PL214913B1 - New 3beta, 11alpha-dihydroxy-17a-oxa-D-homo-androst-5-en-17-one and method of its manufacturing - Google Patents
New 3beta, 11alpha-dihydroxy-17a-oxa-D-homo-androst-5-en-17-one and method of its manufacturingInfo
- Publication number
- PL214913B1 PL214913B1 PL391368A PL39136810A PL214913B1 PL 214913 B1 PL214913 B1 PL 214913B1 PL 391368 A PL391368 A PL 391368A PL 39136810 A PL39136810 A PL 39136810A PL 214913 B1 PL214913 B1 PL 214913B1
- Authority
- PL
- Poland
- Prior art keywords
- androst
- homo
- oxa
- dihydroxy
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- 238000004519 manufacturing process Methods 0.000 title claims 2
- 241000751139 Beauveria bassiana Species 0.000 claims description 6
- 244000005700 microbiome Species 0.000 claims description 6
- 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
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound 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 4
- 230000006698 induction Effects 0.000 claims description 3
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 claims description 2
- 229960002847 prasterone Drugs 0.000 claims description 2
- 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 6
- 150000003431 steroids Chemical class 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 230000009466 transformation Effects 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 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 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000896533 Gliocladium Species 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
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- RSIHSRDYCUFFLA-DYKIIFRCSA-N boldenone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 RSIHSRDYCUFFLA-DYKIIFRCSA-N 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- RSIHSRDYCUFFLA-UHFFFAOYSA-N dehydrotestosterone Natural products O=C1C=CC2(C)C3CCC(C)(C(CC4)O)C4C3CCC2=C1 RSIHSRDYCUFFLA-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 201000000079 gynecomastia Diseases 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- -1 steroid ketones Chemical class 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest nowy 3e,11a-dihydroksy-17a-oxa-D-homo-androst-5-en-17-on, o wzorze 2 przedstawionym na rysunku, oraz sposób jego wytwarzania.The present invention relates to a novel 3e, 11a-dihydroxy-17a-oxa-D-homo-androst-5-en-17-one, of the formula 2 shown in the drawing, and a method of its preparation.
Związek ten, ze względu na swoją potencjalną aktywność biologiczną, może znaleźć zastosowanie w przemyśle farmaceutycznym.Due to its potential biological activity, this compound may find application in the pharmaceutical industry.
Znane steroidowe D-homo-laktony, w zależności od budowy, wykazują różnorodną aktywność biologiczną, między innymi antynowotworową, antyandrogenną i antybakteryjną (J. A. Cella, C. M. Kagawa. J. Am. Chem. Soc. 1957, 79, s. 4808-9; E. A. Djurendić, M. N. Sakac, M. P. Zavis, A. R. Gaković,Known steroidal D-homo-lactones, depending on their structure, exhibit various biological activities, including anti-tumor, anti-androgenic and antibacterial activity (JA Cella, CM Kagawa. J. Am. Chem. Soc. 1957, 79, pp. 4808-9; EA Djurendić, MN Sakac, MP Zavis, AR Gaković,
J. J. Ćanadi, S. A. Andrić, O. R. Klisurić, V. V. Kojić, G. M. Bogdanović, K. M. Penov Gasi, Steroids, 2008, 73, s. 681-8).J. J. Ćanadi, S. A. Andric, O. R. Klisurić, V. V. Kojić, G. M. Bogdanović, K. M. Penov Gasi, Steroids, 2008, 73, pp. 681-8).
Testolakton (17a-oxa-D-homo-androst-1,4-dien-3,17-dion) jest znanym inhibitorem aromatazy, hamującym rozwój hormono-zależnych nowotworów, raka piersi i prostaty oraz zapobiega przerostowi prostaty. Związek ten jest także stosowany w terapii dolegliwości związanych z zachwianiem równowagi estrogenno-androgennej, np. w ginekomastii oraz przedwczesnym dojrzewaniu (H.M. Liu, H. Li, L. Shan, J. Wu, Steroids, 2006, 71, s. 931-4).Testolactone (17a-oxa-D-homo-androst-1,4-dien-3,17-dione) is a known aromatase inhibitor that inhibits the development of hormone-dependent tumors, breast and prostate cancer and prevents prostate hyperplasia. This compound is also used in the treatment of ailments related to estrogen-androgen imbalance, e.g. in gynecomastia and premature puberty (HM Liu, H. Li, L. Shan, J. Wu, Steroids, 2006, 71, pp. 931-4). ).
Aktualnie prowadzone są badania nad syntezą pochodnych testolaktonu zawierających dodatkową grupę hydroksylową, 16-oxa analogów i ich epoksypochodnych oraz poznaniem ich aktywności biologicznej uzyskanych połączeń (A. M. H. Brodie, V. C. O. Njar, J Steroid Biochem. Mol. Biol, 1998, 66, s. 1-10; E. A. Djurendić, M. P. Zavis, M. N. Sakac, J. J. Ćanadi, V. V. Kojić, G.M. Bogdanović,Currently, research is being conducted on the synthesis of testolactone derivatives containing an additional hydroxyl group, 16-oxa analogues and their epoxy derivatives, as well as learning about their biological activity of the obtained combinations (AMH Brodie, VCO Njar, J Steroid Biochem. Mol. Biol, 1998, 66, pp. 1-6). 10; EA Djurendić, MP Zavis, MN Sakac, JJ Ćanadi, VV Kojić, GM Bogdanović,
K. M. Penov Gasi, Steroids, 2009, 74, s. 983-8).K. M. Penov Gasi, Steroids, 2009, 74, pp. 983-8).
Z opisu patentowego PL 194390 znana jest reakcja prowadzenia 11a-hydroksylacji steroidów typu androstanu przez enzymy zawarte w komórkach szczepu z gatunku Beauveria bassiana. W ten sposób uzyskano 11a-hydroksy-1-dehydro-testosteron, z 1-dehydrotestosteronu.The PL 194390 patent describes the reaction of 11a-hydroxylation of androstane-type steroids by enzymes contained in cells of the Beauveria bassiana species. Thus, 11α-hydroxy-1-dehydro-testosterone was obtained from 1-dehydrotestosterone.
Szereg szczepów grzybów z rodzaju Penicillium, Aspergillus, Gliocladium i bakterii Rhodochrous rhodochrous prowadzi utlenienie steroidowych 4-en-3,17-dionów, 4-en-3,20-dionów lub 3e-hydroksy-androst-5-en-17-onów do D-laktonów (T. Kołek, A. Szpineter, A. Świzdor, Steroids, 2008, 73, s. 1441-1445; A. C. Hunter, E. Coyle, F. Morse, C. Dedi, H. T. Dodd, S. J. Koussoroplis, Biochim. Biophys. Acta, 2009, 1791, s. 110-7).A number of fungi of the genus Penicillium, Aspergillus, Gliocladium and Rhodochrous rhodochrous bacteria carry out the oxidation of steroid 4-en-3,17-diones, 4-ene-3,20-diones or 3e-hydroxy-androst-5-en-17-ones to D- lactones (T. Kołek, A. Szpineter, A. Świzdor, Steroids, 2008, 73, pp. 1441-1445; AC Hunter, E. Coyle, F. Morse, C. Dedi, HT Dodd, SJ Koussoroplis, Biochim. Biophys. Acta, 2009, 1791, pp. 110-7).
Dotychczas brak jest doniesień literaturowych na temat otrzymywania jednoprocesowego, mikrobiologicznego utlenienia i hydroksylacji steroidowych ketonów do 11a-hydroksy-D-laktonów.So far, there are no reports in the literature on the preparation of single-process, microbial oxidation and hydroxylation of steroid ketones to 11 [ alpha] -hydroxy-D-lactones.
Istotą wynalazku jest nowy 3e,11a-dihydroksy-17a-oxa-D-homo-androst-5-en-17-on, o wzorze 2 przedstawionym na rysunku.The essence of the invention is the novel 3e, 11a-dihydroxy-17a-oxa-D-homo-androst-5-en-17-one, with the formula 2 shown in the drawing.
Sposób, według wynalazku, polega na tym, że 33-hydroksy-androst-5-en-17-on (dehydroepiandrosteron, DHEA), o wzorze 1, przekształca się za pomocą systemu enzymatycznego zawartego w komórkach grzyba strzępkowego z gatunku Beauveria bassiana.The method according to the invention consists in transforming 33-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA) of the formula I with the enzyme system contained in the cells of the filamentous fungus Beauveria bassiana.
Korzystnie jest, gdy stosuje się 12-godzinną indukcję substratową kultury mikroorganizmu.Preferably, a 12-hour substrate induction of the microorganism culture is used.
Korzystne też jest, gdy proces transformacji prowadzi się wodną kulturą szczepu, przy ciągłym wstrząsaniu reagentów oraz w temperaturze 293-300K.It is also advantageous if the transformation process is carried out with an aqueous strain culture, with continuous shaking of the reactants and at a temperature of 293-300K.
Postępując zgodnie z wynalazkiem, w wyniku działania układu enzymatycznego zawartego w komórkach grzyba strzępkowego Beauveria bassiana, 33-hydroksy-androst-5-en-17-on, o wzorze 1, ulega regioselektywnej hydroksylacji w pozycji 11α- oraz utlenieniu C-17-ketonu do laktonu, o wzorze 2.By following the invention, 33-hydroxy-androst-5-en-17-one, of the formula 1, is regioselective in the 11α-position and oxidation of the C-17-ketone as a result of the enzyme system contained in the cells of the filamentous fungus Beauveria bassiana. to a lactone of formula 2.
Uzyskany w ten sposób produkt wydziela się z wodnej kultury mikroorganizmu, znanym sposobem przez ekstrakcję chloroformem.The product 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 otrzymanie 3e,11a-dihydroksy-17a-oxa-D-homo-androst-5-en-17-onu, z wydajnością około 30%, w temperaturze pokojowej i pH bliskim obojętnemu, a stosując 12-godzinną indukcję substratową kultury mikroorganizmu osiąga się ponad 50% wzrost wydajności reakcji (do 63%).The main advantage of the invention is the preparation of 3e, 11a-dihydroxy-17a-oxa-D-homo-androst-5-en-17-one with a yield of about 30%, at room temperature and close to neutral pH, using a 12-hour substrate induction. in the culture of the microorganism, more than 50% increase in the yield of the reaction is achieved (up to 63%).
Wynalazek jest bliżej objaśniony w przykładach wykonania.The invention is explained in more detail in the working examples.
P r z y k ł a d 1P r z k ł a d 1
Do kolby Erlenmayera o pojemności 250 cm3, w której znajduje się 100 cm3 sterylnej pożywki 3 zawierającej 3 g glukozy i 1 g peptobaku, wprowadza się 1 cm3 zawiesiny komórek Beauveria bassiana, wzrastających przez dwa dni w temperaturze około 293K, na tym samym podłożu przy ciągłym wstrząsaniu. Po 48 godzinach wzrostu, dodaje się 30 mg 3e-hydroksy-androst-5-en-17-onu, o wzorze 1, 3 rozpuszczonego w 0,5 cm3 acetonu. Transformację prowadzi się przy ciągłym wstrząsaniu przez kolejne 48 godzin w takich samych warunkach, w których prowadzi sie hodowlę mikroorganizmu.Into an Erlenmayer flask with a capacity of 250 cm 3 containing 100 cm 3 of sterile medium 3 containing 3 g of glucose and 1 g of peptobak, 1 cm 3 of a suspension of Beauveria bassiana cells, grown for two days at a temperature of about 293K, is added the substrate with continuous shaking. After 48 hours of growth, is added 30 mg of 3e-hydroxy-androst-5-en-17-one of formula 1, 3, dissolved in 0.5 cm 3 of acetone. The transformation is carried out by shaking continuously for a further 48 hours under the same conditions as for the cultivation of the microorganism.
PL 214 913 B1PL 214 913 B1
Uzyskane roztwory transformacyjne ekstrahuje się trzykrotnie chloroformem, osusza bezwodnym siarczanem magnezu i odparowuje rozpuszczalnik. Otrzymuje się 40 mg surowego produktu, który oczyszcza się chromatograficznie używając jako eluentu mieszaniny: octan etylu:chlorek metylenu:aceton:2-propanol, w stosunku 3:1:0,5:0,15.The resulting transformation solutions were extracted three times with chloroform, dried with anhydrous magnesium sulfate, and the solvent was evaporated. 40 mg of crude product are obtained, which are purified by chromatography using a 3: 1: 0.5: 0.15 mixture of ethyl acetate: methylene chloride: 2-propanol as eluent.
Na tej drodze otrzymuje się 10 mg 33,11a-dihydroksy-17a-oxa-D-homo-androst-5-en-17-onu (wydajność izolowana 30%).In this way, 10 mg of 33,11a-dihydroxy-17a-oxa-D-homo-androst-5-en-17-one are obtained (30% isolated yield).
P r z y k ł a d 2P r z k ł a d 2
Do kolby Erlenmayera o pojemności 250 cm3, w której znajduje się 100 cm3 sterylnej pożywki 3 zawierającej 3 g glukozy i 1 g peptobaku, wprowadza się 1 cm3 zawiesiny komórek Beauveria bassiana wzrastających przez dwa dni na tym samym podłożu przy ciągłym wstrząsaniu w temperaturze około 295K. Po 24 godzinach wzrostu, do kultury drobnoustroju dodaje się 2 mg 33-hydroksy-androst5-en-17-onu, o wzorze 1, rozpuszczonego w 0,1 mL acetonu i hodowlę pozostawia się w tych samych warunkach na kolejne 12 godzin. Następnie dodaje się 30 mg 33-hydroksy-androst-5-en-17-onu, o wzorze 1, rozpuszczonego w 0,5 cm3 acetonu. Dalszą transformację i izolację produktu prowadzi się tak jak w przykładzie 1.A 250 cm 3 Erlenmayer flask containing 100 cm 3 of sterile medium 3 containing 3 g of glucose and 1 g of peptobaku is filled with 1 cm 3 of a suspension of Beauveria bassiana cells grown for two days in the same medium with continuous shaking at a temperature of about 295K. After 24 hours of growth, 2 mg of 33-hydroxy-androst-5-en-17-one, of formula 1, dissolved in 0.1 mL of acetone, are added to the culture of the microorganism and the culture is left under the same conditions for another 12 hours. Then is added 30 mg of 33-hydroxy-androst-5-en-17-one of formula 1, dissolved in 0.5 cm 3 of acetone. Further transformation and isolation of the product was carried out as in Example 1.
Na tej drodze otrzymuje się 23 mg 3β,11α-dihydroksy-17a-oxa-D-homo-androst-5-en-17-onu (wydajność izolowana 63%).In this way, 23 mg of 3β, 11α-dihydroxy-17a-oxa- D -homo-androst-5-en-17-one are obtained (63% isolated yield).
Uzyskany produkt charakteryzuje się następującymi danymi spektralnymi:The obtained product is characterized by the following spectral data:
1H-NMR: δ (ppm) w CD3OD: 1,20 (s, 19-H3); 1,38 (s, I8-H3); 3,45 (m, 3α-Η); 3,88 (m, 11β-Η); 5,46 (d, J = 5,7 Hz); 1 H-NMR: δ (ppm) in CD3OD: 1.20 (s, 19-H3); 1.38 (s, I8-H3); 3.45 (m, 3α-Η); 3.88 (m, 11β-Η); 5.46 (d, J = 5.7 Hz);
13C-NMR: δ (ppm) w CD3OD: 174,4 (C-17); 142,7 (C-5); 121,4 (C-6); 83,6 (C-13); 72.5 (C-3); 69,0 (C-11); 56,9 (C-9); 50,3 (C-12); 47,0 (C-14); 43,3 (C-4); 40,4 (C-1); 39.5 (C-10), 35,5 (C-2); 32,3 (C-7); 32,2 (C-8); 29,4 (C-16); 21,1 (C-18); 20,8 (C-15); 19,2 (C-19); 13 C-NMR: δ (ppm) in CD3OD: 174.4 (C-17); 142.7 (C-5); 121.4 (C-6); 83.6 (C-13); 72.5 (C-3); 69.0 (C-11); 56.9 (C-9); 50.3 (C-12); 47.0 (C-14); 43.3 (C-4); 40.4 (C-1); 39.5 (C-10), 35.5 (C-2); 32.3 (C-7); 32.2 (C-8); 29.4 (C-16); 21.1 (C-18); 20.8 (C-15); 19.2 (C-19);
IR omax (cm-1): 3440, 1716.IR omax (cm -1 ): 3440,1716.
Claims (5)
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| PL391368A PL214913B1 (en) | 2010-05-28 | 2010-05-28 | New 3beta, 11alpha-dihydroxy-17a-oxa-D-homo-androst-5-en-17-one and method of its manufacturing |
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| PL391368A PL214913B1 (en) | 2010-05-28 | 2010-05-28 | New 3beta, 11alpha-dihydroxy-17a-oxa-D-homo-androst-5-en-17-one and method of its manufacturing |
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| Publication Number | Publication Date |
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| PL391368A1 PL391368A1 (en) | 2010-10-11 |
| PL214913B1 true PL214913B1 (en) | 2013-09-30 |
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Effective date: 20130528 |