CN1050846C - Antitumor antibiotic-Yunnan-mycin - Google Patents
Antitumor antibiotic-Yunnan-mycin Download PDFInfo
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- CN1050846C CN1050846C CN95109425A CN95109425A CN1050846C CN 1050846 C CN1050846 C CN 1050846C CN 95109425 A CN95109425 A CN 95109425A CN 95109425 A CN95109425 A CN 95109425A CN 1050846 C CN1050846 C CN 1050846C
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- yunnan
- mycin
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Abstract
The present invention relates to a method for separating a new cytidine dipeptide antibiotic, namely Yunnanmycin, from the fermentation liquid of Yunnan streptin strains 2321 by the methods of ion exchange resin extraction, chromatographic separation and purification, concentrated hydrochloric acid hydrolysis, ion exchange resin extraction, chromatographic preparation, etc. The Yunnanmycin has an in-vitro killing and damaging effect on tumor cells, and has an obvious therapeutic effect on sarcomas 180 (solid type) of mice. The inhibiting ratio of the tolerable dose of the Yunnanmycin to tumor growth can reach 87%, and the tumor-inhibiting effect of the Yunnanmycin is stronger than that of 5-fluorouracil with equal toxicity dose. The toxicity of the Yunnanmycin to marrow is lighter, and the therapeutic dose of the Yunnanmycin has a light inhibiting effect on the hematopoietic system. Histopathologic examination shows that the Yunnanmycin can be used to treat the diseases of various principal organs of animals without toxicity pathological changes.
Description
The invention belongs to cytidine(C two peptide antibiotics with antitumor action.
Surplus the microbiotic of having found so far that derives from microorganism nearly ten thousand more than the kind, wherein many agricultural chemicals etc. have obtained widespread use as medicine, but good effect, antitumor antibiotics that toxicity is low are still very few for number.Therefore the new variety of further seeking the ideal antitumor action are still urgent day by day.
The present invention is from the process of Yunnan actinomycetes screening antitumor antibiotics, be separated to active substance in the nutrient solution by streptomycete bacterial strain 2321, from the sour water product of this material, separate the microbiotic Yunnan mycin (Yunnanmycin) that has obtained having antitumor action with antitumor and anti-microbial effect.(the generation bacterium of this Yunnan mycin is deposited in " China Committee for Culture Collection of Microorganisms's common micro-organisms " center ", BeiJing ZhongGuanCun.100080, preservation date nineteen ninety-five, July 26, numbering streptomycete CGMCCNO.0234).
Through spectrum and MASS SPECTRAL DATA ANALYSIS, determine that Yunnan mycin has suc as formula structural formula shown in (1) R=H, this structural formula can be with all of Yunnan mycin and hitherto known cytidine(C dipeptides structure medical and agricultural antibiotic such as gougerotin (Gougerotin) qingfengmeisu (Qingfengmycin) and Ningnanmycin (Ningnanmycin) equiphase zone other, name and be Yunnan mycin.
R is H or K or Na in the formula.Content of the present invention and main points are as follows: one, the generation bacterium of Yunnan mycin, fermentation, anti-microbial activity and manufacture method 1. produce the bacterium source: Guan Ping wilderness area, Yunnan soil.Morphological specificity: fibrillae of spores volution.Spore is polytypism: ellipse, garden shape, melon seeds shape, spore surface spinosity.
Cultural characteristic: it is well white colourless well white colourless well in vain colourless to the colourless no H of the butterfat good white of little yellow Isp.6 culture medium to brown ash to the no Isp.5 culture medium of little ash to brown ash to the no Isp.4 culture medium of little ash to the white extremely brown ash of the colourless no Isp.3 culture medium appropriateness of brown ash to see Table the no light yellow complexion Isp.2 of the 1 table 1 culture medium growth generation mycelia substrate mycelium soluble pigment good white of Isp.1 culture medium culture medium2The dirty yellow glucose asparagine agar appropriateness colourless no sucrose Cha Shi agar difference of the light gray brown ash good brown pale yellow greyness of colourless no glucose Cha Shi agar of the good light gray moccasin of SIsp.7 culture medium look pale yellow glycerine Cha Shi agar is well in vain greyish white to grey colourless or butterfat does not have or the yellowish melanin that do not form to No. 1 agar appropriateness of the yellow Gao Shi of the pale yellow brown dirt of light gray, does not produce H2S.2. fermentation spore cultivations of going down to posterity: Isp.5 substratum, 28 ℃ of cultivations in 10 days.Seed culture: medium component: glucose 1%, starch 1.5%, meat extract 0.5%, peptone (fish) 0.5%, NaCl0.3%, analysis for soybean powder 1%, no salt solution, PH7.0,28 ℃ of shaking culture 48 hours.Fermentation culture: medium component: glucose 2%, starch 1%, meat extract 0.5%, yeast powder 0.5%, peptone (fish) 0.5%, NaCl0.3%, analysis for soybean powder 1%, no salt solution, PH7.0,28 ℃ of shaking culture 96 hours.Active calibrating: test organism: intestinal bacteria B substratum: meat extract 0.3%, peptone 1%, agar 1.5%, no salt solution, PH7.0-7.2.Calibration method: paper dish method.3. the anti-microbial activity Yunnan mycin only has more weak activity to intestinal bacteria B.Paper dish method detected result sees Table 2 tables 2
Test organisms minimum inhibitory concentration (ug/ml)
Bacillus?subtilis?6633 ＞500
Staphylococcus?aureus?209p ＞500
Sarcina?lutea ＞500
Escherichia?coli?B 500
Escherichia?coli?o11 ＞500
Proteus?vulgaris?ox19 ＞500
Pseudomonas?aeruginosa?11 ＞500
Klebsiella?pneumoniae ＞500
Candida?albicans ＞500
Penecillium avellaneum 5404＞5004. manufacture method
The filtrate of the fermentation culture of streptomycete CGMCCNO.0234, with the absorption of 2% (grams per milliliter) gac dress post, 50% acetone wash-out, concentrating under reduced pressure is removed the aqueous solution behind the acetone, transfers PH3, by strong acid cation resin (NH
4 +Type), exchanges, with 1N ammoniacal liquor wash-out, elutriant shows that to intestinal bacteria active part removes deammoniation, lyophilize, cold dry product neutral alumina post adsorption chromatography, 75% methanol-eluted fractions, go the lyophilize of methyl alcohol rear solution, use sephadex G-10 column chromatography after the drying again, the active part lyophilize, cold dry product adds an amount of concentrated hydrochloric acid, hydrolysis is 60 hours under room temperature, removes excessive hydrogen chloride gas, and the aqueous solution is by strong acid cation resin (NH
4 +Type) exchange, 0.1N ammoniacal liquor wash-out, lyophilize, dry product is expanded with sephadex G-10 column chromatography for separation, water, and active part is lyophilize again, and dry product (is made silica gel G F by oneself with the preparation of silica gel thin sheet chromatographic separation
254Plate, 20 * 20cm), 60% methyl alcohol launches, and the cold dry product purity of isolating active part reaches more than 95%, claims Yunnan mycin.Two, the structure of Yunnan mycin and physicochemical data:
Yunnan mycin has structure as the formula (1), its UV, and IR, FAB-MS divides
Minor,
1H-NMR,
13C-NMR reaches
13The C-DEPT data are as follows, and (1) formula is
Reach according to these data
1H-
1Relevant spectrum of H (COSY) and anti-phase detection are long-range
1H-
13C
The analysis of the relevant spectrum of heteronuclear multikey (HMBC) is determined.
UV： λ
max H2O 268nm
λ
max 0.1NNaOH 268nm
λ
Mqx 0.1NHCl275nm (seeing accompanying drawing 1)
IR(KBr)： 3200-3400， 1640-1660，
1485， 1275，?1060-1080，
940,840,780cm
-1(seeing accompanying drawing 2)
FAB-MS(m/z)：445(M+H)
+
443 (M-H)
-(seeing accompanying drawing 3)
Molecular formula: C
16H
24N
6O
9
1H-NMR (400MHz in D
2O, 30 ℃), see Table 3 and accompanying drawing 4
Table 3
1H-NMR(400MHz in?D
2O，30℃)
ppm multi assignment
7.83 1H，d，8Hz H-6
5.12 1H，d，8Hz H-5
5.70 1H，m H-1’
4.56 1H，t，5Hz Ser-α
4.05 1H，m H-4’
4.02 1H，d，11Hz H-5’
3.98 1H，d，16Hz Gly-α
3.93 1H，d，16Hz Gly-α
3.87 2H，m Ser-β
3.81 2H，m H-2’，3’
2.77 3H，s NCH
3
13C-NMR (100MHz in D
2O, 30 ℃), see accompanying drawing 5.
13C-DEPT (100MHz in D
2O, 30 ℃), see accompanying drawing 6.
1H-
1H COSY sees accompanying drawing 7.
1H-
13C HMBC sees Table 4 and accompanying drawing 8.
Table 4
13C-NMR (100MHz in D
2O, 30 ℃)
ppm multi Correlations observed in HMBC (δH) assignment 176.8 s 4.02 (H-5’) C-6’ 174.13 s 4.56 (Ser-α)3.87 (Ser-β) Ser-CO 169.88 s 4.56 (Ser-α)3.98 (Gly-α)3.93 (Ser-α) Gly-CO 168.89 s 7.83 (H-6) 6.12 (H-5) C-4 160.69 s 7.83 (H-6) 5.70 (H-1’) C-2 144.78 d 6.12 (H-5) 5.70 (H-1’) C-6 99.92 d 7.83 (H-6) C-5 85.92 d 7.83 (H-6) 3.81 (H-2’or 3’) C-1’ 80.83 d 4.05 (H-4’) C-5’ 76.65 d 5.70 (H-1’) 4.05 (H-4’)3.81 (H-2’or 3’) C-2’or 3’ 74.66 d 5.70 (H-1’) 3.81 (H-2’or 3’) C-2’or 3’ 64.15 t 4.56 (Ser-α) Ser-β 58.47 d 3.87 (Ser-β) Ser-α 56.35 d 4.02 (H-5’) 3.81 (H-2’or 3’) C-4’ 52.63 t 2.77 (NCH
3) Gly-α 35.84 q 3.98 (Gly-α) 3.93 (Gly-α) NCH
3Three, antitumor action (1) anti tumor activity in vitro of the antitumor action of Yunnan mycin and toxicity 1. Yunnan mycins: KB clone (deriving from people's oral squamous cell carcinomas) is used in experiment, is containing 5%CO with the RPMI1640 nutrient solution that contains 10% calf serum
2Cultivate in 37 ℃ of incubators and adopt clone's generation mensuration (Clonogenic assay) to judge the lethal effect of medicine tumour cell.The KB cell of taking the logarithm vegetative period adds in the 96# culture plate, every #50 cell/0.2ml, cultivate and add medicine after 24 hours, after 6 days under inverted microscope counting cells colony (containing 30 above persons of cell), calculate the colony inhibiting rate, the result proves that Yunnan mycin has lethal effect to the KB cell, and its action intensity is concentration dependent; Yunnan mycin is to the IC of KB cell
50(half colony inhibition concentration) is 3 μ g/ml (seeing accompanying drawing 9).(2) intravital test is to the curative effect of tumour: the Kunming mouse of 18-20g body weight is used in experiment, gets murine sarcoma 180 ascites and adds physiological saline (1: 3) dilution, and it is subcutaneous to be inoculated in the mouse armpit, every mouse 0.2ml.Inoculated tumour oral after 24 hours (po) administration, 2 times (respectively administration in 1,6 day) or 3 times (respectively administration in 1,4,7 day), first administration was put to death animal after 10 days, got tumour and weighed, and calculated tumor control rate.The result shows that Yunnan mycin has significant curative effect to murine sarcoma 180 (solid-type), uses tolerable dose (135mg/kg, po, * 2), and inhibition rate of tumor growth is reached 87% (P＜0.01).See Table 5
Table 5 Yunnan mycin begins/finishes to change (g) mean ± SD (%) I contrast 10/10+10.1 3.80 ± 1.08 Yunnan mycin 60 3 10/10+5.7 2.03 ± 0.48 47** to heavy (g) inhibiting rate lot number (mg/kg) number of times of restraining effect experiment group dosed administration number of animals body weight knurl of murine sarcoma 180 growths
90 3 10/10 +4.5 1.74±0.31 54**
120 3 9/10+4.3 0.84 ± 0.24 78**II contrast 10/10+7.3 2.94 ± 0.83 Yunnan mycin 105 2 10/10+2.0 0.71 ± 0.16 76**
120 2 10/10 -0.3 0.55±0.24 81**
135 2 10/10+1.8 0.38 ± 0.11 87** mouse armpit subcutaneous vaccination tumours, oral (po) administration.The antitumor action of * P＜0.01 (3) Yunnan mycin and 5-fluor-uracil and toxicity compare: toxicity dose (1/3 LD such as employing
50) compare.With (2) In vivo assay Cells, at mouse armpit subcutaneous vaccination sarcoma 180 ascites 0.2ml, begin oral administration (po) after 24 hours, totally 2 times (respectively administration in 1,6 day).First administration was put to death animal after 10 days, got tumour and weighed, and calculated tumor control rate: take out a side femur simultaneously, check the bone marrow nucleated cell number, calculate the medullary cell inhibiting rate.Experimental result, the tumor-inhibiting action of Yunnan mycin is stronger than 5-fluor-uracil, and bone marrow toxicity is lighter, uses to be equivalent to 1/3 LD
50Dosage, the inhibiting rate of Yunnan mycin (120mg/kg) and 5-fluor-uracil (80mg/kg) is respectively 81% (P＜0.01) and 66% (P＜0.01), both relatively, P＜0.01; Yunnan mycin and 5-fluor-uracil are respectively 22% (P＜0.05) and 83% (P＜0.01) to the inhibiting rate of bone marrow nucleated cell, and both compare, P＜0.01.See Table 6
Table 6 Yunnan mycin and 5-fluor-uracil are to the restraining effect of murine sarcoma 180
And relatively to the toxicity of marrow
Dosage number of animals tumor weight (g) bone marrow nucleated cell number (10
7/ femur)
(mg/kg) beginning/end X ± SD inhibiting rate (%) X ± SD inhibiting rate (%) contrast 10,/10 2.94 ± 0.83 1.41 ± 0.27 Yunnan mycin 120 10,/10 0.55 ± 0.24 81** 1.10 ± 0.29 22*5-Ro 2-9757 80 10,/10 0.99 ± 0.33 66** 0.24 ± 0.18 83** mouse armpit subcutaneous vaccination tumour is irritated stomach (po) administration: use to be equivalent to 1/3 LD
50Dosage, totally 2 * P＜0.05, * * P＜0.01, with control group relatively.The above results shows that use waits toxicity dose (1/3 LD
50, po) comparing, Yunnan mycin is stronger than 5-fluor-uracil to the restraining effect of murine sarcoma 180 (solid-type), and lighter to bone marrow toxicity.2. the toxicity of Yunnan mycin (1) chmice acute toxicity: the LD of oral administration (po)
50Be 360mg/kg.
The LD of intraperitoneal administration (ip)
50Be 65mg/kg.(2) use therapeutic dose (* 2, inhibiting rate is 81% for 120mg, po), hemopoietic system is had slight restraining effect, (medullary cell inhibiting rate 22%); Histopathologic examination, the various organs of treatment animal comprise that the heart, lung, tracheae, liver, oesophagus, stomach, small intestine, spleen, kidney, suprarenal gland etc. there is no the toxicity pathology.Four, manufacture method embodiment:
Get fermented liquid 10 liters, add diatomite filtration, discard mycelia, (water wets and adorns post filtrate, and post 5.5 * 55cm) adsorbs by 200 gram activated carbon columns, 50% acetone wash-out is collected portion for per 250 milliliters, and 1-4 part active part merges, remove acetone, about 500 milliliters of the aqueous solution is transferred PH3.0, by 50 milliliter of 001 * 7 ammonium type cation exchange resin column is housed, after the less water flushing, use 1N ammoniacal liquor wash-out, collect portion for per 100 milliliters, 1-5 part active part merges, and removes ammonia, aqueous solution lyophilize, whole cold dry products are by 100 milliliters of post decolourings of neutral alumina (the wet dress of methyl alcohol), and 75% methyl alcohol exhibition layer is received a for per 100 milliliters, 1-10 part active part merges, after removing methyl alcohol, lyophilize gets 2.3 gram dry products, get a gram dry product through sephadex G-10 column chromatography for separation, (post: 1.2 * 100cm), washing is collected a for per 5 milliliters, 7-15 part active part merges, lyophilize gets cold dry product 0.56 gram, and (HPLC detects purity 95%, C
18Waters post 4.6 * 250mm, moving phase is 75% methyl alcohol, flow velocity 1 ml/min detects UV268nm, retention time 8.3 minutes).Get cold dry product 1 gram of this 95% purity, add 40 milliliters of concentrated hydrochloric acids, the wet hydrolysis in chamber is after 60 hours, removes the residue behind the hydrogen chloride gas, adds 200 milliliters in water, by strong acid cation resin Dowex * 50w * 4 (NH
4 +Type) 10 milliliter, exchange, after the washing,, collect a for per 3 milliliters with 0.1N ammoniacal liquor wash-out, 11-20 part active part merges, deammoniation gas postlyophilization obtains 550 milligrams of cold dry products, get 150 milligrams of these cold dry products by sephadex G-10 post (1.2 * 100cm), the washing, the active part lyophilize, cold dry product (is made silica gel G F by oneself with the silica gel thin-layer plate chromatographic separation
254Plate, 20 * 20cm), 60% methyl alcohol exhibition layer separates 60 milligrams of cold dry products that obtain active part, and (HPLC detects purity 96%, C
18Waters post 4.6 * 250mm, moving phase is 75% methyl alcohol, flow velocity 1 ml/min detects UV268nm, retention time 2.9 minutes), claim Yunnan mycin.Description of drawings: Fig. 1 is the UV of Yunnan mycin; Fig. 2 is the IR of Yunnan mycin; Fig. 3 is the FAB-MS of Yunnan mycin; Fig. 4 is a Yunnan mycin
1H-NMR; Fig. 5 is a Yunnan mycin
13C-NMR; Fig. 6 is a Yunnan mycin
13C-DEPT; Fig. 7 is a Yunnan mycin
1H-
1H COSY; Fig. 8 is a Yunnan mycin
1H-
13C HMBC.Fig. 9 is the lethal effect of Yunnan mycin to the KB cell, and the clone generates and measures, and medicine is done
With 6 days time.
Claims (4)
1. the antitumor antibiotics of a following structural formula
R is H or K or Na in the formula.
2. preparation method of the antitumor antibiotics of structural formula according to claim 1, it is characterized in that the shaking culture fermentation under neutrallty condition with streptomycete CGMCCNO.0234, strongly acidic cation-exchange extracts, and sephadex chromatography separates, concentrated hydrochloric acid hydrolysis, purifying obtains finished product.
3. according to the preparation method of the described antitumor antibiotics of claim 2, it is characterized in that it is on the Isp5 substratum that streptomycete CGMCCNO.0234 spore goes down to posterity, cultivated 10 days for 28 ℃; The seed culture medium composition is a glucose 1%, meat extract 0.5%, and fish peptone 0.5%, NaCl 0.3%, analysis for soybean powder 1%, no salt solution, PH7.0,28 ℃ of shaking culture 48 hours; Fermention medium composition glucose 2%, starch 1%, meat extract 0.5%, yeast 0.5%, peptone 0.5%, NaCl 0.3%, analysis for soybean powder 1%, no salt solution, PH7.0,28 ℃ of shaking culture 96 hours.
4. according to the preparation method of the described antitumor antibiotics of claim 2, it is characterized in that streptomycete CGMCCNO.0234 fermented liquid is adsorbed through charcoal, the aqueous acetone wash-out, the strong acid type cationic resin exchange, the aluminum oxide decolouring, sephadex chromatography separates, concentrated hydrochloric acid hydrolysis, by the strongly acidic cation-exchange exchange, gel column separates, silica gel G F again
254Thin-layer chromatography, separation and purification, lyophilize gets product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95109425A CN1050846C (en) | 1995-08-03 | 1995-08-03 | Antitumor antibiotic-Yunnan-mycin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95109425A CN1050846C (en) | 1995-08-03 | 1995-08-03 | Antitumor antibiotic-Yunnan-mycin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1124778A CN1124778A (en) | 1996-06-19 |
| CN1050846C true CN1050846C (en) | 2000-03-29 |
Family
ID=5077204
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95109425A Expired - Fee Related CN1050846C (en) | 1995-08-03 | 1995-08-03 | Antitumor antibiotic-Yunnan-mycin |
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| Country | Link |
|---|---|
| CN (1) | CN1050846C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250176B (en) * | 2011-05-16 | 2014-12-31 | 中国医学科学院医药生物技术研究所 | Antitumor antibiotic ancomycin and its derivative |
| CN109134567B (en) * | 2018-07-23 | 2021-12-24 | 中国科学院成都生物研究所 | Fermentation preparation method of nucleoside antibacterial compound |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51113881A (en) * | 1975-04-01 | 1976-10-07 | Mitsui Pharmaceut Inc | Method for preparing 3',(2')-substituted-5-fluorouridine derivatives |
| JPS60246395A (en) * | 1984-05-18 | 1985-12-06 | Sumitomo Chem Co Ltd | Novel 6-substituted aldohexopyranose derivative |
| CN1065462A (en) * | 1991-04-05 | 1992-10-21 | 拜尔公司 | Replace 2 ', 3 '-dideoxy-5-trifluoromethyl uridine diphosphate glycoside, their preparation method and they application aspect medical |
| CN1072686A (en) * | 1991-09-30 | 1993-06-02 | 三共株式会社 | Has Pyrmidine nucleoside derivatives of anti-tumor activity and its production and use |
| CN1093869A (en) * | 1993-04-23 | 1994-10-26 | 中国科学院成都生物研究所 | A kind of new antibiotic pesticides-Ningnan Meisu |
-
1995
- 1995-08-03 CN CN95109425A patent/CN1050846C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51113881A (en) * | 1975-04-01 | 1976-10-07 | Mitsui Pharmaceut Inc | Method for preparing 3',(2')-substituted-5-fluorouridine derivatives |
| JPS60246395A (en) * | 1984-05-18 | 1985-12-06 | Sumitomo Chem Co Ltd | Novel 6-substituted aldohexopyranose derivative |
| CN1065462A (en) * | 1991-04-05 | 1992-10-21 | 拜尔公司 | Replace 2 ', 3 '-dideoxy-5-trifluoromethyl uridine diphosphate glycoside, their preparation method and they application aspect medical |
| CN1072686A (en) * | 1991-09-30 | 1993-06-02 | 三共株式会社 | Has Pyrmidine nucleoside derivatives of anti-tumor activity and its production and use |
| CN1093869A (en) * | 1993-04-23 | 1994-10-26 | 中国科学院成都生物研究所 | A kind of new antibiotic pesticides-Ningnan Meisu |
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| Publication number | Publication date |
|---|---|
| CN1124778A (en) | 1996-06-19 |
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