CN102492006B - Canthaxanthin compound and application of compound to preparation of antitumor drugs - Google Patents
Canthaxanthin compound and application of compound to preparation of antitumor drugs Download PDFInfo
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- CN102492006B CN102492006B CN 201110421665 CN201110421665A CN102492006B CN 102492006 B CN102492006 B CN 102492006B CN 201110421665 CN201110421665 CN 201110421665 CN 201110421665 A CN201110421665 A CN 201110421665A CN 102492006 B CN102492006 B CN 102492006B
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Abstract
The invention discloses a canthaxanthin compound and application of the compound to preparation of antitumor drugs. The canthaxanthin compound 1-5 is represented by a structural formula (I). As activity test of the compound 1-5 indicates, the compound 1-5 plays a strong growth inhibition role in HepG2 hepatocellular carcinoma cells, SW-1990 pancreatic cancer cells, HeLa cervical carcinoma cells, NCI-H460 large cell carcinoma cells and MCF-7 breast cancer cells of human and B16 mouse melanoma cell lines, is better in effect than a positive control medicine of 5-fluorouracil, and can be used for preparing the antitumor drugs.
Description
Technical field:
The invention belongs to the natural product field, be specifically related to class square ring element compound and the application in preparing antitumor drug thereof.
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 the natural antitumor activeconstituents as lead compound.It is reported, within 1984, to nineteen ninety-five, natural product accounts for more than 60% of antitumor drug of listing, 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.
Summary of the invention:
The square ring chlorins compound that provides a class to have anti-tumor activity is provided first purpose of the present invention.
A class square ring chlorins compound 1-5 of the present invention, is characterized in that, its structural formula is suc as formula shown in (I):
Formula (I).
Active testing result to compound 1-5 shows, compound 1-5 is to human liver cancer cell HepG2, human pancreatic cancer cell SW-1990, human cervical carcinoma cell HeLa, the cell lung cancer cell NCI-H460 of the National People's Congress, human breast cancer cell MCF-7 and mouse melanotic tumor cell B16 have very strong growth-inhibiting effect, and effect is better than the positive control drug 5 FU 5 fluorouracil, can be for the preparation of antitumor drug.
Therefore second purpose of the present invention is to provide suc as formula the compound 1 shown in (I), compound 2, compound 3, compound 4 or compound 5, or the application of its pharmaceutical salts in preparing antitumor drug.
The 3rd purpose of the present invention is to provide a kind of antitumor drug, it is characterized in that, comprise significant quantity as activeconstituents suc as formula the compound 1 shown in (I), compound 2, compound 3, compound 4 or compound 5, or its pharmaceutical salts, and acceptable carrier pharmaceutically.
Square ring chlorins compound 1-5 of the present invention is new compound, tumour cell is had to obvious restraining effect, can be for the preparation of antitumor drug, be used for the treatment of tumour, therefore the present invention provides compound candidate for developing new antitumor drug, and exploitation Chinese Sea drug resource is had great importance.
Streptomyces lusitanus SCSIO LR32 of the present invention openly has been documented in document: Ren Xiangmei, yellow big waves, Liu Jing, Zhang Yun, Ma Junying, Wang Bo, Zhang Changsheng, bring up Jian Hua. the research of aryl amide meta-bolites in marine streptomyces Streptomyces lusitanus SCSIO LR32. and research and development of natural products 2011, in 23:591-595., mentioned microorganism the applicant also hold, and guarantee in 20 years, to the public, to provide from the present patent application day.
Embodiment:
Following examples are to further illustrate of the present invention, rather than limitation of the present invention.
Embodiment 1:
Preparation and Structural Identification suc as formula the compound 1-5 shown in (I).
One, suc as formula the preparation of the compound 1-5 shown in (I)
1. seed culture:
(1) marine streptomyces Streptomyces lusitanus SCSIO LR32 separates and obtains from the abyssal sediment of the South Sea, and this bacterial classification is stored in the ISP-4 slant medium, and the ISP-4 substratum consists of: Zulkovsky starch 10g, K
2hPO
41g, MgSO
4.7H
2o 1g, NaCl 1g, (NH
4)
2sO
42g, CaCO
32g, FeSO
4.7H
2o 0.001g, MnCl
2.7H
2o 0.001g, thick sea salt 30g, agar 15g, water 1000mL, pH 7.2-7.4.
(2) preparation seed culture medium: bean powder 10g, Zulkovsky starch 20g, yeast extract paste 5g, peptone 2g, CaCO
32g, sea salt 4g, add water 1L, pH 7.2-7.4, average mark is loaded in the Erlenmeyer flask of 20 250mL, every bottle of 50ml, 121 ℃ of sterilizings 25 minutes, obtain the seed culture medium of sterilizing.
(3) cultivation of seed: the bacterial strain of marine streptomyces S.lusitanus SCSIO LR32 is linked in above-mentioned seed culture medium, at the temperature of 28 ℃, puts on shaking table with the rotating speed of 200rpm, cultivates 48 hours to obtain seed culture fluid.
2. fermentation culture:
(1) preparation fermention medium: glucose 10g, starch 20g, malt meal 10g, maltose 10g, corn steep liquor 5g, sea salt 30g, Trace element solution 0.1ml, water 1L, pH 7.2-7.4, average mark is loaded in the Erlenmeyer flask of 4 1000mL, every bottle of 250ml, 121 ℃ of sterilizings 25 minutes, obtain the fermention medium of sterilizing.
(2) fermentation culture:
In Bechtop, the access of 50mL seed culture fluid is equipped with in the 1000mL Erlenmeyer flask of 250mL fermention medium, be placed on 28 ℃ of shaking tables, with the rotating speed of 200rpm, cultivate 8 days, obtain the fermenting culture of marine streptomyces S.lusitanus SCSIO LR32.
3. extract and separate:
By above-mentioned fermenting culture centrifugal thalline and fermented liquid, isopyknic butanone extraction three times for fermented liquid, concentrate the butanone extraction liquid and obtain the fermented liquid extract; The acetone extraction of submergence amount three times for thalline, each 24h, concentrated acetone extraction liquid obtains the thalline extract.Fermented liquid extract and thalline extract are merged, through silica gel (100-200 order) column chromatography for separation, adopt chloroform-methanol (volume ratio 100: 0,99: 1,98: 2,95: 5,90: 10,80: 20) gradient elution, after concentrating under reduced pressure, obtain accordingly cut Fr.1～Fr.6.Cut Fr.2 (cut of the chloroform-methanol wash-out that volume ratio is 99: 1) is through anti-phase medium pressure column chromatography, with ODS chromatographic column (20 * 90mm, 40-63 μ m, YMC), using methanol-water as eluent, volume ratio started by 20: 80, reach 100: 0 after 80 minutes, flow velocity 15mL/min, the flow point of every 20 minutes merges, and order obtains four flow point Fr.2-1～Fr.2-4.Fr.2-1, through silica gel (100-200 order) column chromatography for separation, adopts chloroform-methanol (volume ratio 98: 2) drip washing to obtain compound 2 (18mg).Fr.2-3, through silica gel (100-200 order) column chromatography for separation, adopts chloroform-methanol (volume ratio 98: 2) drip washing to obtain compound 4 (5mg).Fr.2-4, through silica gel (100-200 order) column chromatography for separation, adopts petroleum ether-ethyl acetate (volume ratio 100: 0,98: 2,95: 5,90: 10,80: 20,50: 50) as the eluent gradient elution, obtain 6 flow points, be respectively accordingly Fr.2-4-1～Fr.2-4-6.Wherein Fr.2-4-2 (cut of the petroleum ether-ethyl acetate wash-out that volume ratio is 98: 2) is through silica gel (100-200 order) column chromatography, the CHCl that is 97: 3 by volume ratio
3-MeOH obtains compound 1 (12mg) as the eluent wash-out; Fr2.-4-3 (cut of the petroleum ether-ethyl acetate wash-out that volume ratio is 95: 5) is through ODS chromatographic column (20 * 90mm, 40-63 μ m, YMC), using methanol-water as eluent, volume ratio started by 20: 80, reached 100: 0 after 80 minutes, flow velocity 15mL/min, obtain compound 3 (10mg, t
r34min) and compound 5 (13mg, t
r56min).
Two, the Structural Identification of compound 1-5
Compound 1-5 is carried out to the structural analysis test, obtains following physico-chemical property data:
Compound 1: yellow powder;
ultraviolet (PDA) λ
max214,262,442nm; Nucleus magnetic resonance
1h reaches
13the C spectrum is in Table 1; Mass spectrum (+)-ESIMS m/z 943.4[M+Na]
+, 959.3[M+K]
+, (-)-ESIMS m/z919.5[M-H]
-, 951.6[M+MeOH-H]
-; High resolution mass spectrum (-)-HRESIMS m/z 919.3763[M-H]
-(calcd forC
49h
59o
17, 919.3758).
Compound 2: dark red solid;
ultraviolet (PDA) λ
max222,302,512nm; Nucleus magnetic resonance
1h reaches
13the C spectrum is in Table 1; Mass spectrum (+)-ESIMS m/z 1093.6[M+Na]
+, 1125.4[M+Na+MeOH]
+, (-)-ESIMS m/z 1069.7[M-H]
-; High resolution mass spectrum (-)-HRESIMS m/z 1069.4076[M-H]
-(calcd for C
57h
65o
20, 1069.4075).
Compound 3: red solid;
ultraviolet (PDA) λ
max230,258,294,443nm; Nucleus magnetic resonance
1h reaches
13the C spectrum is in Table 2; Mass spectrum (-)-ESIMS m/z 937.7[M-H]
-; High resolution mass spectrum (-)-HRESIMS m/z937.3853[M-H]
-(calcd for C
49h
61o
18, 937.3863).
Compound 4: red solid;
ultraviolet (PDA) λ
max230,258,294,442nm; Nucleus magnetic resonance
1h reaches
13the C spectrum is in Table 2; Mass spectrum (+)-ESIMS m/z 735.0[M+Na]
+, (-)-ESIMS m/z 711.6[M-H]
-, 1462.0[2M+K-H]
-; High resolution mass spectrum (-)-HRESIMS m/z 711.2649[M-H]
-(calcd for C
37h
43o
14, 711.2658).
Compound 5: tawny solid;
ultraviolet (PDA) λ
max230,258,294,442nm; Nucleus magnetic resonance
1h reaches
13the C spectrum is in Table 2; Mass spectrum (+)-ESIMS m/z 845.2[M+Na]
+, (-)-ESIMS m/z 821.3[M-H]
-; High resolution mass spectrum (-)-HRESIMS m/z 821.3002[M-H]
-(calcd for C
43h
49o
16, 821.3026).
According to above physico-chemical property data, the structural formula of authenticating compound 1-5, suc as formula shown in (I), belongs to the square ring chlorins compound:
Formula (I).
Table 1: (500/125MHz, TMS is interior mark to the NMR data of square ring element compound 1-2, ppm)
asolvent is CDCl
3/ CD
3oD
bsolvent is CDCl
3/ CD
3oD
cwith solvent peak, overlap
d, e, f, gpeak under identical footmark overlaps
Table 2: (500/125MHz, TMS is interior mark to the NMR data of square ring element compound 3-5, ppm, CDCl
3)
awith solvent peak, overlap
b, cpeak under identical footmark overlaps
Embodiment 2:
Embodiment 1 preparation suc as formula the compound 1-5 shown in (I) to the inhibiting test of growth of tumour cell.
The application mtt assay, to compound 1-5 to human liver cancer cell HepG2, human pancreatic cancer cell SW-1990, human cervical carcinoma cell HeLa, the cell lung cancer cell NCI-H460 of the National People's Congress, the growth-inhibiting effect of human breast cancer cell MCF-7 and mouse melanotic tumor cell B16 is tested.1640 substratum for each tumour cell (containing 10% calf serum) are containing 5%CO
2incubator in cultivate, then get that 100 μ L cell suspending liquids are put in 96 orifice plates, final concentration is 2 * 10
3individual cells/well, hatch 12 hours, the DMSO solution that adds the sample (compound 1-5) of 50 μ L different concns, cultivate 48 hours, add again 50 μ L MTT solution (1mg/mL in PBS), hatch 4 hours under 37 ℃ after, add 200 μ L DMSO, by microplate reader, measure 550nm place light absorption value.Each drug level arranges 3 parallel group, and blank group and 5 FU 5 fluorouracil positive controls are set simultaneously.Cells survival rate (%)=dosing group/blank group * 100%, calculate its IC
50.
Test result is as shown in table 3, and table 3 shows, compound 1-5 is to suppressing the IC of above-mentioned six kinds of tumour cells
50value is between 1.1 to 30.9 μ M, and effect is better than the positive control drug 5 FU 5 fluorouracil, illustrates that compound 1-5 has very large exploitation to be worth in the anti-tumor medicine field.
Table 3: in vitro cytotoxic effect result (IC
50, μ M, n=3)
aiC
50>100 μ M.
b5-Fluorouracil, positive contrast.
Claims (3)
1. a class square ring chlorins compound 1-5, is characterized in that, its structural formula as shown in the formula (I):
Formula (I).
2. the application of arbitrary square ring chlorins compound claimed in claim 1 in preparing antitumor drug.
3. an antitumor drug, is characterized in that, comprises the claimed in claim 1 arbitrary square ring chlorins compound as activeconstituents of significant quantity, and acceptable carrier pharmaceutically.
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|---|---|---|---|
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|---|---|---|---|
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| CN102492006B true CN102492006B (en) | 2013-12-25 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550231B (en) * | 2013-11-18 | 2015-07-15 | 中国人民解放军第三军医大学第一附属医院 | Application of grincamycin B in preparing anti-glioma drugs |
| CN106834160B (en) * | 2015-01-30 | 2019-12-31 | 中国科学院南海海洋研究所 | Streptomyces erythropolis for producing keratin compound |
| CN110585443A (en) * | 2019-09-04 | 2019-12-20 | 中国人民解放军陆军军医大学第一附属医院 | Compound for inhibiting invasive growth of glioma and application thereof |
| CN111892574A (en) * | 2020-05-19 | 2020-11-06 | 中国科学院南海海洋研究所 | Atypical keratinocyte compounds and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002074800A1 (en) * | 2001-03-19 | 2002-09-26 | Galilaeus Oy | Gene cluster for rabelomycin biosynthesis and its use to generate compounds for drug screening |
| WO2008028050A2 (en) * | 2006-08-30 | 2008-03-06 | Wisconsin Alumni Research Foundation | Reversible natural product glycosyltransferase-catalyzed reactions, compounds and related methods |
| CN102181387A (en) * | 2011-03-17 | 2011-09-14 | 中国科学院南海海洋研究所 | Streptomyces sp. and method for preparing straurosporine and K-252d by utilizing Streptomyces sp. |
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2011
- 2011-12-14 CN CN 201110421665 patent/CN102492006B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002074800A1 (en) * | 2001-03-19 | 2002-09-26 | Galilaeus Oy | Gene cluster for rabelomycin biosynthesis and its use to generate compounds for drug screening |
| WO2008028050A2 (en) * | 2006-08-30 | 2008-03-06 | Wisconsin Alumni Research Foundation | Reversible natural product glycosyltransferase-catalyzed reactions, compounds and related methods |
| CN102181387A (en) * | 2011-03-17 | 2011-09-14 | 中国科学院南海海洋研究所 | Streptomyces sp. and method for preparing straurosporine and K-252d by utilizing Streptomyces sp. |
Non-Patent Citations (1)
| Title |
|---|
| 海洋链霉菌Streptomyces lusitanus SCSIO LR32中芳酰胺类代谢产物的研究;任香梅，等;《天然产物研究与开发》;20111130(第23期);591-595 * |
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