CN102492006A - 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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- CN102492006A CN102492006A CN2011104216656A CN201110421665A CN102492006A CN 102492006 A CN102492006 A CN 102492006A CN 2011104216656 A CN2011104216656 A CN 2011104216656A CN 201110421665 A CN201110421665 A CN 201110421665A CN 102492006 A CN102492006 A CN 102492006A
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- canthaxanthin
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- 0 C[C@@](*)(Cc(c(O)c1C(c2ccc(*)c(O)c22)=O)c3cc1C2=O)CC3=O Chemical compound C[C@@](*)(Cc(c(O)c1C(c2ccc(*)c(O)c22)=O)c3cc1C2=O)CC3=O 0.000 description 4
- FXZLWHNJLLDZMW-IUIJHHPQSA-N CC(CC(COC(OC1C)=CCC1=O)C1)O[C@H]1O[C@@]1(C)C(C)=COC(C)[C@H]1O Chemical compound CC(CC(COC(OC1C)=CCC1=O)C1)O[C@H]1O[C@@]1(C)C(C)=COC(C)[C@H]1O FXZLWHNJLLDZMW-IUIJHHPQSA-N 0.000 description 1
- QFWOUDUACVGRJP-CSLXUYRDSA-N CC1[O]([C@H](CC2)C=C)C12O[C@@H](CC1)OC(C)C1=O Chemical compound CC1[O]([C@H](CC2)C=C)C12O[C@@H](CC1)OC(C)C1=O QFWOUDUACVGRJP-CSLXUYRDSA-N 0.000 description 1
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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 plain compound of one type of square ring and the application in the preparation antitumor drug thereof.
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.
Summary of the invention:
First purpose of the present invention is the square ring chlorins compound that provides one type to have anti-tumor activity.
One type of 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 used to prepare antitumor drug.
Therefore second purpose of the present invention provides 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 the preparation antitumor drug.
The 3rd purpose of the present invention provides 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 had the obvious suppression effect; Can be used to prepare antitumor drug; Be used to treat tumour, so the present invention provides compound candidate for the new antitumor drug of exploitation, exploitation China sea ocean drug resource has been 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, Ju Jianhua. the research of aryl amide meta-bolites among the marine streptomyces Streptomyces lusitanus SCSIO LR32. research and development of natural products 2011, among the 23:591-595.; Mentioned microorganism the applicant also hold, and guarantee in 20 years applyings date of the present invention, to provide to the public.
Embodiment:
Following examples are to further specify of the present invention, rather than limitation of the present invention.
Embodiment 1:
Preparation and structure suc as formula the compound 1-5 shown in (I) are identified.
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 to obtain 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 adds water 1L, and pH 7.2-7.4, average mark are loaded in the Erlenmeyer flask of 20 250mL, and every bottle of 50ml sterilized 25 minutes for 121 ℃, obtained the seed culture medium of sterilization.
(3) cultivation of seed: the bacterial strain of marine streptomyces S.lusitanus SCSIO LR32 is linked in the above-mentioned seed culture medium, under 28 ℃ temperature, puts on the shaking table with the rotating speed of 200rpm, cultivated 48 hours seed culture fluid.
2. fermentation culture:
(1) preparation fermention medium: glucose 10g, starch 20g, malt meal 10g, SANMALT-S 10g; Steeping water 5g, sea salt 30g, Trace element solution 0.1ml; Water 1L, pH 7.2-7.4, average mark are loaded in the Erlenmeyer flask of 4 1000mL; Every bottle of 250ml sterilized 25 minutes for 121 ℃, obtained the fermention medium of sterilization.
(2) fermentation culture:
In Bechtop, the access of 50mL seed culture fluid is equipped with in the 1000mL Erlenmeyer flask of 250mL fermention medium, place on 28 ℃ of shaking tables, with the rotating speed of 200rpm, cultivated 8 days, obtain the fermenting culture of marine streptomyces S.lusitanus SCSIO LR32.
3. extraction separation:
With centrifugal thalline and the fermented liquid of getting of above-mentioned fermenting culture, fermented liquid concentrates the butanone extraction liquid and gets the fermented liquid extract with isopyknic butanone extraction three times; Thalline is with the acetone extraction of submergence amount three times, and each 24h concentrates acetone extraction liquid and gets the thalline extract.Fermented liquid extract and thalline extract are merged,, adopt chloroform-methanol (volume ratio 100: 0,99: 1 through silica gel (100-200 order) column chromatography for separation; 98: 2,95: 5,90: 10; 80: 20) gradient elution, behind concentrating under reduced pressure, obtain cut Fr.1～Fr.6 accordingly.Cut Fr.2 (volume ratio is the cut of 99: 1 chloroform-methanol wash-out) is through the anti-phase medium pressure column chromatography, with ODS chromatographic column (20 * 90mm, 40-63 μ m; YMC), as eluent, volume ratio was by beginning in 20: 80 with methanol-water; Reach 100: 0 after 80 minutes; Flow velocity 15mL/min, per 20 minutes flow point merges, and order obtains four flow point Fr.2-1～Fr.2-4.Fr.2-1 adopts chloroform-methanol (volume ratio 98: 2) drip washing to obtain compound 2 (18mg) through silica gel (100-200 order) column chromatography for separation.Fr.2-3 adopts chloroform-methanol (volume ratio 98: 2) drip washing to obtain compound 4 (5mg) through silica gel (100-200 order) column chromatography for separation.Fr.2-4 adopts petroleum ether-ethyl acetate (volume ratio 100: 0,98: 2 through silica gel (100-200 order) column chromatography for separation; 95: 5,90: 10,80: 20; 50: 50) as the eluent gradient elution, obtain 6 flow points, be respectively Fr.2-4-1～Fr.2-4-6 accordingly.Wherein Fr.2-4-2 (volume ratio is the cut of 98: 2 petroleum ether-ethyl acetate wash-out) is through silica gel (100-200 order) column chromatography, and the use volume ratio is 97: 3 CHCl
3-MeOH obtains compound 1 (12mg) as the eluent wash-out; Fr2.-4-3 (volume ratio is the cut of 95: 5 petroleum ether-ethyl acetate wash-out) through the ODS chromatographic column (20 * 90mm, 40-63 μ m, YMC); As eluent, volume ratio reaches 100: 0 by beginning in 20: 80 after 80 minutes with methanol-water; Flow velocity 15mL/min obtains compound 3 (10mg, t
R34min) and compound 5 (13mg, t
R56min).
Two, the structure of compound 1-5 is identified
Compound 1-5 is carried out 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 seen 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 seen 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 seen 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 seen 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 seen 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 belongs to the square ring chlorins compound suc as formula shown in (I):
Formula (I).
Table 1: (500/125MHz, TMS are interior mark to the NMR data of the plain compound 1-2 of square ring, ppm)
aSolvent is CDCl
3/ CD
3OD
bSolvent is CDCl
3/ CD
3OD
cOverlap with solvent peak
D, e, f, gPeak under the identical footmark overlaps
Table 2: (500/125MHz, TMS are interior mark to the NMR data of the plain compound 3-5 of square ring, ppm, CDCl
3)
aOverlap with solvent peak
B, cPeak under the 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.
Use 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.Each tumour cell is containing 5%CO with 1640 substratum (containing 10% calf serum)
2Incubator in cultivate, get then that 100 μ L cell suspending liquids are put in 96 orifice plates, final concentration is 2 * 10
3Individual cells/well was hatched 12 hours, added the DMSO solution of the sample (compound 1-5) of 50 μ L different concns; Cultivated 48 hours, and added 50 μ L MTT solution (1mg/mL in PBS) again, after hatching 4 hours under 37 ℃; Add 200 μ L DMSO, measure 550nm place light absorption value with ELIASA.Each drug level is provided with 3 parallel-group, and blank control group and 5 FU 5 fluorouracil positive controls are set simultaneously.Cells survival rate (%)=dosing group/blank control group * 100% is calculated its IC
50
Test result is as shown in table 3, and table 3 shows that 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, explains that compound 1-5 has very big exploitation to be worth in the anti-tumor medicine field.
Table 3: cell in vitro cytotoxic activity result (IC
50, μ M, n=3)
aIC
50＞100 μ M.
b5-Fluorouracil, positive contrast.
Claims (3)
1. one type of square ring chlorins compound 1-5 is characterized in that, its structural formula is suc as formula shown in (I):
Formula (I).
2. the described arbitrary square ring chlorins compound of claim 1 or its pharmaceutical salts application in the preparation antitumor drug.
3. an antitumor drug is characterized in that, comprises the described arbitrary square ring chlorins compound of the claim 1 as activeconstituents or its pharmaceutical salts of significant quantity and acceptable carrier pharmaceutically.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110421665 CN102492006B (en) | 2011-12-14 | 2011-12-14 | Canthaxanthin compound and application of compound to preparation of antitumor drugs |
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|---|---|---|---|
| CN 201110421665 CN102492006B (en) | 2011-12-14 | 2011-12-14 | Canthaxanthin compound and application of compound to preparation of antitumor drugs |
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|---|---|
| CN102492006A true CN102492006A (en) | 2012-06-13 |
| CN102492006B CN102492006B (en) | 2013-12-25 |
Family
ID=46183874
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550231A (en) * | 2013-11-18 | 2014-02-05 | 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 |
| CN104744533A (en) * | 2015-01-30 | 2015-07-01 | 中国科学院南海海洋研究所 | Angucycline compounds and application of angucycline compounds in preparation of anti-tumour or antibacterial medicine |
| 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)
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| 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. |
-
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 |
|---|
| 任香梅，等: "海洋链霉菌Streptomyces lusitanus SCSIO LR32中芳酰胺类代谢产物的研究", 《天然产物研究与开发》, no. 23, 30 November 2011 (2011-11-30), pages 591 - 595 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550231A (en) * | 2013-11-18 | 2014-02-05 | 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 |
| 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 |
| CN104744533A (en) * | 2015-01-30 | 2015-07-01 | 中国科学院南海海洋研究所 | Angucycline compounds and application of angucycline compounds in preparation of anti-tumour or antibacterial medicine |
| CN106834160A (en) * | 2015-01-30 | 2017-06-13 | 中国科学院南海海洋研究所 | One class square ring element compound and its application in antitumor or antibacterials are prepared |
| CN104744533B (en) * | 2015-01-30 | 2017-08-25 | 中国科学院南海海洋研究所 | One class square ring element compound and its application in antitumor or antibacterials are prepared |
| 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 |
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| CN102492006B (en) | 2013-12-25 |
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Granted publication date: 20131225 Termination date: 20211214 |