PL212020B1 - Production method of testoloactane (17a-oxa—D-homo-androst-4-en-3,17-dione) - Google Patents
Production method of testoloactane (17a-oxa—D-homo-androst-4-en-3,17-dione)Info
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- PL212020B1 PL212020B1 PL386883A PL38688308A PL212020B1 PL 212020 B1 PL212020 B1 PL 212020B1 PL 386883 A PL386883 A PL 386883A PL 38688308 A PL38688308 A PL 38688308A PL 212020 B1 PL212020 B1 PL 212020B1
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- testoloactane
- androst
- oxa
- dione
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Przedmiotem wynalazku jest sposób wytwarzania testololaktonu, o wzorze 2, przedstawionym na rysunku.The present invention relates to a process for the preparation of testolactone of formula 2 shown in the drawing.
Steroidowe laktony wykazują różnorodną aktywność biologiczną, m.in. antynowotworową, antyandrogenną i antybakteryjną (G. E. Serafini, S. Moslemi. Mol. Cell. Endocrinol. 2001, 178, 117-131). Testolakton jest inhibitorem aromatazy, dzięki czemu hamuje rozwój hormono-zależnych nowotworów, głównie raka piersi i prostaty, a także ogranicza przerost prostaty. Jest skutecznym lekiem w przypadku zaburzenia równowagi estrogeny - androgeny, której skutkiem jest ginekomastia lub przedwczesne dojrzewanie. Enzymatyczne utlenienie, w którym nie stosuje się toksycznych odczynników jest konkurencyjną metodą w stosunku do utlenienia chemicznego. Szereg szczepów z rodzaju Penicillium, Aspergillus i Cylindrocarpon prowadzi efektywne utlenienie progesteronu lub androstendionu do testololaktonu, natomiast literatura nie podaje przykładów mikrobiologicznego utlenienia pregnenolonu do testololaktonu (H-M Liu, H. Li, L. Shan, J. Wu, Steroids 2006, 71, 931-934).Steroidal lactones exhibit various biological activities, including anti-cancer, anti-androgenic and anti-bacterial (G. E. Serafini, S. Moslemi. Mol. Cell. Endocrinol. 2001, 178, 117-131). Testolactone is an aromatase inhibitor, thanks to which it inhibits the growth of hormone-dependent neoplasms, mainly breast and prostate cancer, as well as reduces prostate hypertrophy. It is an effective drug in the case of estrogen-androgen imbalance, which results in gynecomastia or premature puberty. Enzymatic oxidation, which does not use toxic reagents, is a competitive method to chemical oxidation. A number of strains of the genus Penicillium, Aspergillus and Cylindrocarpon efficiently oxidize progesterone or androstenedione to testololactone, while the literature does not provide examples of microbiological oxidation of pregnenolone to testolactone (HM Liu, H. Li, L. Shan, J. Wu, Steroids 2006, 71, 931 -934).
Istota wynalazku polega na tym, że pregnenolon (33-hydroksy-5-pregnen-20-on) przekształcany jest do testololaktonu za pomocą kultury szczepu Penicillium camembertii.The essence of the invention lies in the fact that pregnenolone (33-hydroxy-5-pregnen-20-one) is converted into testolactone by means of the Penicillium camembertii strain culture.
Korzystne jest, gdy proces transformacji prowadzi się wodną kulturą szczepu, przy ciągłym mieszaniu reagentów, w temperaturze 293-300K.It is advantageous if the transformation process is carried out with the aqueous strain, with continuous mixing of the reagents, at the temperature of 293-300K.
Postępując zgodnie z wynalazkiem, w wyniku działania układu enzymatycznego zawartego w komórkach grzyba PeniciIlium camembertii pregnenolon utleniany jest do testololaktonu. Uzyskany w ten sposób produkt wydziela się z wodnej kultury mikroorganizmu, znanym sposobem przez ekstrakcję chloroformem.Proceeding according to the invention, due to the action of the enzyme system contained in the cells of the fungus PeniciIlium camembertii pregnenolone is oxidized to testolactone. 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 testololaktonu, jako głównego produktu reakcji, z wydajnością 74%, w temperaturze pokojowej i pH bliskim obojętnemu.The main advantage of the invention is that testolactone is obtained as the main reaction product with a yield of 74%, at room temperature and pH close to neutral.
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 Erlenmajera o pojemności 250 cm3, w której znajduje się 100 cm3 sterylnej pożywki zawierającej 3 g glukozy i 1g aminobaku, wprowadza się szczep Penicillium camembertii. Po trzech 3 dniach wzrostu dodaje się 20 mg pregnenolonu, o wzorze 1, rozpuszczonego w 1 cm3 acetonu. Transformację prowadzi się przy ciągłym wstrząsaniu przez 24 godziny w pięciu powtórzeniach w tych samych warunkach, w temperaturze 295K, przy pH=6,9. Następnie uzyskane roztwory transformacyjne ekstrahuje się trzykrotnie chloroformem, osusza bezwodnym siarczanem magnezu i odparowuje rozpuszczalnik. Otrzymuje się 130 mg surowego produktu, który oczyszcza się chromatograficznie używając jako eluentu mieszaniny: octan etylu:chlorek metylenu:aceton (3:1:1).The Penicillium camembertii strain is introduced into an Erlenmajer flask with a capacity of 250 cm 3 , in which there is 100 cm 3 of a sterile medium containing 3 g of glucose and 1 g of aminobac. After three 3 days of growth, 20 mg of pregnenolone of formula 1 dissolved in 1 cm 3 of acetone are added. The transformation is performed by shaking continuously for 24 hours in five replications under the same conditions at 295K, pH = 6.9. The resulting transformation solutions were then extracted three times with chloroform, dried with anhydrous magnesium sulfate, and the solvent was evaporated. 130 mg of crude product are obtained, which product is purified by chromatography using as eluent a mixture of: ethyl acetate: methylene chloride: acetone (3: 1: 1).
Na tej drodze otrzymuje się 74 mg testololaktonu (wydajność 74%).In this way 74 mg of testolactone are obtained (74% yield).
Uzyskany produkt charakteryzuje się następującymi danymi spektralnymi: t.t. 209-210oC; [a]20 = +46,2 (c 0.16 CHCI3);The obtained product is characterized by the following spectral data: mp 209-210 o C; [a] 20 = +46.2 (c 0.16 CHCl 3);
IR Vmax (cm-1): 1716, 1666, 1614, 1214; 1H-NMR δ (ppm): 1.16 (s, 19-H3), 1.35 (s, I8-H3), 2.59 (m, 16a-H), 2.68 (m, 16β-Η), 5.75 (s, 4-H);IR Vmax (cm -1 ): 1716, 1666, 1614, 1214; 1H-NMR δ (ppm): 1.16 (s, 19-H3), 1.35 (s, I8-H3), 2.59 (m, 16a-H), 2.68 (m, 16β-Η), 5.75 (s, 4- H);
13C-NMR: δ (ppm): 199.2 (C-3), 171.1 (C-17), 169.2 (C-5), 124.1 (C-4), 82.7 (C-13), 52.5 (C-9), 45.7 (C-14), 39.1 (C-12), 38.4 (C-10), 38.0 (C-8), 35.5 (C-1), 33.8 (C-2), 32.4 (C-6), 30.5 (C-7), 28.6 (C-16), 21.9 (C-11), 20.1 (C-18), 19.9 (C-15), 17.44 (C-19). 13 C-NMR: δ (ppm): 199.2 (C-3), 171.1 (C-17), 169.2 (C-5), 124.1 (C-4), 82.7 (C-13), 52.5 (C-9 ), 45.7 (C-14), 39.1 (C-12), 38.4 (C-10), 38.0 (C-8), 35.5 (C-1), 33.8 (C-2), 32.4 (C-6) , 30.5 (C-7), 28.6 (C-16), 21.9 (C-11), 20.1 (C-18), 19.9 (C-15), 17.44 (C-19).
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL386883A PL212020B1 (en) | 2008-12-22 | 2008-12-22 | Production method of testoloactane (17a-oxa—D-homo-androst-4-en-3,17-dione) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL386883A PL212020B1 (en) | 2008-12-22 | 2008-12-22 | Production method of testoloactane (17a-oxa—D-homo-androst-4-en-3,17-dione) |
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| Publication Number | Publication Date |
|---|---|
| PL386883A1 PL386883A1 (en) | 2009-06-22 |
| PL212020B1 true PL212020B1 (en) | 2012-07-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| PL386883A PL212020B1 (en) | 2008-12-22 | 2008-12-22 | Production method of testoloactane (17a-oxa—D-homo-androst-4-en-3,17-dione) |
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| PL386883A1 (en) | 2009-06-22 |
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