PL229157B1 - Macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone and method for obtaining macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone - Google Patents
Macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone and method for obtaining macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaoneInfo
- Publication number
- PL229157B1 PL229157B1 PL416427A PL41642716A PL229157B1 PL 229157 B1 PL229157 B1 PL 229157B1 PL 416427 A PL416427 A PL 416427A PL 41642716 A PL41642716 A PL 41642716A PL 229157 B1 PL229157 B1 PL 229157B1
- Authority
- PL
- Poland
- Prior art keywords
- deca
- diene
- trimethyl
- pentaone
- macrocyclic lactone
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 12
- 150000002596 lactones Chemical class 0.000 title claims description 8
- VAVLRPNFLKYJPR-UHFFFAOYSA-N IC1CC(C)(C)CC2CC(=O)OC21 Chemical compound IC1CC(C)(C)CC2CC(=O)OC21 VAVLRPNFLKYJPR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 240000001462 Pleurotus ostreatus Species 0.000 claims abstract description 4
- 230000000813 microbial effect Effects 0.000 claims abstract description 4
- 230000009466 transformation Effects 0.000 claims abstract description 4
- 102000004190 Enzymes Human genes 0.000 claims abstract description 3
- 108090000790 Enzymes Proteins 0.000 claims abstract description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 235000007685 Pleurotus columbinus Nutrition 0.000 claims description 3
- 235000001603 Pleurotus ostreatus Nutrition 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- 230000033444 hydroxylation Effects 0.000 claims description 3
- 238000005805 hydroxylation reaction Methods 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000006907 apoptotic process Effects 0.000 abstract description 4
- 206010025323 Lymphomas Diseases 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 230000001093 anti-cancer Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000036983 biotransformation Effects 0.000 description 3
- 229930191624 macrosphelide Natural products 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- QEGNUYASOUJEHD-UHFFFAOYSA-N 1,1-dimethylcyclohexane Chemical compound CC1(C)CCCCC1 QEGNUYASOUJEHD-UHFFFAOYSA-N 0.000 description 2
- 206010020843 Hyperthermia Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000036031 hyperthermia Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- RBXGLVAPOVVBIC-UHFFFAOYSA-N 7-hydroxy-5,5-dimethyl-3,3a,4,6,7,7a-hexahydro-1-benzofuran-2-one Chemical compound OC1CC(C)(C)CC2CC(=O)OC21 RBXGLVAPOVVBIC-UHFFFAOYSA-N 0.000 description 1
- 102000004091 Caspase-8 Human genes 0.000 description 1
- 108090000538 Caspase-8 Proteins 0.000 description 1
- 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
- 241000222350 Pleurotus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000017455 cell-cell adhesion Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000008810 intracellular oxidative stress Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 239000012663 orally bioavailable inhibitor Substances 0.000 description 1
- 229940044205 orally bioavailable inhibitor Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Zgłoszenie dotyczy nowego (3S,9S,15S)-(6E,12E)-3,9,15-trimetylo-4,10,16-trioksacycloheksa-deka-6,12-dien-1,5,8,11,14-pentaonu, o wzorze 2 oraz sposobu jego otrzymywania na drodze transformacji mikrobiologicznej 2-jodo-4,4-dimetylo-9-oksabicyklo[4.3.0]nonan-8-onu, o wzorze 1, za pomocą systemu enzymatycznego szczepu grzyba Pleurotus ostreatus AM482. Związek ten ma potencjalną aktywność indukowania apoptozy w ludzkich komórkach chłoniaka i może znaleźć zastosowanie w przemyśle farmaceutycznym do produkcji preparatów przeciwnowotworowych.The notification concerns a new (3S, 9S, 15S) - (6E, 12E) -3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14 - pentaone, of formula 2 and a method of its preparation by microbial transformation of 2-iodo-4,4-dimethyl-9-oxabicyclo [4.3.0] nonan-8-one, of formula 1, using the enzyme system of the Pleurotus ostreatus fungus AM482. This compound has the potential to induce apoptosis in human lymphoma cells and may find application in the pharmaceutical industry for the production of anti-cancer preparations.
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest sposób otrzymywania makrocyklicznego laktonu, o wzorze 2, przedstawionego na rysunku.The subject of the invention is a process for the preparation of the macrocyclic lactone of formula 2 shown in the drawing.
Związek ten ma potencjalną aktywność indukowania apoptozy w ludzkich komórkach chłoniaka i może znaleźć zastosowanie w przemyśle farmaceutycznym do produkcji preparatów przeciwnowotworowych (K. Ahmed, Q.-L Zhao, Y. Matsuya, D.-Y. Yu, T. L. Salunga, H. Nemoto, T. Kondo, Enhancement of macrosphelide-induced apoptosis by mild hyperthermia, International Journal of Hyperthermia, 2007, 23, 353-361, K. Ahmed, Q.-L., Zhao, Y. Matsuya, D.-Y. Yu, L. B. Feril, Jr., H. Nemoto, T. Kondo, Rapid and transient intracellular oxidative stress due to novel macrosphelides trigger apoptosis via fas/caspase-8-dependent pathway in human lymphoma U937 cells, Chem. Biol. Interact. 2007, 170, 86-99).This compound has the potential to induce apoptosis in human lymphoma cells and may find application in the pharmaceutical industry for the production of anti-cancer preparations (K. Ahmed, Q.-L Zhao, Y. Matsuya, D.-Y. Yu, TL Salunga, H. Nemoto , T. Kondo, Enhancement of macrosphelide-induced apoptosis by mild hyperthermia, International Journal of Hyperthermia, 2007, 23, 353-361, K. Ahmed, Q.-L., Zhao, Y. Matsuya, D.-Y. Yu , LB Feril, Jr., H. Nemoto, T. Kondo, Rapid and transient intracellular oxidative stress due to novel macrosphelides trigger apoptosis via fas / caspase-8-dependent pathway in human lymphoma U937 cells, Chem. Biol. Interact. 2007, 170, 86-99).
Znana jest metoda chemicznej syntezy tego związku (T. Sunazuka, T. Hirose, N. Chikaraishi, Y. Harigaya, M. Hayashi, K. Komiyama, P. A. Sprengeler, A.B. Smith III, S. Omura, Absolute stereochemistries and total synthesis of (+)/(-)-macrosphelides, potent, orally bioavailable inhibitors of cell-cell adhesion Tetrahedron, 2005, 61,3789-3803).There is a known method of chemical synthesis of this compound (T. Sunazuka, T. Hirose, N. Chikaraishi, Y. Harigaya, M. Hayashi, K. Komiyama, PA Sprengeler, AB Smith III, S. Omura, Absolute stereochemistries and total synthesis of ( +) / (-) - macrosphelides, potent, orally bioavailable inhibitors of cell-cell adhesion Tetrahedron, 2005, 61, 3789-3803).
Użycie szczepu Pleurotus ostreatus AM482 do biotransformacji jest opisane w: J. Popłoński, S. Sordon, T. Tronina, A. Bartmańska, E. Huszcza, Fungal metabolism of naphthoflavones, J. Mol. Catal. B: Enzymatic, 2015, 117, 1 -6.The use of Pleurotus ostreatus AM482 for biotransformation is described in: J. Popłoński, S. Sordon, T. Tronina, A. Bartmańska, E. Huszcza, Fungal metabolism of naphthoflavones, J. Mol. Catal. B: Enzymatic, 2015, 117, 1-6.
Brak jest doniesień literaturowych o otrzymywaniu takich makrocyklicznych laktonów na drodze mikrobiologicznej.There are no reports in the literature on the preparation of such macrocyclic lactones in the microbiological way.
Istotą sposobu otrzymywania makrocyklicznego laktonu jest to, że bicykliczny jodolakton z układem gem-dimetylocykloheksanu 2-jodo-4,4-dimetylo-9-oksabicyklo[4.3.0]nonan-8-on poddaje się mikrobiologicznej hydroksylacji za pomocą systemu enzymatycznego szczepu grzyba Pleurotus ostreatus AM482. Biotransformację prowadzi się przy ciągłym mieszaniu, w temperaturze od 25 do 26°C. Otrzymany produkt ekstrahuje się rozpuszczalnikiem organicznym z grupy rozpuszczalników chlorowych pochodnych metanu. Ekstrakt suszy się bezwodnym siarczanem magnezu, po czym, po odparowaniu rozpuszczalnika, surowy produkt oczyszcza się na kolumnie chromatograficznej, otrzymując makrocykliczny lakton.The essence of the macrocyclic lactone preparation method is that the bicyclic iodolactone with the gem-dimethylcyclohexane system 2-iodo-4,4-dimethyl-9-oxabicyclo [4.3.0] nonan-8-one is subjected to microbial hydroxylation using the enzyme system of the Pleurotus fungus strain ostreatus AM482. The biotransformation is carried out under constant stirring at a temperature of 25 to 26 ° C. The obtained product is extracted with an organic solvent from the group of chlorine solvents derived from methane. The extract is dried over anhydrous magnesium sulfate and, after evaporation of the solvent, the crude product is purified by column chromatography to obtain a macrocyclic lactone.
Korzystnie jest, gdy proces transformacji prowadzi się wodną kulturą szczepu.Preferably, the transformation process is carried out with an aqueous culture of the strain.
Korzystnie także jest, gdy rozpuszczalnikiem organicznym jest chloroform. Użycie jako rozpuszczalnika chlorku metylenu pozwala na otrzymanie jako produktu biotransformacji jedynie hydroksylaktonu.It is also preferred that the organic solvent is chloroform. The use of methylene chloride as a solvent allows only hydroxylactone to be obtained as a biotransformation product.
Zasadniczą zaletą sposobu, według wynalazku, jest to, że otrzymuje się go w łagodnych warunkach, jako jeden z dwóch produktów mikrobiologicznej hydroksylacji 2-jodo-4,4-dimetylo-9-oksabicyklo[4.3.0]nonan-8-onu, ze stopniem przereagowania na poziomie 40% (drugim produktem jest znany hydroksylakton 2-hydroksy-4,4-dimetylo-9-oksabicyklo[4.3.0]nonan-8-on, powstający ze stopniem przereagowania na poziomie 60%).The essential advantage of the process according to the invention is that it is obtained under mild conditions as one of the two products of the microbial hydroxylation of 2-iodo-4,4-dimethyl-9-oxabicyclo [4.3.0] nonan-8-one, with a conversion of 40% (the second product is the known hydroxylactone 2-hydroxy-4,4-dimethyl-9-oxabicyclo [4.3.0] nonan-8-one, formed in a conversion of 60%).
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 d:P r z o f e:
Do 10 kolb Erlenmayera o pojemności 300 cm3, w których znajduje się po 100 cm3 sterylnej pożywki, zawierającej: 3% glukozy i 1% aminobaku wprowadza się szczep Pleurotus ostreatus AM482. Po trzech dniach wzrostu dodaje się 100 mg 2-jodo-4,4-dimetylo-9-oksabicyklo[4.3.0]nonan-8-onu, o wzorze 1, rozpuszczonego w 10 cm3 acetonu. Transformację prowadzi się, w temperaturze około 25°C, przy ciągłym wstrząsaniu, przez 7 dni. Następnie roztwór potransformacyjny ekstrahuje się trzykrotnie chloroformem, ekstrakt suszy bezwodnym siarczanem magnezu i odparowuje rozpuszczalnik. Otrzymaną surową mieszaninę produktów wraz z metabolitami szczepu grzyba, oczyszcza się chromatograficznie na żelu krzemionkowym, używając jako eluentu mieszaniny heksan : aceton, w stosunku objętościowym 3:1 .The strain Pleurotus ostreatus AM482 is introduced into 10 Erlenmayer flasks with a capacity of 300 cm 3 , each containing 100 cm 3 of sterile medium containing: 3% glucose and 1% aminobac. After three days of growth, was added 100 mg of 2-iodo-4,4-dimethyl-9-oxabicyclo [4.3.0] nonane-8-one, of formula 1, dissolved in 10 cm 3 of acetone. The transformation is carried out at about 25 ° C with continuous shaking for 7 days. Then the post-transformation solution was extracted three times with chloroform, the extract was dried with anhydrous magnesium sulfate and the solvent was evaporated. The crude product mixture obtained together with the fungus strain metabolites is purified by chromatography on silica gel using a 3: 1 v / v hexane: acetone mixture as the eluent.
Na tej drodze otrzymuje się 13 mg (% wydajności teoretycznej) (3S,9S,15S)-(6E,12E)-3,9,15-trimetylo-4,10,16-trioksacycloheksa-deka-6,12-dien-1,5,8,11,14-pentaonu.In this way, 13 mg (% of theory) of (3S, 9S, 15S) - (6E, 12E) -3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene are obtained. 1,5,8,11,14-pentaon.
Uzyskany produkt charakteryzuje się następującymi danymi spektroskopowymi:The obtained product is characterized by the following spectroscopic data:
1H NMR (800 MHz, CDCIa) δ: 1.44 (d, J = 6.3 Hz, 3H, CHa-C-3), 1.49 (d, J = 7.0 Hz. 3H, CHa-C-15), 1.81 (d, J = 7.2 Hz, 3H, CHa-C-9), 2.70 (dd, J = 16,8 i 2.0 Hz, 1H, jeden z CH2-2), 2.92 (dd, J = 16.8 i 11.3 Hz, 1H, jeden z CHa-2), 5,22 (q, J = 8.9 Hz, 1H, H-15), 5.29 (q, J = 7.1 Hz, 1H, H-9), 5.40 (m, 1H, H-3), 6.66 (d, J = 16.0 Hz, 1H, H-6), 6.87 (d, J = 15.8 Hz, 1H, H-13), 7.18 (d, J = 15.8 Hz, 1H, H-12), 7.38 (d, J = 16.0 Hz, 1H, H-7). 1 H NMR (800 MHz, CDCla) δ: 1.44 (d, J = 6.3 Hz, 3H, CHa-C-3), 1.49 (d, J = 7.0 Hz. 3H, CHa-C-15), 1.81 (d , J = 7.2 Hz, 3H, CHa-C-9), 2.70 (dd, J = 16.8 and 2.0 Hz, 1H, one of CH2-2), 2.92 (dd, J = 16.8 and 11.3 Hz, 1H, one of CHa-2), 5.22 (q, J = 8.9 Hz, 1H, H-15), 5.29 (q, J = 7.1 Hz, 1H, H-9), 5.40 (m, 1H, H-3 ), 6.66 (d, J = 16.0 Hz, 1H, H-6), 6.87 (d, J = 15.8 Hz, 1H, H-13), 7.18 (d, J = 15.8 Hz, 1H, H-12), 7.38 (d, J = 16.0 Hz, 1H, H-7).
PL229 157 Β1 13C NMR (125 Hz, CDCIs), δ: 15.93 (CHsC-15), 17.07 (CHsC-9), 19.52 (CHsC-3), 40.64 (C-2), 69.22 (C-3), 75.56 (C-15), 76.35 (C-9), 132.03 (C-6), 132,30 (C-13), 132.33 (C-12), 134.38 (C-5), 163.11 (C-1), 163.49 (C-9), 170.11 (C-14), 195.61 (C-5), 197.46 (C-11).PL229 157 Β1 13 C NMR (125 Hz, CDCIs), δ: 15.93 (CHsC-15), 17.07 (CHsC-9), 19.52 (CHsC-3), 40.64 (C-2), 69.22 (C-3), 75.56 (C-15), 76.35 (C-9), 132.03 (C-6), 132.30 (C-13), 132.33 (C-12), 134.38 (C-5), 163.11 (C-1) , 163.49 (C-9), 170.11 (C-14), 195.61 (C-5), 197.46 (C-11).
Claims (3)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL416427A PL229157B1 (en) | 2016-03-08 | 2016-03-08 | Macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone and method for obtaining macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone |
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| Application Number | Priority Date | Filing Date | Title |
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| PL416427A PL229157B1 (en) | 2016-03-08 | 2016-03-08 | Macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone and method for obtaining macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone |
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| PL416427A1 PL416427A1 (en) | 2017-02-27 |
| PL229157B1 true PL229157B1 (en) | 2018-06-29 |
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| PL416427A PL229157B1 (en) | 2016-03-08 | 2016-03-08 | Macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone and method for obtaining macrocyclic lactone (3S,9S,15S)-(6E,12E)-3,9,15-trimethyl-4,10,16-trioxacyclohexa-deca-6,12-diene-1,5,8,11,14-pentaone |
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