CN102775427B - Antibiotic Tetrathiazomycin A and preparation method thereof and application in preparing antineoplastic drugs - Google Patents

Antibiotic Tetrathiazomycin A and preparation method thereof and application in preparing antineoplastic drugs Download PDF

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CN102775427B
CN102775427B CN201210230665.2A CN201210230665A CN102775427B CN 102775427 B CN102775427 B CN 102775427B CN 201210230665 A CN201210230665 A CN 201210230665A CN 102775427 B CN102775427 B CN 102775427B
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tetrathiazomycin
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鞠建华
周潇
黄洪波
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South China Sea Institute of Oceanology of CAS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract

The present invention provides antibiotic Tetrathiazomycin A and preparation method thereof and application in preparation of anti-tumor drugs. Its structural formula of TetrathiazomycinA is as shown in the formula (I). The present invention isolated new compound Tetrathiazomycin A with anti-tumor activity from the fermentation culture medium of actinomyces Marinactinospora thermotoleransSCSIO00652, new approach is opened for the preparation of compound Tetrathiazomycin A, and the compound of the present invention Tetrathiazomycin A has preferable anti-tumor activity, lead compound can be provided for the exploitation of anti-tumor drug using preparing in anti-tumor drug.
Figure DDA00001851316500011

Description

Microbiotic Tetrathiazomycin A and preparation method thereof and the application in preparing antitumor drug
Technical field:
The invention belongs to industrial microorganism field, be specifically related to new microbiotic TetrathiazomycinA and preparation method thereof and the application in preparing antitumor drug.
Background technology:
Malignant tumour is one of principal disease of current serious harm human life and quality of life, has now become China resident's underlying cause of death, accounts for the cause of death more than 20%.Since the second half in 20th century, world's malignant tumour and death are all in rising trend, and especially after the seventies, malignant tumour is with average annual 3% ~ 5% speed increase.World Health Organization's prediction, to the year two thousand twenty, will have 2,000 ten thousand de novo malignancy cases, and wherein death toll reaches 1,200 ten thousand, and the overwhelming majority will occur in developing country.In three large therapies of malignant tumour, pharmacological agent takies consequence.In synthetic chemistry class medicine, majority all be take natural antitumor activeconstituents as lead compound.It is reported, within 1984, to nineteen ninety-five, natural product accounts for listing the more than 60% of antitumor drug, 1995-1999,3 natural product derivatives are as new antitumor drug listing, and as can be seen here, natural product is the important sources of the unique antitumor drug of novel structure and effect.The polypeptide compounds of finding at present has biologic activity widely, it is reported, the cyclic peptide that contains thiazole ring and oxazole ring has very strong cytotoxic activity, for example the IC of Urukthapelstatin A to Human Lung Cancer cell 50value is surprising has reached 12nM.
Summary of the invention:
First object of the present invention is to provide new lactam compound Tetrathiazomycin A or its salt containing four thiazoles with anti-tumor activity.
Lactam compound Tetrathiazomycin A or its salt that contains four thiazoles of the present invention, its structure is as shown in formula I:
Second object of the present invention is to provide the preparation method of compound Tetrathiazomycin A, it is characterized in that, described compound Tetrathiazomycin A is that preparation separation obtains from the fermenting culture of actinomycetes Marinactinospora thermotolerans SCSIO00652.
Preferably from the fermenting culture of actinomycetes Marinactinospora thermotolerans SCSIO00652, preparing separation by the following method obtains Tetrathiazomycin A, and concrete steps are as follows:
A) prepare the fermenting culture of actinomycetes Marinactinospora thermotolerans SCSIO00652, the fermented liquid of this fermenting culture and mycelium are separated, fermented liquid is extracted with ethyl acetate, and ethyl acetate obtains extractum A mutually after concentrated;
B) extractum A is through purification on normal-phase silica gel column chromatography, using chloroform/methanol as eluent, from volume ratio 100:0 ~ 1:1, carry out gradient elution, collect the cut Fr.5-8 that chloroform/methanol volume ratio 92:8 ~ 1:1 gradient elution gets off, again through silica gel column chromatography, by ethyl acetate/methanol as eluent, from volume ratio 94:6 ~ 8:2, carry out gradient elution, collected volume is than the component Fr.5-8-1 of 9:1 ~ 8:2 wash-out, again through the anti-phase medium pressure liquid chromatography of ODS, methanol/water gradient elution with volume fraction from 10% ~ 100%, the cut that the methanol/water gradient elution of collected volume mark 80 ~ 90% gets off, finally by obtaining Tetrathiazomycin A after high-efficient liquid phase chromatogram purification.
The fermenting culture of the preparation Marinactinospora thermotolerans SCSIO00652 of described a) step is prepared by the following method: by the Marinactinospora thermotolerans SCSIO00652 access seed culture medium of activation, 28 ° of C, 200rpm, cultivate 4d and make seed liquor, seed liquor is received in fermention medium by 10% inoculum size, 28 ° of C, 200rpm, shaking culture 7d, and make fermenting culture, described seed culture medium and the formula of fermention medium are all to contain in every liter of substratum: starch 10g, (NH 4) 2sO 42g, K 2hPO 41g, MgSO 47H 2o1g, NaCl1g, peptone 1g, yeast extract powder 05g, trace element solution0.1mL, thick sea salt 30g, surplus is water, pH7.4.
The 3rd object of the present invention is to provide the application of Marinactinospora thermotolerans SCSIO00652 in preparing compound Tetrathiazomycin A.
The present invention found through experiments, Tetrathiazomycin A of the present invention is to neuroglial cytoma strain (SF-268), breast carcinoma cell strain (MCF-7), National People's Congress's sclc cell line (NCI-H460) and human liver cancer cell (HepG-2) have good cytotoxic activity, its IC 50be respectively 38 * 10 -2μ M, 43 * 10 -2μ M, 47 * 10 -2μ M and 52 * 10 -2μ M, can be applicable to prepare antitumor drug.
Therefore, the 4th object of the present invention is to provide the application of TetrathiazomycinA in preparing antitumor drug.
Described antitumor drug is preferably anti-glioma medicine, anti-breast cancer medicines, anti-lung-cancer medicament or medicines resistant to liver cancer.
The present invention's separation from the fermenting culture of actinomyces Marinactinospora thermotolerans SCSIO00652 obtains the new compound TetrathiazomycinA with anti-tumor activity, for new approach has been opened up in the preparation of compound TetrathiazomycinA, and compound Tetrathiazomycin A of the present invention has good anti-tumor activity, can application prepare in antitumor drug, for the exploitation of antitumor drug provides lead compound.
Actinomyces Marinactinospora thermotolerans SCSIO00652 of the present invention is known bacterial classification, is disclosed in non-patent literature: the foundation of deep-sea actinomycetes Marinactinospora thermotolerans SCSIO00652 genetic operating system. Li Jun, Zhu Qinghua, Zhang Yun, Ma Junying, Tian Xinpeng, Li Wenjun, Zhang Changsheng, bring up Jian Hua. and Chinese microbiotic magazine .2012(2) 105 ~ 111.The applicant guaranteed in 20 years, to the public, to provide this Marinactinospora thermotolerans SCSIO00652 bacterial strain from the applying date.
Accompanying drawing explanation:
Fig. 1 is the electron-microscope scanning figure of Marinactinospora thermotolerans.SCSIO00652, and wherein Figure 1A and Figure 1B are the electron-microscope scanning figure under different multiples;
Fig. 2 is the X-single crystal diffraction figure of TetrathiazomycinA.
Embodiment:
Following examples are to further illustrate of the present invention, rather than limitation of the present invention.
Embodiment 1:
Separated and the preparation of Tetrathiazomycin A
1, substratum
A, seed culture medium: in every liter of substratum, contain: starch 10g, (NH 4) 2sO 42g, K 2hPO 41g, MgSO 47H 2o1g, NaCl1g, peptone 1g, yeast extract powder 0.5g, trace element solution0.1mL, thick sea salt 30g, surplus is water, pH7.4.121 ℃, sterilizing 30min;
B, fermention medium: the same seed culture medium of filling a prescription.121 ℃, sterilizing 30min.
2, fermentation
By its electron-microscope scanning of actinomyces Marinactinospora thermotolerans.SCSIO00652(figure of activation as shown in Figure 1) in access 6L seed culture medium, 28 ° of C, 200rpm, cultivate 4d and make seed liquor, the seed liquor of 6L is linked in 60L fermention medium to 28 ° of C, 200rpm, shaking culture 7d, and make fermenting culture.
3, extraction
Fermenting culture first carries out centrifugation (4000r.min -1, 10min), fermented liquid and mycelium to be separated, fermented liquid extracts through isopyknic ethyl acetate, and ethyl acetate layer obtains extractum A (20.1g) after distillation and concentration.
4, extraction separation and evaluation compound Tetrathiazomycin A(1)
Extractum A is through purification on normal-phase silica gel column chromatography (silica gel 100 ~ 200 orders); using chloroform/methanol as eluent; from volume ratio 100:0 ~ 1:1, carry out gradient elution; collect the cut Fr.5-8 that chloroform/methanol volume ratio 92:8 ~ 1:1 gradient elution gets off, then through silica gel column chromatography, use ethyl acetate/methanol as eluent; from volume ratio 94:6 ~ 8:2, carry out gradient elution; collected volume is than the component Fr.5-8-1 of 9:1 ~ 8:2 wash-out, then through the anti-phase medium pressure liquid chromatography of ODS (S-50 μ m, 12nm; 100 * 20mm, YMC), flow velocity is 15ml/min; methanol/water gradient elution 60min with volume fraction from 10% ~ 100%, the cut that the methanol/water gradient elution of collected volume mark 80 ~ 90% gets off, finally by high performance liquid chromatography (ODS-A; 250 * 10mm, 5 μ m; YMC), flow velocity is 2.5ml/min, and the acetonitrile/water gradient elution 30min with volume fraction from 70% ~ 100%, is that 22min obtains compound 1(TetrathiazomycinA in retention time) (16mg).
By structural analysis, to the compound 1(TetrathiazomycinA preparing from the fermenting culture of Marinactinospora thermotolerans.SCSIO00652 of the present invention) to identify, its qualification result is as follows:
White solid, its nuclear magnetic data ownership is as shown in table 1, 1hNMR (500MHz, CD 3oD) and 13c NMR (125MHz, CD 3oD), in Table 1.Fusing point: 115 ~ 116 ℃.HR-ESI-MS m/z666.1382 ([M+H] +, theoretical value 666.1444). its X-single crystal diffraction figure is as shown in Figure 2.
Table 1: nuclear magnetic data compound 1(TetrathiazomycinA) ( 1h-NMR data are measured in 500MHz, are coupling constant (Hz) in bracket, 13c-NMR data are measured in 125MHz, and solvent is deuterated methanol)
Figure BDA00001851316300052
Figure BDA00001851316300061
In sum, the structural formula of authenticating compound 1 as shown in formula I, called after TetrathiazomycinA,
Figure BDA00001851316300071
The antitumor cytolytic activity of embodiment 2:Tetrathiazomycin A
Test Tetrathiazomycin A to neuroglial cytoma strain SF-268, breast cancer cell line mcf-7, inhibiting rate and the IC of the sclc cell line NCI-H460 of the National People's Congress and human liver cancer cell HepG-2 50pH-value determination pH.
Adopt international tumor cell line, that is: neuroglial cytoma strain (SF-268), breast carcinoma cell strain (MCF-7), National People's Congress's sclc cell line (NCI-H460) and human liver cancer cell (HepG-2).Test method is international srb assay: according to Growth of Cells speed, tumour cell in logarithmic phase is inoculated in to 96 orifice plates with 180 μ L/ holes, adherent growth dosing again in 24 hours (the RPMI-1640 solution of the compound 1 of different concns) 20 μ L/ holes.Each concentration is established 3 multiple holes.And establish the contrast of corresponding RPMI-1640 solvent and acellular withered hole.Tumour cell is at 37 ℃, 5% CO 2under condition, cultivate 72 hours, the nutrient solution that inclines, every hole adds the 50% cold TCA solid cell of 50 μ L, then adopts 0.4% SRB to dye 30 minutes, the acetic acid washing with 1% 5 times, dry air.The Tris solution that finally adds 200 μ L/ holes, microplate reader 570nm wavelength is measured OD value.Using cis-platinum as positive control.Experimental result is in Table 2:
Restraining effect (the IC of table 2:TetrathiazomycinA to tumor cell line 50, μ M)
Figure BDA00001851316300081
a?Positive?conrol。

Claims (5)

1. lactam compound Tetrathiazomycin A or its salt containing four thiazoles, its structural formula is as shown in (I):
Figure FDA0000407038760000011
2. the preparation method of a compound Tetrathiazomycin A claimed in claim 1, it is characterized in that, described compound Tetrathiazomycin A is that preparation separation obtains from the fermenting culture of actinomycetes Marinactinospora thermotolerans SCSIO00652, and concrete steps are as follows:
A) prepare the fermenting culture of actinomycetes Marinactinospora thermotolerans SCSIO00652, the fermented liquid of this fermenting culture and mycelium are separated, fermented liquid is extracted with ethyl acetate, and ethyl acetate obtains extractum A mutually after concentrated;
B) extractum A is through purification on normal-phase silica gel column chromatography, using chloroform/methanol as eluent, from volume ratio 100:0～1:1, carry out gradient elution, collect the cut Fr.5-8 that chloroform/methanol volume ratio 92:8～1:1 gradient elution gets off, again through silica gel column chromatography, by ethyl acetate/methanol as eluent, from volume ratio 94:6～8:2, carry out gradient elution, collected volume is than the component Fr.5-8-1 of 9:1～8:2 wash-out, again through the anti-phase medium pressure liquid chromatography of ODS, methanol/water gradient elution with volume fraction from 10%～100%, the cut that the methanol/water gradient elution of collected volume mark 80～90% gets off, finally by obtaining Tetrathiazomycin A after high-efficient liquid phase chromatogram purification.
3. preparation method as claimed in claim 2, is characterized in that, the fermenting culture of the actinomycetes Marinactinospora thermotolerans SCSIO00652 of described a) step is prepared by following method:
By in the Marinactinospora thermotolerans SCSIO00652 access seed culture medium of activation, 28 ℃, 200rpm, cultivates 4d and makes seed liquor, and seed liquor is received in fermention medium by 10% inoculum size, 28 ℃, 200rpm, shaking culture 7d, and make fermenting culture, described seed culture medium and the formula of fermention medium are all in every liter of substratum, to contain starch 10g, (NH 4) 2sO 42g, K 2hPO 41g, MgSO 47H 2o1g, NaCl1g, peptone 1g, yeast extract powder 0.5g, trace element solution0.1mL, thick sea salt 30g, surplus is water, pH7.4.
4. compound Tetrathiazomycin A claimed in claim 1 or the application of its salt in preparing antitumor drug, described antitumor drug is anti-glioma medicine, anti-breast cancer medicines, anti-lung-cancer medicament or medicines resistant to liver cancer.
The application of 5.Marinactinospora thermotolerans SCSIO00652 in preparation compound Tetrat hiazomycin A claimed in claim 1.
CN201210230665.2A 2012-07-04 2012-07-04 Antibiotic Tetrathiazomycin A and preparation method thereof and application in preparing antineoplastic drugs Expired - Fee Related CN102775427B (en)

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