CN1190497C - Preparation technology of geldanamycin and its derivative - Google Patents
Preparation technology of geldanamycin and its derivative Download PDFInfo
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- CN1190497C CN1190497C CN 02132163 CN02132163A CN1190497C CN 1190497 C CN1190497 C CN 1190497C CN 02132163 CN02132163 CN 02132163 CN 02132163 A CN02132163 A CN 02132163A CN 1190497 C CN1190497 C CN 1190497C
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Abstract
The present invention relates to a preparation process of broad-spectrum anti-cancer antibiotic geldanamycin and derivatives thereof. Moist Geldanace streptomycetes are cultured in the liquid culture medium, and geldanamycin is extracted from culture solutions, and is purified. A large amount of geldanamycin with high purity and derivatives thereof can be obtained by the process so that the process establishes a basis for the large-scale industrial production for the geldanamycin.
Description
Technical field
The present invention relates to a kind of broad spectrum anticancer microbiotic---the preparation technology of geldanamycin and derivative thereof, relate in particular to preparation high purity, the geldanamycin of high yield and the technology of derivative thereof from the moist streptomycete of Ge Erdenasi (Streptomyces hygroscopicus varGeldanus).
The invention still further relates to the liquid nutrient medium of cultivating the moist streptomycete of Ge Erdenasi.
Background technology
Antitumor antibiotic is the small molecules chemical substance or derivatives thereof with antitumour activity that is produced by microbial metabolism.Antitumor antibiotic is of a great variety, be applied to clinical treating malignant tumor have ten surplus kind, as the antitumor antibiotic of natural origins such as mitomycin, Zorubicin, daunorubicin, bleomycin, Zhengguangmycin A5, gengshengmeisu and through the congener of chemically modified, they have become all kinds of malignant tumours of treatment medicine commonly used.In the last few years, countries in the world had been reported the new type anticancer microbiotic that acts on different target position successively, and its main target position comprises tumor vessel, dna profiling, matrix metalloproteinase and heat shock protein 90 (HSP90) etc.This wherein, the inhibitor geldanamycin of HSP90 (geldanamycin, GA) and the anticancer effect of some derivative especially noticeable.Geldanamycin is the compound that a kind of moist streptomycete excretory contains the benzoquinones structure, belongs to benzoquinones ansamycin (benzoquinone ansamycin) class microbiotic.1971, people found that in the nutrient solution of moist streptomycete this kind has the microbiotic of anti-tumor activity (U.S. Pat 3,595,955), and the solubleness of this microbiotic in the aqueous solution is lower, and experimentation on animals finds that it is toxic to liver etc.Experiment in vitro in recent years shows that GA has good inhibition activity to the growth of kinds of tumor cells, has wide spectrum antiproliferative and antitumor action.
Geldanamycin causes the unstable and degraded of carcinogenic protein by to the specific inhibition of HSP90.Geldanamycin has realized inhibition to multiple cancer target spot and approach to the inhibition of HSP90 function, and this multipath combination restraining effect makes geldanamycin have the broad-spectrum anti-tumor cytoactive.HSP90 belongs to stress response protein, and the content in healthy tissues is extremely low, and the content in malignant tumor tissue is higher, so geldanamycin class medicine can be brought into play optionally restraining effect to tumour cell.The advantage of geldanamycin also is the popularity of its effect, and HSP90 follows proteic conformation to keeping some crucial cancer cells, it is extremely important to stablize its function etc.The albumen of being responsible for maintaining by HSP90 comprises: the p53 of receptor tyrosine kinase, transmembrane conductance regulator, serine/threonine kinase, sudden change, c-erbB, Bcr-Ab1, Raf1, Akt and hypoxic inducing factor-1 etc., they cause breeding, the cell cycle advances and the signal transduction pathway of apoptosis in work; In addition, they are also very important for the characteristics of keeping such as malignant tumour phenotypes such as infiltration, angiogenic growth and transfers.GA by HSP90 to multiple cancer target spot the time restraining effect also have the another one advantage, be exactly that tumour cell is difficult for it is produced resistance, because a tumour cell is difficult to change simultaneously the multiple signal pathway of keeping its growth, to escape the lethal effect of medicine.
Though GA shows good inhibition tumor promotion on human tumor cells and tumor animal model,, fail to be applied to the treatment of clinical tumor because it produces difficulty and bigger to the toxicity of liver.Through screening experiment to multiple geldanamycin derivant, find 17-allyl amido geldanamycin (17-allylamino, 17-demethoxygeldanamycin, 17AAG) kept the restraining effect of GA to HSP90, in cancer cell in vitro cultivation and tumour transplatation model, shown tangible anti-tumor activity, solubleness in the aqueous solution is higher than GA, and hepatotoxicity is lower than GA.The cell in vitro experiment shows, geldanamycin, and 17-allyl amido geldanamycin can be used for multiple treatment for cancer such as leukemia, lung cancer, cancer of the stomach, colorectal carcinoma, the rectum cancer, liver cancer, mammary cancer, prostate cancer.
When the geldanamycin of low dosage or 17-allyl amido geldanamycin are united use with antitumor drug commonly used, can significantly strengthen cis-platinum, ametycin, Zorubicin and cytosine arabinoside cytotoxicity to the human hepatocellular carcinoma BEL-7402 cell.Cell cycle analysis shows that geldanamycin can strengthen the G2-M phase blocking effect of cis-platinum.
Geldanamycin is bigger to the toxicity of liver, is difficult to use separately clinically.With geldanamycin or 17-allyl amido geldanamycin and CEA monoclonal antibody (or monoclonal antibody of other anticancer cell surface marker) crosslinked after, obtain immune conjugate.Monoclonal antibody can take geldanamycin to the position at cancer cells place, cancer cells is positioned kill and wound, and demonstrates the higher tumor cell viabilities such as mammary cancer, colorectal carcinoma, cancer of the stomach, lung cancer that kill and wound.When being applied to the human tumor treatment, can reduce the toxicity of geldanamycin greatly.
Geldanamycin is the raw material of synthetic multiple ansamycin series antineoplastic medicament, owing to extract comparatively difficulty of highly purified geldanamycin in moist streptomycete fermentation liquid, the rate of recovery is lower, becomes the antibiotic obstacle of research geldanamycin class for a long time.Composition in the moist streptomycete fermentation product is very complicated, the technology of therefrom extracting geldanamycin is loaded down with trivial details, organic solvent extraction that multistep is rapid and column chromatography are the major causes that causes the geldanamycin rate of recovery low, therefore in report in the past, do not see that geldanamycin output is above the report of 100mg in every liter of fermented liquid.
The prescription of moist streptomycete fermentation liquid also is to cause the lower major cause of geldanamycin unit volume output without the optimization of science.
Summary of the invention
The object of the present invention is to provide a kind of technology for preparing geldanamycin and derivative 17-allyl amido geldanamycin thereof, adopt this technology can obtain highly purified antitumor antibiotic---geldanamycin and derivative thereof in a large number, this antitumor antibiotic has higher selectivity to multiple malignant cell, is applicable to the chemotherapy of multiple malignant tumour.
Natural geldanamycin (GA) and through the chemical structural formula of the 17-of chemically modified allyl amido geldanamycin (17AAG) following (A) (B) shown in the formula respectively:
According to an aspect of the present invention, a kind of liquid nutrient medium of suitable moist streptomycete growth is provided, comprise organism such as containing glucose, Tryptones, refined edible oil, proteolysate, yeast extract, yeast nitrogen base, Zulkovsky starch, honey, the content of each composition is in every liter of substratum:
Glucose 0.1～100 gram
Peptone 0.5～15 gram
1～50 milliliter of refining Trisun Oil R 80
Proteolysate 0.1～25 gram
Yeast extract 0.1～20 gram
Yeast nitrogen base 0.1～50 gram
Zulkovsky starch 0.1～15 gram
0.1～10 milliliter in molasses; And
An amount of inorganic microelement;
Transfer pH to 5.0～8.0 of substratum;
Above-mentioned substratum is cultivated moist streptomycete (Streptomyces hygroscopicus varGeldanus) at 25～35 ℃, obtain to contain the nutrient solution of geldanamycin.
According to a further aspect in the invention, the technology of preparation geldanamycin from the liquid nutrient medium of cultivating moist streptomycete is provided, comprise and adopt liquid culture of the present invention based on the moist streptomycete of fermentation culture in the bio-reactor of different volumes, centrifugal or remove by filter insoluble substance such as thalline.Utilize GA solubleness in organic solvent high and in the aqueous solution the low characteristics of solubleness, add organic solvents such as ethyl acetate or propyl carbinol in the nutrient solution supernatant after clarification, the volume ratio of organic solvent and supernatant liquor is 1: 1～1: 8, fully stirs the back standing demix, collects organic phase.Organic solvent is reclaimed in underpressure distillation, residue adsorbs with diatomite powder, dry back filling column chromatography, use hexane, methylene dichloride, methylene dichloride-methyl alcohol and methyl alcohol to wash chromatography column successively, collect cut and be concentrated into suitable volume, after the subcooling, remove by filter sediment, filtered solution is concentrated into original volume, ice bath once more.Centrifugal results precipitation, dissolve with methylene chloride (1: 1), and place dry absorption (2.5kg diatomite/1kg precipitates) on the diatomite, diatomite after the absorption places (16kg diatomite/1kg precipitation) on the original diatomite, the dress chromatography column, use methylene dichloride, methylene dichloride-methyl alcohol, the methyl alcohol stream of different volumes to wash successively, the cut that obtains places the vacuum drying oven dried overnight, and the solid substance of acquisition is geldanamycin.
According to another aspect of the invention, the preparation geldanamycin derivant further is provided---the technology of 17-allyl amido geldanamycin, it is mainly by synthesizing 17-allyl amido geldanamycin with highly purified geldanamycin and excessive propylene ammonia react.
The geldanamycin of prepared is measured through HPLC according to the present invention, its purity is greater than 98.5%, therefore, technology of the present invention can obtain highly purified geldanamycin, and then in follow-up technology, can obtain derivative---the 17-allyl amido geldanamycin (yield 98.1%) of high yield, every liter of fermented liquid can obtain more than the geldanamycin 200mg, so output is higher.The present invention is that industrialization, scale operation geldanamycin and derivative thereof are laid a good foundation.
Brief description of drawings
Fig. 1 is a C18 reversed-phase column high performance liquid chromatography (HPLC), 50% acetonitrile moving phase color atlas;
Fig. 2 is a C18 reversed-phase column high performance liquid chromatography (HPLC), methyl alcohol color atlas, moving phase: 50% acetonitrile;
Fig. 3 is a C18 reversed-phase column high performance liquid chromatography (HPLC), geldanamycin (methanol solvate) color atlas, moving phase: 50% acetonitrile;
Fig. 4 is a C18 reversed-phase column high performance liquid chromatography (HPLC), 17-allyl amido geldanamycin (methanol solvate) color atlas, moving phase: 50% acetonitrile.
Embodiment
Below by description, describe the present invention in detail to better embodiment of the present invention:
Embodiment 1
The extraction of geldanamycin and purifying
Geldanamycin is extracted the nutrient solution from the moist streptomycete of Ge Erdenasi (Streptomyces hygroscopicus varGeldanus).Streptomycete is cultivated, product extracts and purifying process is as follows:
(1) substratum is formed
Contain organism such as glucose, Tryptones, refined edible oil, proteolysate, yeast extract, yeast nitrogen base, Zulkovsky starch, molasses in the liquid nutrient medium, each component content is variable 0.01～5%, the an amount of simultaneously inorganic microelements such as dipotassium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, calcium chloride that add are regulated pH between 5.0～8.0.
The composition of preferred a kind of liquid nutrient medium following (every liter):
Glucose 40 grams
Tryptones 2.5 grams
Zulkovsky starch 5 grams
Yeast extract 2.5 grams
10 milliliters of refining Trisun Oil R 80s
Proteolysate 2.5 grams
Yeast nitrogen base 1 gram
10 milliliters in molasses
Dipotassium hydrogen phosphate 0.015 gram
SODIUM PHOSPHATE, MONOBASIC 0.005 gram
Calcium chloride 0.03 gram
1 milliliter of trace element mixed solution
Trace element mixed solution sulfur acid ketone, manganous sulfate, iron(ic) chloride, zinc sulfate, cobalt chloride, sodium manganate, Sodium Tetraborate and boric acid etc., concentration separately is 0.1～10mmol/L;
Adjust pH to 7.0～7.2.Standby after autoclaving or the filtration sterilization.
(2) plant daughter bacteria inoculation and fermentation:
Moist streptomycete (the Streptomyces hygroscopicus varGeldanus) bacterial classification of the used Ge Erdenasi of the present invention derives from USDA agricultural research institute preservation center (Northern Utilizationand Research Division, Agricultural Research, U.S.Department of Agriculture, Peoria, Ill., U.S.A.), this bacterial classification was submitted permanent preservation in 1969, preserving number is: NRRL 3602, can not have any restrictedly granting at present and give the public.
In-70 ℃ of refrigerators or liquid nitrogen container, take out the frozen bacterial classification (4ml) of low temperature, be inoculated in 2 50ml flasks, 28 ℃, cultivate after 60 hours for 220 rev/mins, 4 200ml flasks are gone in switching, 28 ℃, 200 rev/mins are continued to cultivate after 36 hours, be inoculated into 6 2000ml flasks, 28 ℃, cultivate in the seed fermentation jar that is inoculated into 150 liters after 36 hours for 220 rev/mins, cultured continuously 30 hours, took a sample to check once in per 6 hours and (control dissolved oxygen, pH and foam), be inoculated in the fermentor tank of 1500 liters (or bigger volumes) the culturing process control foam afterwards, dissolved oxygen and pH, the content (high performance liquid chromatography) of per 6 hours sampling one-time detection geldanamycin, stop to cultivate when geldanamycin content no longer obviously increases, the last incubation time is about 100～170 hours.
(3) extraction of geldanamycin (ethyl acetate extraction process)
Adopt and filter or centrifuging clarification nutrient solution, in filtered liquid or supernatant liquor, press 1: 2 (ethyl acetate: filtered solution) add ethyl acetate, placed 2 hours, remove aqueous liquid phase, with the organic phase concentrate drying, the resistates diatomite adsorption, with the dried diatomite chromatography column of packing into, use the hexane of 4 times of volumes, 2 times of volumes methylene chloride, 7 times of volumes methylene chloride/methyl alcohol (99: 1) and 2 times of volumes methanol flushings successively, collect cut and be concentrated into 1/5 volume, put the after-filtration that spends the night in the ice bath and remove sediment, filtered solution is concentrated into 1/5 volume, ice bath once more.Centrifugal collecting precipitation, precipitation is dissolved with methylene chloride (1: 1), and place dry absorption (2.5kg diatomite/1kg precipitates) on the diatomite, diatomite after the absorption places (16kg diatomite/1kg precipitation) on the original diatomite, the dress chromatography column, use 2 times of volumes methylene chloride, 6 times of volumes methylene chloride/methyl alcohol (98: 2), 4 times of volumes methylene chloride/methyl alcohol (95: 5), 2 times of volumes methanol flushings successively, the cut that the obtains dried overnight in the vacuum drying oven that is placed in, the solid substance that obtains is geldanamycin, and HPLC measures purity greater than 98.5%.The mass spectrograph determining molecular weight is 560, fusing point 252-255 ℃, be soluble in organic solvents such as chloroform, methylene dichloride, dimethyl sulfoxide (DMSO), and be dissolved in acetone, methyl alcohol etc. slightly, be slightly soluble in water, room temperature preservation is stable after the freeze-drying.The results are shown in Figure 1, Fig. 2 and Fig. 3.
Embodiment 2
The chemosynthesis of 17-allyl amido geldanamycin
In the ground glass flask that fills the 100ml trichloromethane, add 560mg geldanamycin (purity is not less than 98.5%), shake well 10 minutes, fully after the dissolving, with G6/G3 sintered glass funnel suction filtration, add 2ml propylene ammonia (purity is not less than 99%) in the filtrate, stirring at low speed reaction 20～24 hours.After this add the ultrapure water of 100ml precooling (2～4 ℃) in reactor, transfer pH to 3.0 with 6M hydrochloric acid, high-speed stirring at least 30 minutes moves into liquid in the 250ml separating funnel after stopping to stir and leaves standstill, and treats its natural layering, collects the trichloromethane phase of lower floor.Add the 100ml trichloromethane once more to aqueous phase, fully stir, treat to collect the trichloromethane phase after its layering, the trichloromethane of twice collection is merged mutually, pour in the sintered glass funnel that contains anhydrous sodium sulphate, stir with glass stick, suction filtration is removed solid sodium sulfate, collect filtered solution, with getting orange solid substance behind the rotatory evaporator concentrating under reduced pressure.This solid substance can obtain 575mg 17-allyl amido geldanamycin (rate of recovery 98.1%) with acetone-n-hexane recrystallization behind the drying under reduced pressure, fusing point is 212～214 ℃, and the mass spectrograph determining molecular weight is about 586, fusing point 212-214 ℃, the results are shown in Figure 4.Be soluble in organic solvents such as chloroform, methylene dichloride, dimethyl sulfoxide (DMSO), be dissolved in acetone, methyl alcohol etc. slightly, be slightly soluble in water.Room temperature preservation is stable after the freeze-drying.
Embodiment 3
Be used for leukemic chemotherapy
The main at present dependence chemotherapy of leukemic treatment and marrow/stem cell transplantation, the major cause of treatment failure is the tolerance of leukemia cell to chemotherapeutics.Experimental studies have found that geldanamycin can induce the K562 cell that significant cell cycle takes place and suppress, make most cells stagnate the phase in G2/M.Find that 17AAG can be by removing the Bcr-Ab1 of high expression level among the leukemia cell, make the Bcr-Ab1 positive cell improve 3-8 doubly to the susceptibility of chemotherapeutics, 17AAG can make the leukemia cell that obvious apoptosis takes place and impel it to break up to normal cell simultaneously, thereby brings up to leukemic result of treatment from a plurality of different approach.Clinical study finds that combined utilization 17AAG can bring up to 92% from 58% with Bcr-Ab1 male leukemia curative ratio.
Embodiment 4
Be used for the treatment of lung cancer
Experimental studies have found that, 17AAG can bring into play restraining effect from many aspects to the growth of lung carcinoma cell, except as to other tumour cells, bring into play antiproliferative and make tumour cell to effect such as chemotherapy drug susceptibility enhancing, 17AAG can also obviously suppress the expression of erB1/erB2, suppress tumor cell secretion MMP-9 and VEGF, strengthen the expression of E-cadherins, thereby suppress the transfer of tumour cell.Experiment shows that the chemotherapy regimen that contains 17AAG can obviously dwindle the volume of nude mice lotus knurl than other schemes in the animal body, prolongs survival time of mice, and 17AAG treatment group has the tumour completely dissolve of 50% nuclear knurl mouse approximately.
The above description of this invention does not limit the present invention, and those skilled in the art can make various changes and distortion according to the present invention, has only not break away from spirit of the present invention and content, all should belong to the scope of claims of the present invention.
Claims (7)
1, the preparation technology of geldanamycin may further comprise the steps:
Cultivate the moist streptomycete NRRL of Ge Erdenasi 3602 bacterial strains with liquid nutrient medium, described substratum contains for every liter:
Glucose 0.1～100 gram
Peptone 0.5～15 gram
1～50 milliliter of refining Trisun Oil R 80
Proteolysate 0.1～25 gram
Yeast extract 0.1～20 gram
Yeast nitrogen base 0.1～50 gram
Zulkovsky starch 0.1～15 gram
0.1～10 milliliter in molasses; And
An amount of inorganic microelement, described inorganic microelement are the mixed solution of sulfur acid copper, manganous sulfate, iron(ic) chloride, zinc sulfate, cobalt chloride, sodium manganate, Sodium Tetraborate and boric acid, and concentration separately is 0.1～10mmol/L;
Transfer pH to 5.0～8.0 of substratum;
Cultivate moist streptomycete (Streptomyceshygroscopicus var Geldanus) NRRL 3602 bacterial strains of Ge Erdenasi at 25～35 ℃, obtain to contain the nutrient solution of geldanamycin;
Purifying geldanamycin from nutrient solution comprises:
1) centrifugal or filtration nutrient solution obtains supernatant liquor;
2) add organic solvent in described supernatant liquor, described organic solvent is 1: 1～1: 8 with the ratio of supernatant liquor volume, stirs the back layering, collects organic phase;
3) behind the removal organic solvent, with carrier absorption residue;
With described carrier filling chromatography column, with organic solvent wash-out successively and the concentrated geldanamycin that obtains purifying.
2, according to the described technology of claim 1, every liter contains in the wherein said substratum:
Glucose 40 grams
Tryptones 2.5 grams
Zulkovsky starch 5 grams
Yeast extract 2.5 grams
10 milliliters of refining Trisun Oil R 80s
Proteolysate 2.5 grams
Yeast nitrogen base 1 gram
10 milliliters in molasses
Dipotassium hydrogen phosphate 0.015 gram
SODIUM PHOSPHATE, MONOBASIC 0.005 gram
Calcium chloride 0.03 gram
1 milliliter of trace element mixed solution
Adjust pH to 7.0～7.2.
3, technology according to claim 1, wherein step 2) described organic solvent is propyl carbinol or ethyl acetate.
4, technology according to claim 1, wherein the described carrier of step 3) is a diatomite powder.
5, technology according to claim 1, wherein the described wash-out of step 4) uses hexane, methylene dichloride, methylene dichloride and methanol mixture and methyl alcohol successively with organic solvent.
6, be used to cultivate the substratum of moist streptomycete (Streptomyces hygroscopicusvar Geldanus) NRRL 3602 bacterial strains of Ge Erdenasi, it is characterized in that every liter of described substratum contains following composition:
Glucose 0.1～100 gram
Peptone 0.5～15 gram
1～50 milliliter of refining Trisun Oil R 80
Proteolysate 0.1～25 gram
Yeast extract 0.1～20 gram
Yeast nitrogen base 0.1～50 gram
Zulkovsky starch 0.1～15 gram
0.1～10 milliliter in molasses; And
An amount of inorganic microelement, described inorganic microelement are the mixed solution of sulfur acid copper, manganous sulfate, iron(ic) chloride, zinc sulfate, cobalt chloride, sodium manganate, Sodium Tetraborate and boric acid, concentration 0.1～10mmol/L separately
The pH of substratum is 5.0～8.0.
7, substratum according to claim 6 is characterized in that described substratum contains for every liter:
Glucose 40 grams
Tryptones 2.5 grams
Zulkovsky starch 5 grams
Yeast extract 2.5 grams
10 milliliters of refining Trisun Oil R 80s
Proteolysate 2.5 grams
Yeast nitrogen base 1 gram
10 milliliters in molasses
Dipotassium hydrogen phosphate 0.015 gram
SODIUM PHOSPHATE, MONOBASIC 0.005 gram
Calcium chloride 0.03 gram
1 milliliter of trace element mixed solution
Medium pH is 7.0～7.2.
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| CN 02132163 CN1190497C (en) | 2002-08-30 | 2002-08-30 | Preparation technology of geldanamycin and its derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20110034686A1 (en) * | 2008-04-21 | 2011-02-10 | Nitin Sopanrao Patil | Process for Isolation and Purification of Geldanamycin |
| CN102190620B (en) * | 2010-03-17 | 2014-06-04 | 上海医药工业研究院 | Method for separating and purifying geldanamycin |
| CN102584704B (en) * | 2011-01-05 | 2016-01-13 | 华北制药集团新药研究开发有限责任公司 | A kind of polymer microballoon is separated the method preparing geldanamycin |
| CN103484515B (en) * | 2013-09-25 | 2016-03-23 | 宁夏泰瑞制药股份有限公司 | A kind of substratum of streptomyces erythareus fermentative production erythromycin and cultural method |
| CN103642881B (en) * | 2013-11-18 | 2015-06-17 | 宁夏泰瑞制药股份有限公司 | Medium for producing daunorubicin by fermenting streptomyces peucetius or streptomyces coeruleorubidus and fermentation method |
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