of 293-300K.
Postępując zgodnie z wynalazkiem, w wyniku działania układu enzymatycznego zawartego w komórkach grzyba Mortierella isabellina AM212 3β-hydroksyandrost-5-en-17-on przekształca się do 3β,7α-dihydroksyandrost-5-en-17-onu i 3β,7β-dihydroksyandrost-5-en-17-onu. Uzyskaną w ten sposób mieszaninę produktów oddziela się, od wodnej kultury mikroorganizmu, znanym sposobem przez ekstrakcję chloroformem.Following the invention, as a result of the action of the enzyme system contained in the cells of the fungus Mortierella isabellina AM212 3β-hydroxyandrost-5-en-17-one is converted into 3β, 7α-dihydroxyandrost-5-en-17-one and 3β, 7β-dihydroxyandrost -5-en-17-one. The product mixture obtained in this way is separated from the aqueous culture of the microorganism by a known method by extraction with chloroform.
Zasadniczą zaletą wynalazku jest jednoczesne otrzymanie 3β,7α-dihydroksyandrost-5-en-17-onu i 3β,7β-dihydroksyandrost-5-en-17-onu, z łączną wydajnością 77,5%, w temperaturze pokojowej i pH bliskim obojętnemu.The main advantage of the invention is the simultaneous preparation of 3β, 7α-dihydroxyandrost-5-en-17-one and 3β, 7β-dihydroxyandrost-5-en-17-one, with a total yield of 77.5%, at room temperature and near neutral pH.
Wynalazek jest bliżej objaśniony na przykładzie wykonania.The invention is explained in more detail using an exemplary embodiment.
P r z y k ł a dP r z k ł a d
Do kolby Erlenmayera o pojemności 300 cm3, w której znajduje się 100 cm3 sterylnej po3 żywki zawierającej 3 g glukozy i 1 g aminobaku, wprowadza się 2 cm3 zawiesiny komórek Mortierella isabellina AM212, które wzrastają, przez trzy dni na tym podłożu, przy stałym wstrząsaniu w temperaturze 295K.To the Erlenmeyer flask with a capacity of 300 cm 3, which is 100 cm 3 of sterile 3 nutrient medium containing 3 g of glucose and 1 g aminobaku introduced 2 cm 3 cell suspension Mortierella isabellina AM212 that grow for three days on this substrate. with constant shaking at a temperature of 295K.
PL 214 910 B1PL 214 910 B1
Po trzech dniach wzrostu dodaje się 20 mg 33-hydroksyandrost-5-en-17-onu (DHEA), o wzorze 1, rozpuszczonego w 1 cm3 acetonu. Transformację prowadzi się, przy ciągłym wstrząsaniu, przez kolejne 8 godzin w warunkach, w których prowadzi się hodowlę mikroorganizmu. Następnie uzyskane roztwory transformacyjne ekstrahuje się trzykrotnie chloroformem, osusza bezwodnym siarczanem magnezu i odparowuje rozpuszczalnik. Otrzymuje się 25,8 mg surowego produktu, który oczyszcza się chromatograficznie, używając jako eluentu mieszaniny aceton : octan etylu : chlorek metylenu (0,5:1,5:1).After three days of growth, was added 20 mg of 33-hydroxyandrost-5-en-17-one (DHEA), of formula 1, dissolved in 1 cm 3 of acetone. The transformation is carried out under continuous shaking for another 8 hours under culturing conditions for the microorganism. The resulting transformation solutions were then extracted three times with chloroform, dried with anhydrous magnesium sulfate, and the solvent was evaporated. 25.8 mg of crude product is obtained, which product is purified by chromatography using acetone: ethyl acetate: methylene chloride (0.5: 1.5: 1) as the eluent.
Na tej drodze otrzymuje się 11,3 mg (53,5%) 3β,7α-dihydroksyandrost-5-en-17-onu i 5,1 mg (24%) 33,73-dihydroksyandrost-5-en-17-onu (łączna wydajność 77,5%).In this way, 11.3 mg (53.5%) of 3β, 7α-dihydroxyandrost-5-en-17-one and 5.1 mg (24%) of 33.73-dihydroxyandrost-5-en-17-one are obtained (total yield 77.5%).
Uzyskane produkty charakteryzują się następującymi danymi spektralnymi:The obtained products are characterized by the following spectral data:
3β,7α-dihydroksyandrost-5-en-17-on:3β, 7α-dihydroxyandrost-5-en-17-one:
1H-NMR (δ ppm) w CDCl3: 0,88 (3H, s, 18-CH3); 1,01 (3H, s, 19-CH3); 3,58 (1H, m, Wh=32,6 Hz, 3α-Η); 3,97 (1H, t, J = 3,6 Hz, 7β-Η); 5,64 (1H, d, J = 5,0 Hz, 6-H). 1 H-NMR (δ ppm) in CDCl 3: 0.88 (3H, s, 18-CH 3); 1.01 (3H, s, 19-CH3); 3.58 (1H, m, Wh = 32.6 Hz, 3α-Η); 3.97 (1H, t, J = 3.6 Hz, 7β-Η); 5.64 (1H, d, J = 5.0 Hz, 6-H).
13C NMR (δ ppm): 220 (C-17); 146,3 (C-5); 123,3 (C-6); 70,9 (C-3); 64,0 (C-7); 46,8 (C-14); 44,6 (C-9); 42,3 (C-13); 41,6 (C-4); 37,2 (C-8); 36,9 (C-1); 36,6 (C-10); 35,5 (C-16); 31,0 (C-12); 30,8 (C-2); 21,6 (C-15); 19,8 (C-11); 18,0 (C-19); 13,0 (C-18). 13 C NMR (δ ppm): 220 (C-17); 146.3 (C-5); 123.3 (C-6); 70.9 (C-3); 64.0 (C-7); 46.8 (C-14); 44.6 (C-9); 42.3 (C-13); 41.6 (C-4); 37.2 (C-8); 36.9 (C-1); 36.6 (C-10); 35.5 (C-16); 31.0 (C-12); 30.8 (C-2); 21.6 (C-15); 19.8 (C-11); 18.0 (C-19); 13.0 (C-18).
IR omax(cm1): 3394, 2932, 1731.IR o ma x (cm 1 ): 3394, 2932, 1731.
3β,7β-dihydroksyandrost-5-en-17-on:3β, 7β-dihydroxyandrost-5-en-17-one:
1H-NMR (δ ppm) w CDCl3: 0,89 (3H, s, 18-CH3); 1,07 (3H, s, 19-CH3); 3,55 (1H, m, Wh = 31,6 Hz, βα-ή); 3,95 (1H, dt, J = 2,0; 8,1 Hz, 7α-ή); 5,31 (1H, t, J = 1,8 Hz, 6-H). 1 H-NMR (δ ppm) in CDCl 3: 0.89 (3H, s, 18-CH 3); 1.07 (3H, s, 19-CH3); 3.55 (1H, m, Wh = 31.6 Hz, βα-ή); 3.95 (1H, dt, J = 2.0; 8.1 Hz, 7α-ή); 5.31 (1H, t, J = 1.8Hz, 6-H).
13C NMR (δ ppm): 221,2 (C-17); 143,6 (C-5); 125,4 (C-6); 72,8 (C-7); 71,2 (C-3); 51,1 (C-14); 13 C NMR (δ ppm): 221.2 (C-17); 143.6 (C-5); 125.4 (C-6); 72.8 (C-7); 71.2 (C-3); 51.1 (C-14);
48.1 (C-9); 47,7 (C-13); 41,5 (C-4); 40,4 (C-8); 36,8 (C-1); 36,6 (C-10); 35,9 (C-16); 31,4 (C-12);48.1 (C-9); 47.7 (C-13); 41.5 (C-4); 40.4 (C-8); 36.8 (C-1); 36.6 (C-10); 35.9 (C-16); 31.4 (C-12);
31.1 (C-2); 24,1 (C-15); 20,3 (C-11); 19,1 (C-19); 13,5 (C-18).31.1 (C-2); 24.1 (C-15); 20.3 (C-11); 19.1 (C-19); 13.5 (C-18).
IR umajcm'1): 3429, 2933, 1731.IR umajcm-1): 3429, 2933, 1731.
Claims (3)
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| PL392488A PL214910B1 (en) | 2010-09-23 | 2010-09-23 | Process for simultaneous preparation of 3ß, 7alpha-dihydroxyandrost-5-en-17-one and 3ß, 7ß-dihydroxyandrost-5-en-17-one |
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| PL392488A PL214910B1 (en) | 2010-09-23 | 2010-09-23 | Process for simultaneous preparation of 3ß, 7alpha-dihydroxyandrost-5-en-17-one and 3ß, 7ß-dihydroxyandrost-5-en-17-one |
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