CN1296347C - Compound of antitumor antibiotic of new carbon framework as well as preparation method and application - Google Patents
Compound of antitumor antibiotic of new carbon framework as well as preparation method and application Download PDFInfo
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- CN1296347C CN1296347C CNB2003101052927A CN200310105292A CN1296347C CN 1296347 C CN1296347 C CN 1296347C CN B2003101052927 A CNB2003101052927 A CN B2003101052927A CN 200310105292 A CN200310105292 A CN 200310105292A CN 1296347 C CN1296347 C CN 1296347C
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Abstract
The present invention belongs to the technical field of medicine, which specifically discloses a new carbon skeleton antitumor antibiotic compound, a preparation method thereof and an application thereof. The compound is prepared from marine streptomycete Streptomyces sp. by fermentation, accumulation of crude extract, separation by silica gel chromatograph and a plurality of other chromatograph methods, and is called chinikomycin A and chinikomycin B. The extrasomatic antineoplasmic activity experiment proves: the compound in the present invention has inhibiting effects on many human body tumor cells which comprise the lung cancer cell systems LXFA 629L and LXFL 529L, the breast cancer cell system MAXF 401NL, the melanoma cell system MEXF 462NL, the renal tumor cell system RXF 944L, the uterus carcinoma cell system UXF 1138L, etc. The present invention provides a mode for reference to develop the abundant marine micro biological resources of China.
Description
Technical field
The invention belongs to medical technical field, specifically a kind of new carbon skeleton antitumor antibiotics compound and its production and application.
Background technology
Since nineteen thirties, penicillin was found, microorganism became the important source of active lead compound.But in recent years, the probability that is separated to the new texture active compound from soil microorganisms descends significantly, for example at present just can screen the bacterial strain that a strain can produce the new texture active compound usually from the soil microorganisms of strain more than 20,000.For another example, in all known microbial secondary meta-bolitess, the overwhelming majority is from the actinomycetes Actinomycetes in the soil, particularly streptomyces Streptomyces wherein; Yet present present Research is: 90% have in the bioactive streptomycete, people are difficult to find new compound, especially new framework compound, and this possibility is also at straight line decline (document 1:Fencial, W., Chemical Studies of Marine Bacteria:Developinga New Resource, Chem.Rev., 1993,93:1673-1683).
After resistant organism extensively occurs, especially in recent years because environmental degradation and movement of population cause resistance to produce the problem that the cycle shortens day by day, the kind that in addition tolerates medicine is increasing, makes whenever more urgent people are than in the past to the demand of new antibiotic.Along with improving constantly of malignant tumour sickness rate, also urgent day by day to the antibiotic demand of new antitumoral.The twentieth century people turn to sight and are containing the ocean of enriching Microbial resources, the singularity of the marine eco-environment and diversity, determined the diversity of marine microorganism kind and secondary metabolite thereof, find to have antitumor and lead compound bacteriostatic action from marine microorganism, become a solution route finding the new biological activity material.The cephamycin C of being contributed from the Italian Sardinia and the two strain marine microorganisms in Japanese mould mutually gulf and little promise (mould mutually) mycin proved absolutely the potentiality of marine microorganism aspect the active lead compound of generation respectively.Particularly developed countries such as America and Europe, Japan have strengthened the investment that the marine microorganism active substance is studied in recent years, (document 2:Marwick makes remarkable progress, J.D., et al., Bioprocess Intensification for Production of Novel Marine Bacterial AntibioticsThrough Bioreactor Operation and Design, Marine Biotechnology, 1999,1 (5): 495-507; Document 3:Jensen, P.R., et al., Strategies for the Discovery of SecondaryMetabolites from Marine Bacteria:Ecological Perspectives, Annu.Rev.Microbiol, 1994,48:559-584).
It is similar to produce microbiotic with the land actinomycetes, and the marine actinomycete in the marine microorganism also is the important source of new antibiotic.The alkaloid altemicidin of novel structure, sulfur-bearing and the nitrogen that is separated to from marine streptomyces Streptomyces sioyaensisSA-1758 has the monoterpene skeleton, shows strong external anti-L1210 lymphoma and IMC tumor cell viability, IC
50Be respectively 0.84 and 0.82 μ g/ml, but it is to the also toxic (LD of mouse
50=0.3 μ g/ml).(document 4:Takahashi, A., et al., Altemicidin, a new acaricidal and antitumor substance I, Taxonomy, fermentation, isolationand physico-chemical and biological properties, J.Antibiot., 1989,42 (11): 1556-1561; Document 5:Takahashi, A., et al., Altemicidin, a new acaricidal andantitumor substance II, Structure determination, J.Antibiot., 1989,42 (11): 1562-1566).Separation is from the streptomycete PG-19 of coral Pacifigotgio sp. body surface, therefrom obtain two octatomic ring lactone octalactins A and B, octalactins A has remarkable cytotoxicity (IC external to B16-F10 melanoma cell and human colon carcinoma HCT-116 cell
50Be respectively 7.2 * 10
-3μ g/ml, 0.5 μ/ml), and octalactins B no cytotoxicity, this explanation epoxy construction is essential active group.(document 6:Fenical, W., and Jensen, P.R., In Marine Biotechnology, Volume1:Pharmaceutical and Bioactive Natural Products; Attaway, D.H., Zaborsky, O.R., Eds.; Plenum Press:New York, 1993; Pp 419-457).
(document 7:Zeeck such as Zeeck, A., et al., The Structure of Manumycin, I.Characterization, Structure Elucidation and Biological Activity, J.Antibiot.1987,11:1530-1540) separation obtains microbiotic manumycin (C from a streptomycete Streptomyces.parvulus
31H
38N
2O
7), it has very strong restraining effect to gram positive bacterium and fungi.The novel carbon skeleton structure of compound c hinikomycin involved in the present invention still finds no patent or bibliographical information up to now.
Summary of the invention
The object of the invention is to provide a kind of new carbon skeleton antitumor antibiotics compound and its production and application.
To achieve these goals, technical scheme of the present invention is as follows:
New carbon skeleton antitumor antibiotics compound has following chemical structure:
Or
In the formula, R
1, R
2, R
3, R
4, R
5, R
6Be hydrogen, hydroxyl, alkyl, aryl, aryl, halo alkyl, acyl group, alkoxyl group, aldehyde radical, halogen, amino, hydrocarbon amino, amide group, sulphur, sulfydryl, sulfonic group or carboxylic acid group; Wherein chemical structure can for:
Called after chinikomycin A; Or
Called after chinikomycin B.
Its preparation method is as follows:
(1) solid culture: marine streptomyces Streptomyces sp. is inoculated in M
2+Solid medium was cultivated 3～4 days for 25～40 ℃, until the spore that grows white;
(2) shaking table is cultivated: inoculate described white fibrillae of spores to the fish meal liquid nutrient medium, carry out shaking table under 25～40 ℃ of temperature and cultivate, rotating speed is 90～130rpm, cultivates after 3～4 days the results fermented liquid;
(3) extraction: fermented liquid concentrates evaporate to dryness with organic solvent lixiviate 3～4 times, obtains the paste crude extract;
(4) purifying: crude extract hexanaphthene lixiviate, the dissolving part is an extract I, does not dissolve part and is extract II; Carry out following operation then respectively:
1) extract I with hexanaphthene and ethyl acetate gradient elution, obtains containing the component of compound c hinikomycin A through silica gel column chromatography, washes 2～3 times with hexanaphthene again, obtains Yellow reactive compound c hinikomycin A;
2) extract II is through silica gel column chromatography, methylene dichloride and methyl alcohol gradient elution, obtain containing the component of active compound, use hexanaphthene and washed with dichloromethane 2～3 times again, obtain yellow powder shape insoluble substance, process preparation type thin-layer chromatography (Preparative Thin Layer Chromatography, PTLC), in R
f=0.58 place obtains red compound chinikomycin B, and reclaims R
f=0.34 yellow compound chinikomycin A of place;
Wherein: the present invention adopts the middle products therefrom chinikomycin A of purification step (4) can be oxidized to product chinikomycin B, being about to product chinikomycin A dissolves with methylene dichloride, slowly add silver suboxide, stir, reaction becomes redness until solution colour fully by yellow, after the solvent evaporated, dissolve with methylene dichloride again, discard the precipitation insolubles, the dissolving part reclaims R through preparation type thin-layer chromatography (PTLC)
fThe red compound at=0.58 place is chinikomycin B;
In addition, adopting the middle products therefrom chinikomycin B of purification step (4) reducible is chinikomycin A, that is: product chinikomycin B is dissolved with methylene dichloride, slowly add the SODIUM HYDROSULPHITE sodium solution again, vibrate to solution colour and become yellow by redness, (ThinLayer Chromatography TLC) analyzes R to utilize thin-layer chromatography
f=0.34 place's reaction product is yellow compound chinikomycin A;
Lixiviate fermented liquid of the present invention can be ethyl acetate or methyl alcohol with organic solvent; Per-cent meter by volume, methylene dichloride/hexanaphthene washing usage ratio is 15/85～40/60; Use methylene chloride, the cyclohexane/ethyl acetate gradient elution, type of elution by volume per-cent counts 100/0～0/100; Methylene dichloride and the methyl alcohol wash-out under 100/0～90/10 gradient is good, and hexanaphthene and the ethyl acetate wash-out under 50/50～0/100 gradient is good; The used developping agent of described preparation type thin-layer chromatography (PTLC) is a methylene chloride, and the volumetric usage ratio is 95/5～90/10.
The new carbon skeleton antitumor antibiotics of the present invention compound can be applicable to prepare antitumor, antibiotic, antiviral.
The present invention has following advantage:
1. the carbon skeleton of compound c hinikomycin involved in the present invention is a novel structure, up to now, still finds no patent or bibliographical information.
2. the present invention makes full use of the abundant marine microorganism resource that China does not further investigate exploitation as yet, search out a kind of compound of chemical structure novelty, it has antitumor, antibiotic, antiviral activity, to comprising lung cancer cell line LXFA 629L and LXFL 529L, breast cancer cell line MAXF 401NL, K-1735 MEXF 462NL, kidney tumor cell are that human body tumour cells such as RXF 944L and uterus carcinoma clone UXF 1138L have restraining effect; Clinical newtype drug or the lead compound of providing is provided.
Description of drawings
Fig. 1 is the new carbon skeleton antitumor antibiotics of the present invention chinikomycin A, the HMBC (→) of the hydrocarbon amide side chains (Ia) of B and NOESY () effect.
Fig. 2 is the new carbon skeleton antitumor antibiotics of the present invention chinikomycin A (Ib), the HMBC (→) and the H of B (Ic) carbon skeleton structure, H COSY () effect.
Fig. 3 is the new carbon skeleton antitumor antibiotics of the present invention chinikomycin A, the preparation flow figure of B.
Embodiment
Below in conjunction with specific embodiment in detail the present invention is described in detail.
Embodiment 1
Prepare new carbon skeleton antitumor antibiotics chinikomycin A and B (preparation flow figure is referring to Fig. 3):
(1) sample collecting: gather the ooze sample from the coastal waters, Qingdao, in the laboratory, utilize Gause I substratum (Zulkovsky starch 20g, saltpetre 1g, potassium primary phosphate 0.5g, sal epsom 0.5g, sodium-chlor 0.5g, ferrous sulfate 0.01g, potassium bichromate 0.1g, agar powder 18g, natural sea-water 500ml, tap water 500ml, adjusting pH is 7.2) to carry out gradient dilution streak culture, and purifying obtains a strain marine streptomyces Streptomyces sp.;
(2) solid culture: described marine streptomyces Streptomyces sp. is inoculated in M
2+Solid medium (Fructus Hordei Vulgaris extract 10g, yeast powder 4g, glucose 4g, natural sea-water 500ml, tap water 500ml, agar powder 14g, adjusting pH is 7.4), cultivated 3 days for 28 ℃, until the spore that grows white;
(3) shaking table is cultivated: from described M
2+Picking white fibrillae of spores is inoculated in the Erlenmeyer triangular flask of 60 1000ml on the solid medium, contains sterilized 250ml fish meal liquid nutrient medium (fish meal 5g, wheat-flour 10g in each triangular flask, yeast powder 1g, glucose 21g, sal epsom 0.5g, sodium-chlor 1g, calcium chloride 0.5g, trace element solution 10ml, natural sea-water 500ml, tap water 500ml, adjusting pH is 6.4), 35 ℃ of following Clothoid type shaking tables are cultivated, rotating speed is 120rpm, after 4 days, and the results fermented liquid;
Wherein: the trace element solution composition: ferrous sulfate 10.2g, cobalt chloride 0.04g, calcium chloride 0.04g, Manganous chloride tetrahydrate 0.04g, zinc sulfate 0.08g, Sodium Tetraborate 0.08g, Sodium orthomolybdate 0.74g is dissolved in 500ml distilled water;
(4) organic solvent extraction: fermented liquid separates bacterium liquid and bacterium mud by plate filter, uses the ethyl acetate lixiviate respectively 4 times, merges organic solvent phase, and the Rotary Evaporators rotation concentrates evaporate to dryness, obtains paste crude extract 14g;
(5) separation and purification: with 250ml hexanaphthene lixiviate crude extract, the dissolving part is an extract I, does not dissolve part and is extract II; Do following operation then respectively:
1) extract I is through silica gel column chromatography, with hexanaphthene and ethyl acetate gradient (100/0～0/100) wash-out, under hexanaphthene and ethyl acetate (50/50～0/100) gradient, obtain containing the component of compound c hinikomycinA, with 50ml hexanaphthene washed twice, obtain product chinikomycin A (100mg);
2) extract II is through silica gel column chromatography, methylene dichloride and methyl alcohol gradient (100/0～0/100) wash-out, 100% methylene dichloride wash-out obtains component a (80mg), obtain components b (325mg) under methylene dichloride and methyl alcohol (99.5/0.5～98/2) gradient, obtain amount of component b (414mg) under methylene dichloride and methyl alcohol (95/5～90/10) gradient, get the described components b hexanaphthene 25ml washed twice that contains 25% methylene dichloride, obtain yellow powder shape insoluble substance, through preparation type thin-layer chromatography (PTLC, chromatoplate is 20 * 20cm, developping agent is 95% methylene dichloride and 5% methyl alcohol), in R
f=0.34 place obtains product chinikomycin A (50mg), in R
f=0.58 place obtains red compound chinikomycinB (3.5mg);
Chinikomycin A chemical structure is as follows:
The chemical structure of chinikomycin B is as follows:
The physical constant of described chinikomycin A and B, proton nmr spectra data, carbon-13 nmr spectra data are respectively referring to table 1～3.
The physical constant of described chinikomycin A of table 1 and chinikomycin B
| chinikomycin A | chinikomycin B | |
| Properties R f(CH 2Cl 2/5％ MeOH) Molecular formula EI HRMS (+)-ES-MS (-)-ES-MS IR(KBr)νcm -1 UV/VIS(MeOH)： λ max(lgε) | Tawny powder solid 0.34 C 31H 37ClN 2O 6 568.2326(calc.568.197629) 615([M+2Na-H] +1，5)，613 ([M+2Na-H] +1，25)，615([M+Na] +1， 32)，613([M+Na] +1，100) 569([M-H] -1，52)，567([M-H] -1，100) 3425，2965，2924，2851，1657，1620， 1538，1501，1383，1319，1228，1173， 1084，1008，873，662，546 260(4.46)，335(s，4.46)，395(4.62) | Red solid 0.58 C 31H 35ClN 2O 6566.2290(calc.566.181979) 611([M+2Na-H] +1) 568([M-H] -1，29)，566([M-H] -1，100) 3425，2963，2923，2857，1655，1620， 1502，1457，1382，1318，1297，1233， 1173，1121，1083，1035，1008，874，851， 653，546 261(4.68)，344(4.72)，500(3.98) |
The proton nmr spectra data of described chinikomycin A of table 2 and chinikomycin B
(δvalues，J＝[Hz])
| H No. | A a | B b |
| 3-H 7-H 8-H 9-H 10-H 11-H 12-H CONH Ar-NH 1-OH 4-OH 4′-H 2 5′-H 2 3′-OH 3″-H 5″-H 6″-H 7″-H 2 8″-H 2 9″-H 2 10″-H 3 2″-Me 4″-Me 6″-Me | 7.47(s) 6.97(d，15.5) 7.45(dd，15.5，11.1) 6.86(dd，15.1，11.1) 6.49(dd，14.6，11.2) 7.26(dd，15.1，11.2) 6.51(d，14.6) 9.86(s) 9.12(s) 9.06(s) 10.04(s) 2.53(m) 2.53(m) 13.90(s，br) 6.82(s) 5.36(d，9.5) 2.51(m) 1.4～1.2(m) 1.4～1.2(m) 1.4～1.2(m) 0.88(t，6.8) 2.03(s) 1.82(s) 0.96(d，6.8) | 7.60(s) 6.83(d，15.6) 7.80(dd，15.6，10.0) 6.73(dd，14.8，10.1) 6.68(dd，14.8，10.3) 7.37(dd，14.8，10.3) 6.28(d，14.8) 8.13(s) 8.60(s) 2.56(s，br) 2.62(s，br) 13.64(s，br) 6.86(s) 5.40(d，9.7) 2.45(m) 1.4～1.2(m) 1.4～1.2(m) 1.4～1.2(m) 0.86(t，7.0) 2.08(s) 1.83(s) 0.97(d，6.5) |
aDMSO-d
6，
bCDCl
3
The carbon-13 nmr spectra data of described chinikomycin A of table 3 and chinikomycin B
(δvalues)
| C No. | A a | B b | C No. | A a | B b |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 1′ 2′ 3′ | 136.8 128.6 107.6 150.3 117.0 122.2 130.4 132.8 143.0 129.8 142.6 121.0 166.1 no 114.9 no | 176.3 137.7 114.7 185.2 138.4 135.0 127.3 144.3 141.5 136.3 142.8 123.7 165.2 197.5 115.1 174.6 | 4′ 5′ 1″ 2″ 3″ 4″ 5″ 6″ 7″ 8″ 9″ 10″ 2″-Me 5″-Me 6″-Me | no no 168.3 128.5 138.7 130.0 141.6 32.1 36.4 29.2 22.2 13.9 14.1 16.3 20.6 | 32.1 25.6 168.3 127.6 141.8 129.9 144.2 32.9 37.0 29.7 22.8 14.0 14.1 16.4 20.6 |
no＝not observed，
aDMSO-d
6，
bCDCl
3
Embodiment 2
Be oxidized to chinikomycin B by chinikomycin A:
Get the product chinikomycin A of 20mg, join in the reaction flask, with the dissolving of 50ml methylene dichloride (present embodiment is just dissolving), slowly add about 1g silver suboxide (it is excessive with respect to the chinikomycin A in the solution), stir, reacted about 3 hours, solution colour becomes redness fully by yellow, the rotation evaporate to dryness, with the dissolving of 6ml methylene dichloride (present embodiment is fully dissolving), discard the precipitation insolubles, the dissolving part is prepared type thin-layer chromatography (PTLC), with 95% methylene dichloride/5% methyl alcohol is developping agent, reclaims R
fThe red compound 7mg at=0.58 place by proton nmr spectra, carbon-13 nmr spectra, mass spectrum, infrared spectra and ultraviolet spectral analysis, has determined the chemical structure of this compound, is chinikomycin B.
Embodiment 3
Be reduced to chinikomycin A by chinikomycin B:
In test tube, add the chinikomycin B of 0.5mg, with the dissolving of 2ml methylene dichloride, slowly add 1ml0.1N SODIUM HYDROSULPHITE sodium solution again, vibration becomes yellow until solution colour by redness, utilizes thin-layer chromatography (TLC) analysis, R
f=0.34 place's yellow compound promptly is chinikomycinA.
Compound c hinikomycin A and chinikomycin B are done the two dimensional NMR Spectrum Analysis, further verified the structure of compound c hinikomycin A and chinikomycin B, the HMBC (→) of its hydrocarbon amide side chains and NOESY () effect are referring to Fig. 1, the HMBC (→) and the H of carbon skeleton, H COSY () effect is referring to Fig. 2.
Embodiment 4
The anti-tumor activity experiment of chinikomycinA and chinikomycin B:
Anti-tumor activity experiment is measured by German BIOLEADS biotech firm, select human tumour cell line (Human Cancer Cell Lines) for use, comprise lung cancer cell line LXFA 629L and LXFL529L (lung carcinoma cell), breast cancer cell line MAXF 401NL (breast cancer cell), K-1735 MEXF 462NL (melanoma cell), kidney tumor cell are RXF 944L (renal carcinoma cell) and uterus carcinoma clone UXF 1138L (uterus cancer cell).Experimental result shows: the effective concentration IC of chinikomycin A and B
70Be respectively 5.6 μ g/ml and 5.9 μ g/ml, show anti-tumor activity.
Claims (9)
1. new carbon skeleton antitumor antibiotics compound, it is characterized in that: particular chemical is as follows:
Called after chinikomycin A, or
Called after chinikomycin B.
2. the preparation method of a new carbon skeleton antitumor antibiotics compound is characterized in that operating as follows:
(1) solid culture: marine streptomyces Streptomyces sp. is inoculated in M
2+Solid medium was cultivated 3～4 days for 25～40 ℃, until the spore that grows white;
Wherein: M
2+Solid medium: Fructus Hordei Vulgaris extract 10g, yeast powder 4g, glucose 4g, natural sea-water 500ml, tap water 500ml, agar powder 14g, adjusting pH is 7.4;
(2) shaking table is cultivated: inoculate described white fibrillae of spores to the fish meal liquid nutrient medium, carry out shaking table under 25～40 ℃ of temperature and cultivate, rotating speed is 90～130rpm, cultivates after 3～4 days the results fermented liquid;
(3) extraction: fermented liquid concentrates evaporate to dryness with organic solvent lixiviate 3～4 times, obtains the paste crude extract;
(4) purifying: crude extract hexanaphthene lixiviate, the dissolving part is an extract I, does not dissolve part and is extract II; Carry out following operation then respectively:
1) extract I with hexanaphthene and ethyl acetate gradient elution, obtains containing the component of compound c hinikomycin A through silica gel column chromatography, washes 2～3 times with hexanaphthene again, obtains Yellow reactive compound c hinikomycin A;
2) extract II is through silica gel column chromatography, and methylene dichloride and methyl alcohol gradient elution obtain containing the component of active compound, use hexanaphthene and washed with dichloromethane 2～3 times again, obtain yellow powder shape insoluble substance, through preparation type thin-layer chromatography, in R
f=0.58 place obtains red compound chinikomycin B, and reclaims R
f=0.34 yellow compound chinikomycin A of place.
3. press the preparation method of the described new carbon skeleton antitumor antibiotics compound of claim 2, it is characterized in that: products therefrom chinikomycin A can be oxidized to product chinikomycin B in the purification step (4), be about to product chinikomycin A and dissolve, slowly add silver suboxide, stir with methylene dichloride, reaction becomes redness until solution colour fully by yellow, after the solvent evaporated, with the methylene dichloride dissolving, discard the precipitation insolubles again, the dissolving part reclaims R through preparation type thin-layer chromatography
fThe red compound at=0.58 place is chinikomycin B.
4. press the preparation method of the described new carbon skeleton antitumor antibiotics compound of claim 2, it is characterized in that: wherein products therefrom chinikomycin B is reducible in the purification step (4) is chinikomycinA, that is: product chinikomycin B is dissolved with methylene dichloride, slowly add the SODIUM HYDROSULPHITE sodium solution again, vibrate to solution colour and become yellow by redness, utilize thin layer chromatography analysis, R
f=0.34 place's reaction product is compound c hinikomycin A.
5. by the preparation method of the described new carbon skeleton antitumor antibiotics compound of claim 2, it is characterized in that: described lixiviate fermented liquid organic solvent is ethyl acetate or methyl alcohol; Per-cent meter by volume, methylene dichloride/hexanaphthene washing usage ratio is 15/85～40/60.
6. by the preparation method of the described new carbon skeleton antitumor antibiotics compound of claim 2, it is characterized in that: use methylene chloride, the cyclohexane/ethyl acetate gradient elution, type of elution by volume per-cent counts 100/0～0/100.
7. press the preparation method of the described new carbon skeleton antitumor antibiotics compound of claim 2, it is characterized in that: methylene dichloride and methyl alcohol are that wash-out under 100/0～90/10 gradient is good in volume percent, and hexanaphthene and ethyl acetate are that wash-out under 50/50～0/100 gradient is good in volume percent.
8. by the preparation method of the described new carbon skeleton antitumor antibiotics compound of claim 2, it is characterized in that: the used developping agent of described preparation type thin-layer chromatography is a methylene chloride, and the volumetric usage ratio is 95/5～90/10.
9. press the described new carbon skeleton antitumor antibiotics application of compound of claim 1 for one kind, it is characterized in that: as antitumor, antibiotic, the antiviral of preparation.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1037539A (en) * | 1988-05-13 | 1989-11-29 | 中国医学科学院医药生物技术研究所 | The manufacture method of new antitumor antibiotic C-1027 |
| CN1132756A (en) * | 1994-10-19 | 1996-10-09 | 西巴-盖尔基股份公司 | Antiviral ethers of aspartate protease substrate isosteres |
| WO2002060858A1 (en) * | 2001-01-31 | 2002-08-08 | Meiji Seika Kaisha, Ltd. | Novel compound having maillard reaction inhibitory activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1037539A (en) * | 1988-05-13 | 1989-11-29 | 中国医学科学院医药生物技术研究所 | The manufacture method of new antitumor antibiotic C-1027 |
| CN1132756A (en) * | 1994-10-19 | 1996-10-09 | 西巴-盖尔基股份公司 | Antiviral ethers of aspartate protease substrate isosteres |
| WO2002060858A1 (en) * | 2001-01-31 | 2002-08-08 | Meiji Seika Kaisha, Ltd. | Novel compound having maillard reaction inhibitory activity |
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