CN101041640A - Antineoplastic active substance of diketopiperazine PJ147and PJ157 - Google Patents
Antineoplastic active substance of diketopiperazine PJ147and PJ157 Download PDFInfo
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- CN101041640A CN101041640A CN 200710006650 CN200710006650A CN101041640A CN 101041640 A CN101041640 A CN 101041640A CN 200710006650 CN200710006650 CN 200710006650 CN 200710006650 A CN200710006650 A CN 200710006650A CN 101041640 A CN101041640 A CN 101041640A
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- diketopiperazine
- acetone
- mycelium
- active substance
- gliocladium
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
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Abstract
The invention discloses two tumour-proof active material PJ 147 and PJ 157, which is characterized by the following: gathering acetone extract of Gliocladium sp.YUP08 mycelium as raw material to separate through chromatogram method; obtaining the compound with the following structural formula; fermenting the Gliocladium sp to obtain large amount of ferment liquid; filtering; obtaining mycelium and water layer; drying the mycelium in the bottle; extracting acetone through ultrasound; decompressing to recycle solvent without residule; drying; dissolving through carbinol repeatingly; obtaining dissolvable concrete of carbinol; dissolving mycelium extract through acetone; separating through silicon sol column chromatogram; proceeding gradient elution through ligarine-acetone; obtaining each fraction as the product; fitting for preparing tumour-proof drug.
Description
Technical field:
The invention belongs to medical technical field, what relate to is to separate diketopiperazine Compound P J147 and the PJ157 with anti-tumor activity that obtains from the mycelium of thalassiomycetes Gliocladium sp.YUP08.
Background technology:
The antitumor natural product in ocean occupies main status always in marine drug research, not only carry out the earliest but also have sturdy research basis.Have at least 10% to have cytotoxic activity in the marine organism extract that has now found that.The U.S. has 1500 ocean compound monomers to be separated every year, 1% tool antitumor action.At present existing a plurality of oceans cancer therapy drug enters clinical or the preclinical study stage, estimates that in the near future the part kind can formally drop into clinical use.
The research of marine microorganism anti-tumor activity is compared with other marine organisms, and is later relatively, but prospect is more wide.Though found the anti-tumor biologically active substance of many high-efficiency low-toxicities in marine animal and plant, because the finiteness in marine animal and plant source makes the application of marine animal and plant antitumor drug be subjected to certain restriction.And utilize marine microorganism to carry out the fermentative production anti-tumor active substance, and then not limited, can avoid the ecological damage that causes because excessively gather marine animal and plant, and marine microorganism can improve the output of active substance by methods such as mutagenesis.Therefore, the batch production production that is developed as antitumor drug of marine microorganism has brought more tempting prospect.
Research starting to the thalassiomycetes secondary metabolite is later relatively, and relevant bibliographical information was just arranged since 1988, and the new compound of finding from thalassiomycetes by 1992 has only 15.Obtained investigator's attention since 1994 to the secondary research of thalassiomycetes, the research work development is swift and violent, is surging forward, and the compound of increasing novel structure is found.
The 2004.05.14 of U.S. DMI Biosciences, Inc. has applied for that in China name is called the patent of invention of " treatment of diseases that T-is cell-mediated ", application number is 200480013249.0, and it provides the method for synthetic diketopiperazines and comprises the pharmaceutical composition of some diketopiperazines.Wherein the synthetic method of diketopiperazines is different with the present invention, and the structure of product is also different.
Summary of the invention:
The objective of the invention is to utilize abundant marine microorganism resource to seek new cyclic peptide antineoplastic compound, provide lead compound for researching and developing new anticarcinogen.Two diketopiperazine PJ 147s involved in the present invention and PJ157 are the compounds of a pair of rotamerism, in the similar compound of having found, also do not have the diketopiperazine compound that same geranyl replaces group.
The present invention utilizes the ooze of gathering from the Rushan to separate the mycelial acetone extract that obtains thalassiomycetes Gliocladium sp.YUP08 to be raw material, fully utilizes various chromatogram means separation and has obtained this two compounds.And utilize various chemistry and spectrum means, identified the plane and the three-dimensional arrangement of these two compounds.Called after diketopiperazine PJ 147 and PJ157, the structure of these two compounds is as follows:
The present invention realizes that according to following scheme culture medium prescription is as follows: potato is soaked juice 200ml, and ooze soaks juice 80ml, peptone 2g, glucose 15g, NaCl 12g, MgCl
26H
2O 1.1g, KCl0.1g, distilled water 1000ml; Bacterial strain is the bacterium colony beige on this substratum, and mucus is arranged, and the conidiophore top is arranged between the broom shape branch, the conidium terra brown, and sphere or oval are assembled agglomeratingly, are Penicillium Gliocladium sp according to this characterized; Under 24 ℃ temperature, the 150rpm shaking table, shaking culture 9 days, bulk fermentation is produced bacterium Gliocladium sp.YUP08 bacterial strain, obtains fermented liquid 35L, 16 layers of filtered through gauze, obtain mycelium and water layer, mycelium dries back net weight 200g, places the 2000mL volumetric flask, uses the acetone supersound extraction, till noresidue behind the decompression and solvent recovery, powdered extract dissolves repeatedly with methyl alcohol, obtains methanol soluble medicinal extract 36g, the mycelium extract acetone solution, separate with silica gel column chromatography, with sherwood oil-acetone gradient elution, obtain each stream part, utilize chromatographic technique to separate again and obtain compound of diketopiperazine PJ 147 and diketopiperazine PJ157.
The used raw material thalassiomycetes of the present invention is picked up from the ooze that gather the Rushan, is accredited as Gliocladium sp. through professor Tian Li of Oceanographic Inst. No.1 of State Bureau of Oceanography.
The invention provides two diketopiperazine PJ 147s and PJ157, it is the compound of a pair of rotamerism, in the similar compound of having found, the diketopiperazine compound that does not also have same geranyl replacement group, diketopiperazine PJ 147 and PJ157 have stronger anti-tumor activity, and the present invention provides lead compound for researching and developing new anticarcinogen.
Embodiment:
Bacterial strain is tested through culture condition, and it is the highest to soak the antifungal activity that produces on the juice substratum at the potato ooze, and it is as follows to cultivate prescription: potato is soaked juice 200ml, and ooze soaks juice 80ml, peptone 2g, glucose 15g, NaCl 12g, MgCl
26H
2O 1.1g, KCl 0.1g, distilled water 1000ml.
Bacterial strain is the bacterium colony beige on this substratum, and mucus is arranged, and the conidiophore top is arranged between the broom shape branch, the conidium terra brown, and sphere or oval are assembled agglomeratingly, are Penicillium Gliocladium sp. according to this characterized.
Under 24 ℃ the temperature, the 150rpm shaking table, shaking culture 9 days, bulk fermentation is produced bacterium Gliocladium sp.YUP08 bacterial strain, obtains fermented liquid 35L.16 layers of filtered through gauze obtain mycelium and water layer.Mycelium dries back net weight 200g, places the 2000mL volumetric flask, uses the acetone supersound extraction, (extracts 4 times) till noresidue behind the decompression and solvent recovery, and powdered extract dissolves repeatedly with methyl alcohol, obtains methanol soluble medicinal extract 36g.The mycelium extract acetone solution separates with silica gel column chromatography, with sherwood oil-acetone gradient elution, obtains each stream part, utilizes various chromatographic techniques to separate again and obtains this 2 compounds.Physical constant and spectral data are as follows:
Diketopiperazine PJ 147
The white amorphous powder, [α]
D 20-150 ° (c 0.1, CH
3OH), UV (CH
3OH) λ
MaxNm 315,225,203 UV (CH
3OH) λ
MaxNm 315,225,203, IR (KBr) ν
Max(cm
-1) 3310,2921,1688,1606,1521,1442,1251;
1H and
13C NMR data see Table 2; EI-MS m/z:368[M]
+, 248,232,217,133,81,69 (base), 41; HRFABMS m/z:368.4689 (calcd for C
22H
28N
2O
3, 368.4693).
Diketopiperazine PJ157
White indefiniteness powder (methyl alcohol), [α]
D 20-78 (c 0.5, CH
3OH), UV (CH
3OH) λ
MaxNm319,230,202; IR (KBr) ν
Max(cm
-1) 3319,2922,1670,1641,1510,1466,1386,1253;
1H and
13C NMR data see Table 2; EI-MS m/z:368[M]
+, 248,217,133,81,69 (base), 41; HRFABMS m/z:368.4685 (calcd for C
22H
28N
2O
3, 368.4693).
Nuclear magnetic data (the DMSO-d of table 2.PJ147 and PJ157
6)
| Posit ion | PJ147 | PJ157 | ||
| δ C δ H (J Hz) | δ C δ H (J Hz) | |||
| 1 2 3 4 5 6 7 8 9 10， 10′ 11， 11′ 12 13 | 166.3 60.0 157.3 123.4 17.1 115.2 125.7 131.0 114.9 158.4 64.5 | 9.96(s) 4.31(q， 6.8) 10.22 (s) 1.45(d， 6.8) 6.74(s) 7.45(d， 8.7) 6.96(d， 8.7) 4.57(d， 6.6) | 162.0 59.3 157.8 126.0 16.8 117.9 125.1 132.5 113.7 158.7 64.5 | 10.31 (s) 4.40(q， 6.8) 10.49 (s) 1.45(d， 6.8) 6.92(s) 7.36(d， 8.7) 6.84(d， 8.7) 4.56(d， 6.6) |
| 14 15 16 17 18 19 20 21 22 | 119.6 140.5 38.9 25.9 123.9 131.2 25.6 17.7 16.5 | 5.43(t， 6.6) 2.04(m) 2.09(m) 5.08(t) 1.64(s) 1.57(s) 1.71(s) | 119.7 140.5 38.9 25.9 123.9 131.1 25.6 17.7 16.5 | 5.42(t， 6.6) 2.04(m) 2.08(m) 5.08(t) 1.63(s) 1.57(s) 1.71(s) |
Through anti tumor activity in vitro test, two compounds are to the IC of tumour cells such as mouse leukemia P388, human lung adenocarcinoma A-549, human leukemia HL-60, people's liver cancer BEL-7402, Humanmachine tumour A375-S2, human cervical carcinoma Hela
50As shown in table 1:
Table 1:PJ147 and PJ157 are to the cytotoxic activity (IC of 6 kinds of tumor cell lines
50, μ mol/L)
。
| P388 | A-549 | HL-60 | BEL-7402 | A375-S2 | Hela | |
| PJ147 PJ157 | 3.37 2.86 | 4.47 1.37 | 1.48 1.73 | 9.69 3.20 | 3.86 4.60 | 1.60 3.40 |
Claims (4)
1, antineoplastic active substance of diketopiperazine PJ147 and PJ157, it is characterized in that: to separate the mycelial acetone extract that obtains thalassiomycetes Gliocladium sp.YUP08 from the ooze of gathering is raw material, utilize the chromatogram means to separate the compound that obtains, diketopiperazine PJ 147 and PJ157, the structural formula of compound is as follows.
2, antineoplastic active substance of diketopiperazine PJ147 according to claim 1 and PJ157 is characterized in that: described ooze is the ooze that gather the Rushan.
3, the preparation method of a kind of antineoplastic active substance of diketopiperazine PJ147 as claimed in claim 1 and PJ157, it is characterized in that: culture medium prescription is as follows: potato is soaked juice 200ml, and ooze soaks juice 80ml, peptone 2g, glucose 15g, NaCl 12g, MgCl
26H
2O 1.1g, KCl 0.1g, distilled water 1000ml; Bacterial strain is the bacterium colony beige on this substratum, and mucus is arranged, and the conidiophore top is arranged between the broom shape branch, the conidium terra brown, and sphere or oval are assembled agglomeratingly, are Penicillium Gliocladium sp according to this characterized; Under 24 ℃ temperature, the 150rpm shaking table, shaking culture 9 days, bulk fermentation is produced bacterium Gliocladium sp.YUP08 bacterial strain, obtains fermented liquid 35L, 16 layers of filtered through gauze, obtain mycelium and water layer, mycelium dries back net weight 200g, places the 2000mL volumetric flask, uses the acetone supersound extraction, till noresidue behind the decompression and solvent recovery, powdered extract dissolves repeatedly with methyl alcohol, obtains methanol soluble medicinal extract 36g, the mycelium extract acetone solution, separate with silica gel column chromatography, with sherwood oil-acetone gradient elution, obtain each stream part, utilize chromatographic technique to separate again and obtain compound of diketopiperazine PJ 147 and diketopiperazine PJ157.
4, antineoplastic active substance of diketopiperazine PJ147 and the PJ157 application in the preparation antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710006650 CN101041640A (en) | 2006-07-09 | 2007-01-22 | Antineoplastic active substance of diketopiperazine PJ147and PJ157 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610101066.5 | 2006-07-09 | ||
| CN200610101066 | 2006-07-09 | ||
| CN 200710006650 CN101041640A (en) | 2006-07-09 | 2007-01-22 | Antineoplastic active substance of diketopiperazine PJ147and PJ157 |
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|---|---|
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ID=38807456
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101935306A (en) * | 2010-07-22 | 2011-01-05 | 沈阳药科大学 | New diketone piperazidine-like derivative and application thereof |
| CN101255139B (en) * | 2008-03-18 | 2012-11-07 | 沈阳药科大学 | Method for synthesizing antitumor compound of diketopiperazine PJ147 |
| CN103074233A (en) * | 2012-12-25 | 2013-05-01 | 浙江工业大学 | Marine fungus penicillium chrysogenum and application thereof to preparation of anti-tumor medicines |
-
2007
- 2007-01-22 CN CN 200710006650 patent/CN101041640A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101255139B (en) * | 2008-03-18 | 2012-11-07 | 沈阳药科大学 | Method for synthesizing antitumor compound of diketopiperazine PJ147 |
| CN101935306A (en) * | 2010-07-22 | 2011-01-05 | 沈阳药科大学 | New diketone piperazidine-like derivative and application thereof |
| CN101935306B (en) * | 2010-07-22 | 2013-12-25 | 沈阳药科大学 | Diketone piperazidine-like derivative and application thereof |
| CN103074233A (en) * | 2012-12-25 | 2013-05-01 | 浙江工业大学 | Marine fungus penicillium chrysogenum and application thereof to preparation of anti-tumor medicines |
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Open date: 20070926 |