CN1253464C - Ansi glycoside compound and its medicinal composition, preparation and use - Google Patents
Ansi glycoside compound and its medicinal composition, preparation and use Download PDFInfo
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Abstract
The present invention provides ansi avermectin glycoside compound of a formula (I), a preparation method, a medicinal composition using the compound as an active component, and the application of the compound to the preparation of medicine for treating pathogen infectious diseases and the medicine for treating and preventing lung cancer and leukaemia.
Description
Technical field: the present invention relates to the ansamitocin glycosides compound, its preparation method, with this compound is the pharmaceutical composition of activeconstituents, and its application and application in preparation treatment and prevention lung cancer and leukemic medicine thereof in the medicine of preparation treatment pathogenic bacterial infection disease.
Background technology: maytenin or ansamitocin are anticancer compounds that at first was separated to from Celastraceae plant Caulis Mayteni (Maytenusserrata, old name M.ovatus) in 1972.Its content in plant is extremely low, is approximately 2mg/kg (dry sample), because the ED50 of its anti-KB cell is 10
-4-10
-5G/mL uses the pharmacology tracking to detect just to be separated and has obtained this compound.Afterwards, finding that other content that is collected in maytenin among African plant Maytenus buchanaii of this section and the Putterlickia verrucosa is higher, is respectively 14mg/kg and 100mg/kg.On structure, maytenin belongs to Macrocyclic lactams or the many ketone compounds of I type.The main variation of its natural derivative structure is: the L-Ala acyl group that 1, the difference of ester group on the hydroxyl of C-3 position, common ester group have simple fatty acids acyl group, N-to replace.2, there is not lateral chain of ester group.÷ does not have C-3 oxygen to replace.≠ there is not C-3 oxygen to replace and C-4,5 ring oxane.≡ does not have the N-methyl substituted.Although this compounds mainly is to separate to obtain from the Celastraceae plant, yet the plant that belongs to from other section also has discovery, for example report such as Wani is isolated the ansamitocin compounds that C-15 oxygen replaces, colubrinol and acetic ester thereof from Rhamnaceae plant Colubrina texensis; Powell etc. have also reported from euphorbia plant trewianudiflora (Trewianudiflora) seed isolation identification a series of new CHROMATOGRAPHIC FRACTIONATION AND MASS compounds.From liver moss, also separate even more noteworthy and obtained the CHROMATOGRAPHIC FRACTIONATION AND MASS compound.The most noticeable is to have found this compounds from microorganism.In the process of screening anticancer active constituent, Higashide etc. (are accredited as Nocardia sp.C-15003 at first from the microorganism that separates from Cyperaceae carex leaf, corrected into afterwards Actinosynnema pretiosum) in obtained six maytenin derivatives, called after ansamitocin P-0-P-4 is respectively ansamitocin alcohol and its acetic ester, propionic ester, isobutyrate, butyric ester (P-3 '), isopentanoate.Already plant 15 new ansamitocins that separate (A.pretiosumssp.Auranticum) except that above-mentioned six compounds from another orange synnema actinomycetes subsequently, wherein P-3 and P-4 are main components.These microorganisms make them be able to the structure activity relationship by semi-synthetic this compounds of research for Takeda company provides competent ansamitocin source.The preclinical pharmacology experiment shows: external, maytenin is 10 to the inhibition dosage of leukemia clone
-3-10
-7G/ml; In vivo, it is 25-32g/kg days to the restraining effect that has of P-388 leukemic lymphoblastoid to mouse L-1210 leukemia, Lewis lung cancer, the melanomatous effective dose of B-16.Its mechanism of action is the vincaleucoblastine binding site that covers microtubule, thereby has stoped the polymerization of microtubule.But, disappointing in the cancer patients first phase and second phase clinical experiment result on one's body.Clinical in the first phase, because of stomach toxicity and neurotoxicity have limited dosage.Several different tumours of second phase clinical trial, but, limited using dosage, to such an extent as to can not observe obvious curative effects because toxicity is obvious.Yet, because the physiologically active of CHROMATOGRAPHIC FRACTIONATION AND MASS compound is very strong, also making great efforts that they are developed as useful clinically anticarcinogen at present, for example maytenin or maytenin derivative are combined with the microbiotic that with the tumour cell is target spot and make the guided missile medicine.Research also shows, thereby the CHROMATOGRAPHIC FRACTIONATION AND MASS compound is owing to have antifeedant activity that killing action is arranged to insect.So far, do not see the report that the ansamitocin glycosides compound is arranged in the prior art.
Summary of the invention: the object of the present invention is to provide a kind of ansamitocin glycosides compound, its preparation method, with this compound is the pharmaceutical composition of activeconstituents, and its application and application in preparation treatment and prevention lung cancer and leukemic medicine thereof in the medicine of preparation treatment pathogenic bacterial infection disease.
In order to realize above-mentioned purpose of the present invention, the invention provides following technical scheme:
Ansamitocin glycosides compound shown in the formula (I):
| R＝H | Ansamitocin glycosides P-0 |
| R＝COCH 3 | Ansamitocin glycosides P-1 |
| R＝COCH 2CH 3 | Ansamitocin glycosides P-2 |
| R＝COCH(CH 3) 2Or CO (CH 2) 2CH 3 | Ansamitocin glycosides P-3 |
| R＝COCH 2CH(CH 3) 2Or CO (CH 2) 3CH 3 | Ansamitocin glycosides P-4 |
| R＝CO(CH 2) 2CH(CH 3) 2Or CO (CH 2) 1CH 3 | Ansamitocin glycosides P-5 |
| R＝CO(CH 2) 3CH(CH 3) 2Or CO (CH 2) 5CH 3 | Ansamitocin glycosides P-6 |
The preparation method of above-mentioned ansamitocin glycosides compound comprises that the mixed solvent that uses the prescription composition to be different from routine extracts orange synnema actinomycetes (Actinosynnema pretiosum ssp.aurantium ATCC31565) solid fermentation product and formula (I) compound is arrived in the separation and purification of ansamitocin glycosides compound.
Particularly, with the YMG substratum orange synnema actinomycetes is carried out solid fermentation (3.5L), culture is cut into small pieces, with ethyl acetate/methanol/glacial acetic acid (80: 15: 6) lixiviate, lixiviate repeatedly repeatedly, united extraction liquid, concentrating under reduced pressure boils off organic phase, residue water chloroform extraction, behind chloroform and the water separatory, evaporate to dryness separates respectively with water extract then respectively, use positive repeatedly, anti-phase, macroporous resin, the dextrane gel column chromatography, anti-mycotic activity is followed the trail of, thin-layer chromatography detects the elutriant that component is identical with liquid chromatography-GC-MS and merges the compound that gets respectively in the formula (I).
Be used for prevention and treatment lung cancer drugs composition, wherein contain formula (I) compound for the treatment of significant quantity and acceptable carrier pharmaceutically.
Be used for prevention and treat leukemic pharmaceutical composition, wherein contain formula (I) compound for the treatment of significant quantity and acceptable carrier pharmaceutically.
In addition, the invention provides formula (I) compound, in the application for preparing on the medicine that prevents and treat the application on the leukemic medicine and preparing treatment pathogenic bacterial infection disease in the application for preparing on prevention and the treatment lung cancer drugs.
The contriver finds that The compounds of this invention has prevention and therapeutic action to lung cancer, leukemia, multiple human body pathogenic bacterial infection.Pharmaceutical composition of the present invention contains formula (I) compound for the treatment of significant quantity and acceptable carrier pharmaceutically.
Compound of the present invention and pharmaceutical composition can be used for preparing the medicine of prevention and treatment lung cancer, leukemia and anti-human body pathogenic bacteria.
Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, for example: thinner, vehicle such as water etc., weighting agent such as starch, sucrose etc., tackiness agent such as derivatived cellulose, alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerine; Disintegrating agent such as agar, lime carbonate and sodium bicarbonate; Absorption enhancer such as quaternary ammonium compound; Tensio-active agent such as cetyl alcohol; Absorption carrier such as kaolin and soap clay; Lubricant such as talcum powder, calcium stearate and magnesium and polyoxyethylene glycol etc.Can also in composition, add other assistant agent such as flavouring agent, sweeting agent etc. in addition.
The compounds of this invention can composition form by oral, snuffing is gone into, the mode of rectum or administered parenterally is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis, granula, capsule etc., make liquid preparation such as water or oil-suspending agent or other liquid preparation such as syrup, elixir etc.; When being used for administered parenterally, can be made into solution, water or the oiliness suspension agent etc. of injection.Preferred form is tablet, coated tablet, capsule, suppository, nasal spray and injection, the preparation that discharges particularly preferably in the privileged site of enteron aisle.
The various formulations of pharmaceutical composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.Activeconstituents is mixed with one or more carriers, be made into required formulation then.
Pharmaceutical composition of the present invention preferably contains the activeconstituents that weight ratio is 0.1%-99.5%, most preferably contains the activeconstituents that weight ratio is 0.5%-95%.
The amount of application of The compounds of this invention can be according to variations such as the type of route of administration, patient's age, body weight, the disease of being treated and severity, and its per daily dose can be the 0.01-10mg/kg body weight, preferred 0.1-5mg/kg body weight.Can use by one or many.
Description of drawings: Fig. 1 is for the orange synnema actinomycetes fermentation and extract schema;
Fig. 2 is the separation process of compound ansamitocin glycosides P-2.
Embodiment: make those skilled in the art more fully understand the present invention below in conjunction with accompanying drawing of the present invention with embodiment, but do not limit the present invention in any way.
Embodiment 1:
1, the preparation of ansamitocin glycosides compound (is example with ansamitocin glycosides P-2):
Orange synnema actinomycetes is the generation bacterium of ansamitocin compounds.From the fermented product extract of this bacterium, separate obtain a series of ansamitocin compounds (ansamitocins P-0, P-1, P-2, P-3, P-4).The applicant utilizes solid fermentation and LC-MS to detect and active method of following the tracks of, and has not only detected the ansamitocin compounds, also is separated to anticancer from its aqueous extract and ansamitocin glycosides P-0 anti-mycotic activity, P-1, P-2, P-3, P-4, P-5, P-6.Also detected and ansamitocin P-0 with LC-MS, P-1, P-2,, P-3, the molecular ion peak of the corresponding glucoside of P-4 (ansamitocin glycosides P-0, P-1, P-2, P-3 and P-4).
1.1 the solid fermentation of orange synnema actinomycetes and the extraction of compound
At first the orange synnema actinomycetes bacterial classification is migrated out from the glycerine pipe, carry out slant activation.Activation is solid YMG substratum [it consists of glucose 4g, malt extract 10g, yeast extract 4g, agar 15g distilled water 1000mL, pH 7.2 (before the sterilization)] with substratum, cultivates 5 days in 28 ℃ of constant incubators.Solid fermentation YMG substratum.Rule and cultivated 7 days in back 28 ℃ of constant incubators, the fermentation scale is 3.5 liters.
The solid fermentation thing is divided into fritter together with substratum, soaks with ethyl acetate/methyl alcohol/glacial acetic acid (80: 15: 5) and extract repeatedly.After the filtration, united extraction liquid, concentrating under reduced pressure boils off organic phase, and the residue water is with chloroform extraction repeatedly.Behind chloroform and the water separatory, the difference evaporate to dryness.The anti-mycotic activity experiment shows water (15g) and CHCl
3Extract (1.177g) all demonstrates extremely strong anti-mycotic activity, and TLC shows that the ansamitocin compounds is mainly at CHCl
3In the extract, aqueous phase does not then have.In order to determine the anti-mycotic activity composition of aqueous phase, therefore aqueous extract is separated with active tracing.The indication fungi of this experiment is orange mould (Penicillium.avellaneum UC-4376).Concrete fermentation and extraction flow process are as shown in Figure 1.
1.2 the activity of active compound ansamitocin glycoside composition is followed the trail of and is separated (is example with ansamitocin glycosides P-2) in the aqueous extract
At first with in press reversed phase column chromatography to carry out initial gross separation, use 30%MeOH respectively, 50%MeOH, 70%MeOH, each 1L of 100%MeOH carries out wash-out, is divided into four parts.Antimycotic experiment shows 50%MeOH, and the 70%MeOH wash-out partly has the activity that suppresses the indicator growth.Through repeated gelatin column chromatography, silica gel column chromatography and reversed-phase silica gel column chromatography, obtain an active compound ansamitocin glycosides P-2 in conjunction with active tracking separation from aqueous extract.Separation process as shown in Figure 2.
The ansamitocin glycosides P-2 purity that obtains is still bad, therefore with pressing in anti-phase, with MeOH/H
2O (1: 1) obtains compound ansamitocin glycosides P-2. for eluent is further purified
2. the structure of compound ansamitocin glycosides P-2 is identified:
The molecular weight that fast atom bombardment MS FABMS provides compound is 767, and the fragment peak 607 that splits glucose is arranged.The molecular formula that the high resolution fast atom bombardment MS provides this compound is C
36H
18ClN
2O
14(HRFAB
-MS, measured value: 767.2811 calculated values: 767.2794).
The carbon spectrum (comprising DEPT) of compound ansamitocin glycosides P-2 provides 36 signals: comprise 4 methyl, 3 methoxyl groups, 5 methylene radical, 15 methynes and 9 quaternary carbons.According to HMQC and HMBC experiment, we have determined that the structure of ansamitocin glycosides P-2 is the ansamitocin compounds.According to C-1 " the long-range correlationship of position proton and C-1; determined that sugared the position of substitution is on the N of amido bond; so the chemical structural formula of compound ansamitocin glycosides P-2 is accredited as shown in Figure 1, and whole NMR spectroscopic datas is specified, be defined as a new compound.
3, the antibiotic and antitumour activity of compound ansamitocin glycosides P-2 test:
Compound ansamitocin glycosides P-2 separates as indicator with orange mould (P.avellaneum UC-4376) and obtains, and also has the activity of anti-other fungies and bacterium so infer this compound.So having carried out other anti-microbial activity, we detect.
3.1 anti-microbial activity
Indicator: orange mould (P.avellaneum UC-4376), streptococcus aureus (Staphylococcusaureus), mycobacterium tuberculosis (Mycobacterium tuberculosis).
Experimental technique: disk diffusion method
Activity index: have or not the size of transparent inhibition zone and inhibition zone, inhibition zone is big more, shows that activity is strong more.
The nuclear magnetic resonance data of table 1, ansamitocin glycosides P-2.
| No | 13C | 1H b | HMBC |
| 1 | 172.9s | / | / |
| 2 | 34.7t | 2.50(m)，2.20(m) | C-1，C-3，C-4 |
| 3 | 77.8d | 4.76(dd，2.9，10.0) | C-1，C-2，C-4，C-4a，C-5(w) |
| 4 | 62.0s | / | / |
| 5 | 68.0d | 2.72(d，9.3) | C-3，C-4，C-6a |
| 6 | 39.2d | 1.18(m) | C-6a |
| 7 | 75.9d | 4.20(dt，2.8，11.1) | COO-7 |
| 8 | 37.4t | 1.53(m) | C-7，C-9，C-10 |
| 9 | 81.8s | / | / |
| 10 | 89.7d | 3.55(m) | C-9 |
| 11 | 129.3d | 5.53(dd，8.1，15.2) | C-9，C-13 |
| 12 | 134.0d | 6.63(dd，11.0，15.8) | C-10，C-13，C-14 |
| 13 | 125.5d | 6.26(d，10.8) | C-11，C-12，C-14，C-15，C-15a |
| 14 | 141.5s | / | / |
| 15 | 47.5t | 3.61(m)，3.32(m) | C-1，C-13，C-14，C-14a，C-21 |
| 16 | 123.4s | / | / |
| 17 | 126.3d | 7.21(s) | C-15，C-16，C-19，C-21 |
| 18 | 137.3s | / | / |
| 19 | 155.3s | / | / |
| 20 | 157.1s | / | / |
| 21 | 115.2d | 7.17(dt，1.9，5.0) | C-14，C-17，C-20 |
| MeO-10 | 56.9q | 3.36(s，3H) | C-10 |
| NHCO-9 | 159.3s | / | / |
| MeO-20 | 57.1q | 3.98(s，3H) | C-20 |
| 1’ | 175.2s | / | / |
| 2’ | 27.7t | 2.77(m)，2.56(m) | C-3’ |
| 3’ | 8.5q | 1.08(t，7.4，3H) | C-1’，C-2’ |
| 4a | 12.1q | 0.8(s，3H) | C-1，C-4，C-5，C-6 |
| 6a | 14.7q | 1.21(d，6.3，3H) | C-5，C-6，C-7 |
| 14a | 15.8q | 1.75(s，3H) | C-13，C-14，C-15 |
| 1” | 84.4d | 5.74(dd，9.4，13.4) | C-1，C-2’ |
| 2” | 71.7d | 3.13(t，9.3) | C-1”，C-5” |
| 3” | 78.6d | 3.48(m) | C-2” |
| 4” | 73.0d | 4.25(t，9.4) | C-3”，C-3”，C-5” |
| 5” | 77.0d | 6.90(br d，16.0) | C-1’，C-3’ |
| 6” | 62.9t | 3.64(m)，3.45(m) | C-4” |
Table 2. ansamitocin glycosides P-2 is to the restraining effect of indicator
Table 2.Inhibitory activities of compound ansamitocinoside P-2 against tested
microorganisms at 100g/disc
| Bacterial strain | P.avellaneum UC-4376 | Staphylococcus aureus | Mycobacterium tuberculosis |
| Active | 100g/disc(MIA) | - | - |
Conclusion: from the active result of table 2 as can be seen, this compound has certain growth-inhibiting effect to orange mould (P.avellaneum UC-4376).But under the concentration of 100g/disc, compound ansamitocin glycosides P-2 does not show the inhibition activity to other bacteria tested.
3.2 anti-tumor biological in-vitro screening experiment
Screening method: tetrazolium (methyl-thiazol-tetozolium, MTT) reduction method *
Sulfonyl rhodamine B (sulforhodamine B, SRB) protein staining method
Cell strain: P388 mouse leukemia * and A-549 human lung adenocarcinoma
Action time: 48*-72 hour
Result evaluation: invalid: 10
-5Mol/L＜85%
The weak effect: 10
-5Mol/L 〉=85% or 10
-6Mol/L＞50%
Potent: 10
-6Mol/L＞85% or 10
-7Mol/L＞50%
Table 3, ansamitocin glycosides P-2 are to the inhibiting rate of mouse leukemia cell P388 and human lung adenocarcinoma cell A-549.Table 3.The inhibitory rate of ansamitocinosideP-2 against tumor cells
| Concentration (M) | 10 -1 | 10 -5 | 10 -6 | 10 -7 | 10 -8 | IC 50 (M) | 95% fiducial limit | Estimate |
| Cell strain inhibiting rate cell strain inhibiting rate | 100 90.6 | 99.9 83.7 | 93.3 72.0 | 41.5 0 | P388 15.7 A-549 0 | 0.07 6.47 | 0.03-0.15 0.56-75.29 | Potent weak the effect |
Conclusion: as can be seen from Table 3, ansamitocin glycosides P-2 is 10 in concentration
-6During M, mouse leukemia cell P388 there is potent restraining effect, human lung adenocarcinoma cell A-549 is had weak restraining effect of imitating, so this compound is to the selectable restraining effect of tumour cell, so reactive site can be used as the chemical inhibitor of relevant cancer cells.
Embodiment 2:
Tablet: ansamitocin glycosides P-2 1mg
Lactose 180mg
W-Gum 50mg
Magnesium Stearate 3mg
Embodiment 3:
Capsule: ansamitocin glycosides P-2 1mg
Lactose 190mg
Magnesium Stearate 2mg
The preparation method: P-2 mixes with auxiliary agent with the ansamitocin glycosides, sieves, and uniform mixing in suitable containers, the mixture that the obtains hard gelatin capsule of packing into, the heavy 200mg of each capsule, ansamitocin glycosides P-2 content is 1mg.
Embodiment 4:
Ampulla: ansamitocin glycosides P-2 1mg
Sodium-chlor 9mg
The preparation method: ansamitocin glycosides P-2 and sodium-chlor are dissolved in the proper amount of water for injection, and filtration gained solution is packed under aseptic condition in the ampoule.
Claims (7)
1, the ansamitocin glycosides compound shown in the formula (1).
R＝H
R＝COCH
3
R＝COCH
2CH
3
R＝COCH(CH
3)
2
R＝COCH
2CH(CH
3)
2
2, the preparation method of claim 1 ansamitocin glycosides compound is characterized in that comprising that using the three-phase solvent systems is that ethyl acetate/methanol/glacial acetic acid extracts orange synnema actinomycetes solid fermentation product and the separation and purification of the sweet compounds of ansamitocin obtains formula (1) compound.
3, preparation method according to claim 2, it is characterized in that orange synnema actinomycetes being carried out solid fermentation with the YMG substratum, YMG consists of glucose 4 grams, malt extract 10 grams, yeast extract 4 grams, agar 15 grams, 1000 milliliters of distilled water, culture is cut into small pieces, and with the lixiviate in 80: 15: 5 of ethyl acetate/methanol/glacial acetic acid, lixiviate repeatedly repeatedly, united extraction liquid, concentrating under reduced pressure boils off organic phase, and residue water chloroform extraction is behind chloroform and the water separatory, the difference evaporate to dryness, then extract is separated respectively with water, use positive repeatedly, anti-phase, macroporous resin, the dextrane gel column chromatography, anti-mycotic activity is followed the trail of, thin-layer chromatography is with liquid chromatography-GC-MS detection elutriant that component is identical merges respectively must formula (I) compound.
4, be used for prevention and treatment lung cancer and leukemic pharmaceutical composition, wherein contain claim 1 compound for the treatment of significant quantity and acceptable carrier pharmaceutically.
5, the application of the compound of claim 1 on preparation prevention and treatment lung cancer drugs.
6, the compound of claim 1 is in preparation prevention with treat application on the leukemic medicine.
7, the application of the compound of claim 1 on the medicine of preparation treatment pathogenic bacterial infection disease.
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| CN101319241B (en) * | 2008-07-17 | 2011-03-30 | 上海交通大学 | Solid fermentation method of ansamitocin |
| CN101928291B (en) * | 2009-12-30 | 2012-05-30 | 四川大学 | Method for separating and purifying ansamitocin from precious orange synnema actinomycetes fermentation liquor |
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