CN102775427A - 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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CN102775427A
CN102775427A CN2012102306652A CN201210230665A CN102775427A CN 102775427 A CN102775427 A CN 102775427A CN 2012102306652 A CN2012102306652 A CN 2012102306652A CN 201210230665 A CN201210230665 A CN 201210230665A CN 102775427 A CN102775427 A CN 102775427A
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tetrathiazomycin
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methanol
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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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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 the preparation antitumor drug
Technical field:
The invention belongs to the industrial microorganism field, be specifically related to new microbiotic TetrathiazomycinA and preparation method thereof and the application in the preparation antitumor drug.
Background technology:
Malignant tumour is one of principal disease of present serious harm human life and quality of life, has become China resident's underlying cause of death at present, 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 New Development malignant tumour cases, and wherein death toll reaches 1,200 ten thousand, and the overwhelming majority will occur in developing country.In three big therapies of malignant tumour, pharmacological agent takies consequence.Majority is a lead compound with the natural antitumor activeconstituents all in synthetic chemistry class medicine.It is reported that natural product accounted for more than 60% of antitumor drug of listing to nineteen ninety-five in 1984; 1995-1999; 3 natural product verivates this shows that as new antitumor drug listing natural product is the important source of the novel structure and the antitumor drug of effect uniqueness.The polypeptide compounds of finding at present has BA widely, it is reported that the cyclic peptide that contains thiazole ring and oxazole ring has very strong cytotoxic activity, and for example Urukthapelstatin A is to the IC of human body lung carcinoma cell 50Value is surprising has reached 12nM.
Summary of the invention:
First purpose of the present invention provides new the lactam compound Tetrathiazomycin A that contains four thiazoles or its salt with anti-tumor activity.
Lactam compound Tetrathiazomycin A or its salt that contains four thiazoles of the present invention, its structure is shown in formula I:
Figure BDA00001851316300021
Second purpose of the present invention provides the preparation method of compound Tetrathiazomycin A; It is characterized in that described compound Tetrathiazomycin A is that the preparation separation obtains from the fermenting culture of actinomycetes Marinactinospora thermotolerans SCSIO00652.
Preferably from the fermenting culture of actinomycetes Marinactinospora thermotolerans SCSIO00652, prepare separation through following method and obtain Tetrathiazomycin A, concrete steps are following:
A) fermenting culture of preparation actinomycetes Marinactinospora thermotolerans SCSIO00652 is separated the fermented liquid and the mycelium of this fermenting culture, and fermented liquid is used ethyl acetate extraction, and ETHYLE ACETATE obtains extractum A mutually after concentrating;
B) extractum A as eluent, is carried out gradient elution from volume ratio 100:0 ~ 1:1 with chloroform/methanol through the purification on normal-phase silica gel column chromatography; Collect the chloroform/methanol volume ratio cut Fr.5-8 that 92:8 ~ the 1:1 gradient elution gets off, again through silica gel column chromatography, with ethyl acetate/methanol as eluent; Carry out gradient elution from volume ratio 94:6 ~ 8:2; Collected volume is than the component Fr.5-8-1 of 9:1 ~ 8:2 wash-out, again through ODS anti-phase medium pressure liquid chromatography, with the methanol gradient elution of volume(tric)fraction from 10% ~ 100%; The cut that the methanol gradient elution of collected volume mark 80 ~ 90% gets off is after obtain Tetrathiazomycin A behind the high-efficient liquid phase chromatogram purification.
The fermenting culture of the preparation Marinactinospora thermotolerans SCSIO00652 of described a) step prepares through following method: activatory Marinactinospora thermotolerans SCSIO00652 is inserted in the seed culture medium 28 ° of C, 200rpm; Cultivate 4d and make seed liquor; Seed liquor is received in the fermention medium 28 ° of C, 200rpm by 10% inoculum size; Shaking culture 7d; And making fermenting culture, the prescription of described seed culture medium and fermention medium all is 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 a water, pH7.4.
The 3rd purpose of the present invention provides the application of Marinactinospora thermotolerans SCSIO00652 in preparation compound Tetrathiazomycin A.
The present invention finds through experiment; 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 cytotoxic activity preferably, 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 purpose of the present invention provides the application of TetrathiazomycinA in the preparation 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 separates from the fermenting culture of actinomyces Marinactinospora thermotolerans SCSIO00652 and 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 better antitumor activity; Can use in the preparation 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, Ju Jianhua. and Chinese microbiotic magazine .2012 (2) 105 ~ 111.The applicant guarantees in 20 years applyings date, to the public this Marinactinospora thermotolerans SCSIO00652 bacterial strain to be provided.
Description of drawings:
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 the different multiples;
Fig. 2 is the X-single crystal diffraction figure of TetrathiazomycinA.
Embodiment:
Following examples are to further specify of the present invention, rather than limitation of the present invention.
Embodiment 1:
The separation of Tetrathiazomycin A and preparation
1, substratum
A, seed culture medium: contain in every liter of substratum: 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 a water, pH7.4.121 ℃, sterilization 30min;
B, fermention medium: prescription is with the seed substratum.121 ℃, sterilization 30min.
2, fermentation
Activatory actinomyces Marinactinospora thermotolerans.SCSIO00652 (figure is as shown in Figure 1 for its electron-microscope scanning) is inserted in the 6L seed culture medium 28 ° of C, 200rpm; Cultivate 4d and make seed liquor; The seed liquor of 6L is linked in the 60L fermention medium 28 ° of C, 200rpm; Shaking culture 7d, and make fermenting culture.
3, extraction
Fermenting culture carries out spinning (4000r.min earlier -1, 10min), fermented liquid and mycelium to be separated, fermented liquid is through equal volume of ethyl acetate, and ethyl acetate layer obtains extractum A (20.1g) through distilling after concentrating.
4, extraction separation and the evaluation of compound Tetrathiazomycin A (1)
Extractum A as eluent, is carried out gradient elution from volume ratio 100:0 ~ 1:1 with chloroform/methanol through purification on normal-phase silica gel column chromatography (silica gel 100 ~ 200 orders); Collect the chloroform/methanol volume ratio cut Fr.5-8 that 92:8 ~ the 1:1 gradient elution gets off, again through silica gel column chromatography, with ethyl acetate/methanol as eluent; Carry out gradient elution from volume ratio 94:6 ~ 8:2; Collected volume is than the component Fr.5-8-1 of 9:1 ~ 8:2 wash-out, again through ODS anti-phase medium pressure liquid chromatography (S-50 μ m, 12nm; 100 * 20mm, YMC), flow velocity is 15ml/min; With the methanol gradient elution 60min of volume(tric)fraction from 10% ~ 100%, the cut that the methanol gradient elution of collected volume mark 80 ~ 90% gets off is after performance liquid chromatography (ODS-A; 250 * 10mm, 5 μ m; YMC), flow velocity is 2.5ml/min, with the acetonitrile/water gradient elution 30min of volume(tric)fraction from 70% ~ 100%, is that 22min obtains compound 1 (TetrathiazomycinA) (16mg) in RT.
Through structural analysis, the compound that from the fermenting culture of Marinactinospora thermotolerans.SCSIO00652, prepares 1 of the present invention (TetrathiazomycinA) is identified that its qualification result is following:
White solid, its nuclear magnetic data ownership is as shown in table 1,
Figure BDA00001851316300051
1HNMR (500MHz, CD 3OD) reach 13C NMR (125MHz, CD 3OD), see table 1.Fusing point: 115 ~ 116 ℃.HR-ESI-MS m/z666.1382 ([M+H] +, theoretical value 666.1444). figure is as shown in Figure 2 for its X-single crystal diffraction.
Table 1: the nuclear magnetic data of compound 1 (TetrathiazomycinA) ( 1The H-NMR data are measured in 500MHz, are coupling constant (Hz) in the bracket, 13The C-NMR data are measured in 125MHz, and solvent is a deuterated methanol)
Figure BDA00001851316300052
In sum, the structural formula of authenticating compound 1 shown in formula I, called after TetrathiazomycinA,
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 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).TP is international srb assay: according to the cell speed of growth; The tumour cell that will be in logarithmic phase is inoculated in 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 contrast of corresponding RPMI-1640 solvent and acellular withered hole.Tumour cell is at 37 ℃, 5% CO 2Cultivated 72 hours under the condition, the nutrient solution that inclines, every hole adds the 50% cold TCA solid cell of 50 μ L, adopts 0.4% SRB to dye then 30 minutes, the acetate washing with 1% 5 times, dry air.The Tris solution that adds 200 μ L/ holes at last, ELIASA 570nm wavelength is measured the OD value.With cis-platinum as positive control.Experimental result is seen table 2:
Table 2:TetrathiazomycinA is to the restraining effect (IC of tumor cell line 50, μ M)
a?Positive?conrol。

Claims (7)

1. lactam compound Tetrathiazomycin A or its salt that contains four thiazoles, its structural formula is shown in (I):
Figure FDA00001851316200011
2. the preparation method of the described compound Tetrathiazomycin of claim 1 A; It is characterized in that described compound Tetrathiazomycin A is that the preparation separation obtains from the fermenting culture of actinomycetes Marinactinospora thermotolerans SCSIO00652.
3. the preparation method of compound Tetrathiazomycin A as claimed in claim 2 is characterized in that concrete steps are following:
A) fermenting culture of preparation actinomycetes Marinactinospora thermotolerans SCSIO00652 is separated the fermented liquid and the mycelium of this fermenting culture, and fermented liquid is used ethyl acetate extraction, and ETHYLE ACETATE obtains extractum A mutually after concentrating;
B) extractum A as eluent, is carried out gradient elution from volume ratio 100:0 ~ 1:1 with chloroform/methanol through the purification on normal-phase silica gel column chromatography; Collect the chloroform/methanol volume ratio cut Fr.5-8 that 92:8 ~ the 1:1 gradient elution gets off, again through silica gel column chromatography, with ethyl acetate/methanol as eluent; Carry out gradient elution from volume ratio 94:6 ~ 8:2; Collected volume is than the component Fr.5-8-1 of 9:1 ~ 8:2 wash-out, again through ODS anti-phase medium pressure liquid chromatography, with the methanol gradient elution of volume(tric)fraction from 10% ~ 100%; The cut that the methanol gradient elution of collected volume mark 80 ~ 90% gets off is after obtain Tetrathiazomycin A behind the high-efficient liquid phase chromatogram purification.
4. preparation method as claimed in claim 3 is characterized in that, the fermenting culture of the actinomycetes Marinactinospora thermotolerans SCSIO00652 of described a) step prepares through following method:
Activatory Marinactinospora thermotolerans SCSIO00652 is inserted in the seed culture medium 28 ° of C, 200rpm; Cultivate 4d and make seed liquor, seed liquor is received in the fermention medium 28 ° of C by 10% inoculum size; 200rpm, shaking culture 7d, and make fermenting culture; The prescription of described seed culture medium and fermention medium all is to contain starch 10g, (NH in every liter of substratum 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 a water, pH7.4.
5. the described compound TetrathiazomycinA of claim 1 or its salt application in the preparation antitumor drug.
6. application as claimed in claim 5 is characterized in that, described antitumor drug is anti-glioma medicine, anti-breast cancer medicines, anti-lung-cancer medicament or medicines resistant to liver cancer.
7.Marinactinospora the application of thermotolerans SCSIO 00652 in the described compound Tetrat of preparation claim 1 hiazomycin A.
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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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014005408A1 (en) * 2012-07-04 2014-01-09 中国科学院南海海洋研究所 Antibiotic tetrathiazomycin a and preparation method thereof and use in preparation of antitumour drug
CN104257641A (en) * 2014-08-11 2015-01-07 云南西力生物技术有限公司 C36 polyacetylene compound and preparation and application of C36 polyacetylene compound

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CN102775427B (en) * 2012-07-04 2014-04-09 中国科学院南海海洋研究所 Antibiotic Tetrathiazomycin A and preparation method thereof and application in preparing antineoplastic drugs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHUNG-MAO PAN等: "Progress toward the synthesis of Urukthapelstatin A and two analogues", 《TETRAHEDRON LETTERS》 *
YOSHIHIDE MATSUO等: "Urukthapelstatin A, a Novel Cytotoxic Substance from Marine-derived Mechercharimyces asporophorigenens YM11-542", 《J. ANTIBIOT.》 *
田树红等: "海洋微生物抗肿瘤天然产物研究进展", 《微生物学通报》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014005408A1 (en) * 2012-07-04 2014-01-09 中国科学院南海海洋研究所 Antibiotic tetrathiazomycin a and preparation method thereof and use in preparation of antitumour drug
CN104257641A (en) * 2014-08-11 2015-01-07 云南西力生物技术有限公司 C36 polyacetylene compound and preparation and application of C36 polyacetylene compound

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