CN102603769B - Sulfur-containing chromone compound and preparation method thereof and application in preparation of antitumor drugs - Google Patents
Sulfur-containing chromone compound and preparation method thereof and application in preparation of antitumor drugs Download PDFInfo
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- CN102603769B CN102603769B CN 201210081918 CN201210081918A CN102603769B CN 102603769 B CN102603769 B CN 102603769B CN 201210081918 CN201210081918 CN 201210081918 CN 201210081918 A CN201210081918 A CN 201210081918A CN 102603769 B CN102603769 B CN 102603769B
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- thiochromone
- chloroform
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- antitumor drug
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- -1 chromone compound Chemical class 0.000 title claims abstract description 40
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 21
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229910052717 sulfur Inorganic materials 0.000 title description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title description 2
- 239000011593 sulfur Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 229940125904 compound 1 Drugs 0.000 claims abstract description 33
- 229940125782 compound 2 Drugs 0.000 claims abstract description 15
- 201000001441 melanoma Diseases 0.000 claims abstract description 15
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 13
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 13
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 13
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 11
- 241000985513 Penicillium oxalicum Species 0.000 claims abstract description 10
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 7
- 229940126214 compound 3 Drugs 0.000 claims abstract description 7
- 229940125898 compound 5 Drugs 0.000 claims abstract description 7
- JJYKJUXBWFATTE-SECBINFHSA-N (2r)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid Chemical group CO[C@](C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-SECBINFHSA-N 0.000 claims abstract description 5
- JJYKJUXBWFATTE-VIFPVBQESA-N (2s)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid Chemical group CO[C@@](C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-VIFPVBQESA-N 0.000 claims abstract description 5
- 201000007270 liver cancer Diseases 0.000 claims abstract description 4
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
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- 201000002313 intestinal cancer Diseases 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- 201000005202 lung cancer Diseases 0.000 claims description 9
- 208000020816 lung neoplasm Diseases 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 230000001580 bacterial effect Effects 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 235000002595 Solanum tuberosum Nutrition 0.000 claims description 6
- 244000061456 Solanum tuberosum Species 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 239000002024 ethyl acetate extract Substances 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 239000006916 nutrient agar Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 235000002639 sodium chloride Nutrition 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000004809 thin layer chromatography Methods 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 239000002026 chloroform extract Substances 0.000 claims description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 4
- 239000002027 dichloromethane extract Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229920001817 Agar Polymers 0.000 claims description 3
- 239000008272 agar Substances 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 238000001641 gel filtration chromatography Methods 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 claims description 2
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 claims description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 abstract description 5
- 206010023825 Laryngeal cancer Diseases 0.000 abstract description 5
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 5
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 abstract description 5
- 206010023841 laryngeal neoplasm Diseases 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 4
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- 239000012071 phase Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 4
- FLGZHHJNRZUPIL-UHFFFAOYSA-N chromene-4-thione Chemical compound C1=CC=C2C(=S)C=COC2=C1 FLGZHHJNRZUPIL-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
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- 229910002027 silica gel Inorganic materials 0.000 description 3
- HAEQAUJYNHQVHV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 HAEQAUJYNHQVHV-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 241000228143 Penicillium Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 244000309464 bull Species 0.000 description 2
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- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 1
- ZYCNQWOKCMJKEZ-UHFFFAOYSA-N Aloesol Natural products C1=C(O)C=C2OC(CC(O)C)=CC(=O)C2=C1C ZYCNQWOKCMJKEZ-UHFFFAOYSA-N 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 244000082204 Phyllostachys viridis Species 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
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- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HNBDRPTVWVGKBR-UHFFFAOYSA-N methyl pentanoate Chemical group CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses one kind containing Thiochromone compound and preparation method thereof and application in preparation of anti-tumor drugs. Such as formula (I) containing its structure of Thiochromone compound is shown, wherein compound 1:R1=R2=R3=H; Compound 2:R1=R3=H, R2=CH3; Compound 3:R1=R3=Ac, R2=H; Compound 4:R1=R2=R3=Ac; Compound 5:R1=R2=Ac, R3=H; Compound 6:R1=Ac, R2=R3=H; Compound 7:R1=(R)-MTPA, R2=R3=H; Compound 8:R1=(S)-MTPA, R2=R3=H. Compound 1 and compound 2 are that preparative separation obtains from 93256 fermentation liquid of fungi Penicillium oxalicum CCTCC AF. Compound 1 carries out acetylization reaction and obtains compound 3-6; Compound 1 carries out Mosher esterification and obtains compound 7 and 8. Of the invention having containing Thiochromone compound inhibits malignant melanoma cell, lung carcinoma cell, cervical cancer cell, breast cancer cell, laryngeal cancer cell, liver cancer cells, the activity of colon-cancer cell growth, therefore has good application prospect in terms of preparing anti-tumor drug.
Formula (I).
Description
Technical field:
The invention belongs to biological technical field, be specifically related to a class containing Thiochromone compound and preparation method thereof and the application in preparing antitumor drug.
Background technology:
Fungi can produce the secondary metabolite of the types such as alkaloid, peptide class, polyketone class, steroidal and terpene, wherein much has significantly antitumor, antibacterium, the biological activity such as antimycotic, pest-resistant.Find the focus that active compound is the natural drug research and development from fungi.Chromone compounds be a class occurring in nature exist there is multiple bioactive material, no matter be naturally occurring, or synthetic obtaining, all caused the extensive concerns such as chemist.But very rare containing Thiochromone compound.
Summary of the invention:
First purpose of the present invention is to provide the Thiochromone compound that contains that a class has anti-tumor activity.
The present invention is by multiple column chromatography and one dimension, two dimensional NMR wave spectrum, from the fermented liquid of fungi Penicillium oxalicum CCTCCAF 93256, separate obtain a class new containing Thiochromone compound, this cytotoxic activity that there is inhibition kinds cancer Growth of Cells containing Thiochromone compound, can be used for preparing antitumor drug, thereby realized purpose of the present invention.
Of the present invention containing Thiochromone compound, its structure is suc as formula shown in (I):
Formula (I)
Compound 1:R wherein
1=R
2=R
3=H; Compound 2:R
1=R
3=H, R
2=CH
3; Compound 3:R
1=R
3=Ac, R
2=H; Compound 4:R
1=R
2=R
3=Ac; Compound 5:R
1=R
2=Ac, R
3=H; Compound 6:R
1=Ac, R
2=R
3=H; Compound 7:R
1=(R)-MTPA, R
2=R
3=H; Compound 8:R
1=(S)-MTPA, R
2=R
3=H.
Second purpose of the present invention is to provide suc as formula the preparation method containing Thiochromone compound shown in (I).
Of the present invention suc as formula shown in (I) containing the preparation method of Thiochromone compound, it is characterized in that, comprise the following steps:
(1) prepare the fermented liquid of fungi Penicillium oxalicum CCTCC AF 93256;
(2) ethyl acetate, methylene dichloride or the chloroform solvent extraction for fermented liquid that step (1) are obtained, concentrated ethyl acetate extract, dichloromethane extract or the chloroform extract of obtaining;
(3) by the described ethyl acetate extract of step (2), dichloromethane extract or chloroform extract are through the normal pressure silica gel column chromatography, with chloroform-methanol, chloroform-acetone, chloroform-ethyl acetate, sherwood oil-acetone or petroleum ether-ethyl acetate solvent systems are eluent, within 100: 0 to 0: 100, carry out gradient elution from volume ratio, follow the trail of and merge component with thin-layer chromatography, the component that to can launch by the volume ratio chloroform of 8: 2-acetone solvent system on thin-layer chromatography, obtain crude product through gel filtration chromatography, purified, obtain shown in formula (I) containing Thiochromone compound 1 and 2,
(4) compound 1 is dissolved in anhydrous pyridine and reacts with acetic anhydride and prepare compound 3-6 as catalyzer with DMAP in room temperature.
(5) compound 1 is dissolved in anhydrous pyridine and prepares compound 7 and 8 with (S)-2-methoxyl group-2-trifluoromethyl phenyllacetyl chloride and (R)-2-methoxyl group-2-trifluoromethylbenzene excess acetyl chloride respectively in room temperature.
The described fungi Penicillium of step (1) oxalicum CCTCC AF 93256 is purchased from Chinese Typical Representative culture collection center (CCTCC), address: China, and Wuhan, Wuhan University, preserving number is CCTCC AF 93256.
The fermented liquid of fungi Penicillium oxalicum CCTCC AF 93256 described in step (1) can be inoculated into fungi Penicillium oxalicum CCTCC AF 93256 in the applicable substratum of Penicillium fungi, under common fermentation condition, makes.Preferred preparation method is inoculated in fungi Penicillium oxalicum CCTCC AF 93256 in the PDA nutrient agar, cultivate 3 days for 28 ℃, obtain cultivating the flat board that bacterial classification is arranged, then bacterial classification in flat board is inoculated in the PDA substratum, in rotating speed 200r/min shaking table, 28 ℃ of cultivations of temperature 3 days, obtain seed liquor, seed liquor is inoculated in the PDA substratum again, in the standing cultivation of room temperature 30 days, obtain fermented liquid, every liter of described PDA nutrient agar contains potato 200g, glucose 20g, sea salt 30g, agar 20g, surplus is water, every liter of described PDA substratum contains potato 200g, glucose 20g, sea salt 30g, surplus is water.
The most handy ethyl acetate of the described extraction of step (2), described concentrating can adopt conventional method as concentrating under reduced pressure.
The described purifying of step (3) can adopt chromatographic column to separate or recrystallization.
By the anti tumor activity in vitro screening experiment, result shows: of the present invention suc as formula shown in (I), containing Thiochromone compound, suppressing the growth of malignant melanoma cell strain A375, lung cancer cell line A549, cervical cancer cell strain HeLa, breast cancer cell line mcf-7, laryngeal cancer cell strain Hep-2, hepatoma cell strain HepG2, colon-cancer cell strain SW-620, their IC
50be worth as shown in table 3, prove thus of the present invention suc as formula shown in (I) containing Thiochromone compound can be for the preparation of anti-tumor drug.
Therefore, the 3rd purpose of the present invention be to provide suc as formula shown in (I) containing the application of Thiochromone compound in preparing antitumor drug.
Preferably, described containing Thiochromone compound while being compound 1, described antitumor drug is melanoma, lung cancer, cervical cancer, mammary cancer, laryngocarcinoma, liver cancer or bowelcancer medicine.
Preferably, described while containing Thiochromone compound, being compound 2, compound 3 or compound 4, described antitumor drug is melanoma, lung cancer, cervical cancer or bowelcancer medicine.
Preferably, described containing Thiochromone compound while being compound 5, described antineoplastic compound is melanoma, cervical cancer or bowelcancer medicine.
Preferably, described containing Thiochromone compound while being compound 6, described antineoplastic compound is melanoma or bowelcancer medicine.
Preferably, described containing Thiochromone compound while being compound 7, described antitumor drug is melanoma, lung cancer, cervical cancer or bowelcancer medicine.
A kind of antitumor drug, is characterized in that, comprise significant quantity as activeconstituents containing Thiochromone compound and acceptable carrier pharmaceutically.
Of the present invention suc as formula shown in (I), containing Thiochromone compound, the growth of malignant melanoma cell, lung carcinoma cell, cervical cancer cell, breast cancer cell, laryngeal cancer cell, liver cancer cell, colon-cancer cell being had to stronger restraining effect, good application prospect is arranged preparing aspect antitumor drug.
The accompanying drawing explanation:
Fig. 1 be compound 1 in methylene dichloride the CD that surveys figure;
Fig. 2 is that compound 1 is containing Mo
2(OAc)
4dMSO in the CD that surveys figure.
Embodiment:
Following examples are to further illustrate of the present invention, rather than limitation of the present invention.
Embodiment 1: containing the preparation of Thiochromone compound 1 and 2
Every liter of PDA substratum is preparation like this: by 200 gram potatoes, and 20 gram glucose, 30 gram sea salt mix, and the water constant volume is to 1L.The PDA substratum is packed in the Erlenmeyer flask of about 200 500mL, and every bottle of about 150mL, 121 ℃ of high pressure steam sterilizations 25 minutes.
Every liter of PDA nutrient agar is preparation like this: by 200 gram potatoes, and 20 gram glucose, 30 gram sea salt, 20 gram agar mix, and the water constant volume is to 1L.121 ℃ of high pressure steam sterilizations 25 minutes, standby.
Inhaling approximately fungi Penicillium oxalicum CCTCC AF 93256 bacterial classifications of 2 microlitres with liquid-transfering gun inoculates on the PDA nutrient agar, cultivate 3 days for 28 ℃, obtain cultivating the flat board that bacterial classification is arranged, then choose approximately 3 microlitre bacterial classifications from flat board inoculates in the Erlenmeyer flask containing the above-mentioned PDA of the being equipped with substratum of 150mL with bamboo let, in 28 ℃ of shaking table (rotating speed 200r/min) temperature, cultivate 3 days, obtain seed liquor, inoculation 7.5mL seed liquor in above-mentioned every bottle approximately contains the triangular flask of 150mL PDA substratum, after 30 days, collect fermented liquid in the standing cultivation of room temperature (28 ℃).
The fermented liquid 30L that will obtain through the PDA culture medium culturing is extracted with ethyl acetate, and concentrating under reduced pressure obtains ethyl acetate extract 16g.After purification on normal-phase silica gel for ethyl acetate extract (100-200 order) dry method is mixed sample, the glass chromatography column (containing the about 300g of purification on normal-phase silica gel 100-200 order) of packing into, carry out the Column at Normal Temperature chromatography, using chloroform-methanol as eluent, within 100: 0 to 0: 100, carry out gradient elution from volume ratio, according to thin-layer chromatography (GF
254silica-gel plate) situation merges every flow part, reclaims eluting solvent, and the evaporate to dryness flow point shifts with methyl alcohol.The component (2.4g) that to can launch by the volume ratio chloroform of 8: 2-acetone solvent system on thin-layer chromatography is through gel filtration chromatography (diameter 18mm, column length 1600mm, gel is sephedex LH-20, moving phase is the volume ratio chloroform-methanol of 1: 1) separate, collect stream part, separate out crude product, crude product adopts high performance liquid phase half preparation, and (the detection wavelength is 254nm, flow velocity is 3mL/min, chromatographic column is YMC-Pack 10mm * 250mm, and moving phase is the methanol-water that volume ratio is 45: 55) at appearance time, be 20 to separate purifying during with 23 minutes and obtain compound 1 and 2 respectively.
Wherein the structure elucidation of compound 1 is as follows:
By high resolution mass spectrum (HRESIMS) at m/z 447.0693[M+Na]
+, 425.0919[M+H]
+place provides quasi-molecular ion peak, and in conjunction with the NMR spectral data, the molecular formula of learning compound 1 is C
19h
20o
9s.
13c spectrum and DEPT spectrum show in molecule that 19 carbon atoms are arranged, comprising 3 methyl [δ
c22.34,53.02,53.77], 2 methylene radical [δ
c35.45,37.96], 4 methyne [δ
c50.77,71.21,107.86,113.04] and 10 quaternary carbon [δ
c79.61,109.12,120.51,147.22,157.12,160.88,171.01,173.16,173.41,178.87].The hydrogen spectrum shows 2 phenyl ring hydrogen signal [δ
h(6.63 1H, s), 6.72 (1H, s)], 2 methoxyl group [δ
h(3.82 3H, s), 3.88 (3H, s)] and a low phenolic hydroxyl group reactive hydrogen [δ
h12.6].NMR signal similar [1.Kashiwada, the Y. of these NMR signals and compound (2 ' R)-aloesol, (2 ' S)-aloesol basic framework; Nonaka, G.I.; Nishioka, I.Chem.Pharm.Bull.1984,32,3493-3500.2.Che, Q.M.; Akao, T.; Hattori, M.; Kyoichi, K.; Namba, T.Chem.Pharm.Bull.1991,39,704-708.], this explanation compound 1 has the constitutional features (A ring and this skeleton of B cyclic group) of chromone compounds.
In the HMBC spectrum, H-2 and C-1, C-3, C-4, C-8a, C-17 is relevant, H-4 and C-2, C-3, C-3, C-4a, C-8a, C-17 is relevant, Me-17 and C-2, C-3, C-4 is relevant, there is one 1,2 in this explanation compound 1,3, H-7 and C-6 in 5-tetra-substituted benzene rings (A ring) .HMBC spectrum, C-9, C-10 relevant and
1h-
1in H COSY spectrum, H-7 is relevant to H-6 and encircle and be connected with B in conjunction with the five-ring (C ring) of the sulfur-bearing of 1D NMR data-speculative existence of H-7/H-6/C-7/C-6.In addition, H-6 and C-11 in the HMBC spectrum, C-14 is relevant, H-11 and C-6, C-12, C-13 is relevant, and Me-15 is relevant to C-14, and Me-16 is relevant to C-13, in conjunction with
1h-
1in H COSY spectrum, H-11 is relevant to H-12, infers that existing 1,5-, bis-formyls-2,4-dihydroxyl to replace two valeric acid methyl esters fragments is connected with the C ring.In addition, by NOESY compose, Mosher esterification and circular dichroism spectrum (see Fig. 1,2) further determine that the absolute configuration of chiral carbon atom C-6, C-11, C-13 is respectively S, S, R.Therefore the structure of deterministic compound 1 is suc as formula shown in (I), its R
1=R
2=R
3=H.Compound 1 is yellow powder, is soluble in chloroform, ethyl acetate, methyl alcohol, DMSO, is insoluble in water, specific rotatory power value [a]
20 d=+31.43 (c, 0.42in CH
3cl).
The hydrogen spectrum of compound 2 is very similar to compound 1 with carbon spectrum data, just many methoxyl groups, infer that by reference point in the NMR data with compound 1 and HMBC spectrum this methoxyl group is connected on the C-11 position, so the structure of deterministic compound 2 is suc as formula shown in (I), its R
1=R
3=H, R
2=CH
3.
Compound 1 and 2 hydrogen spectrum and carbon are composed data as shown in Table 1 and Table 2.
Formula (I)
Compound 1:R wherein
1=R
2=R
3=H; Compound 2:R
1=R
3=H, R
2=CH
3; Compound 3:R
1=R
3=Ac, R
2=H; Compound 4:R
1=R
2=R
3=Ac; Compound 5:R
1=R
2=Ac, R
3=H; Compound 6:R
1=Ac, R
2=R
3=H; Compound 7:R
1=(R)-MTPA, R
2=R
3=H; Compound 8:R
1=(S)-MTPA, R
2=R
3=H.
The hydrogen spectrum NMR data of table 1. compound 1-6 are (at CDCl
3in solvent)
The carbon spectrum NMR data of table 2. compound 1-4 are (at CDCl
3in solvent)
Embodiment 2: containing the preparation of Thiochromone compound 3-6
Take 4.0mg compound 1 and be dissolved in the 5mL flask that the 0.8mL anhydrous pyridine is housed, in solution, add 0.8mL acetic anhydride and 2.0mg DMAP (as catalyzer), in room temperature reaction 11 hours.By after the solvent evaporated under reduced pressure, crude product is adopted to high performance liquid phase half preparation, and (the detection wavelength is 254nm, and flow velocity is 3mL/min, and chromatographic column is YMC-Pack 10mm * 250mm, and moving phase is CH
3cN/H
2o is from volume ratio 20% to 100% gradient elution, and collecting respectively appearance time is 19.6min, 21.4min, and 23.9min, the sample of 26.0min obtains compound 3,4,5,6.
Compound 3-6 is the acetylate of compound 1, and according to the nuclear magnetic resonance data of compound 3-6 and compare with the nuclear magnetic resonance data of compound 1 and 2, the structure of deterministic compound 3-6 is suc as formula shown in (I), wherein compound 3:R
1=R
3=Ac, R
2=H; Compound 4:R
1=R
2=R
3=Ac; Compound 5:R
1=R
2=Ac, R
3=H; Compound 6:R
1=Ac, R
2=R
3=H.
The hydrogen of compound 3-6 spectrum and carbon compose data as table 1 and table 2 listed.
Embodiment 3: containing the preparation of Thiochromone compound 7 and 8
Take 2.0mg compound 1 and be dissolved in the 5mL flask that the 0.5mL anhydrous pyridine is housed, in solution, add Mosher reagent 10 μ L (S)-2-methoxyl group-2-trifluoromethyl phenyllacetyl chloride and 1.0mg DMAP (as catalyzer), in room temperature reaction 9 hours.By after the solvent evaporated under reduced pressure, crude product is adopted to high performance liquid phase half preparation, and (the detection wavelength is 254nm, and flow velocity is 3mL/min, and chromatographic column is YMC-Pack 10mm * 250mm, and moving phase is CH
3cN/H
2o (from 20% to 100% gradient elution, volume ratio v/v) separation and purification obtains compound 7.
The method for preparing the method for compound 8 and compound 7 is similar, and just Mosher reagent is changed to (R)-2-methoxyl group-2-trifluoromethyl phenyllacetyl chloride.
Compound 7 and 8 is Mosher esterification products of compound 1, according to nuclear magnetic resonance data and with the nuclear magnetic resonance data of compound 1 and 2, compares, and deterministic compound 7 and 8 structure be suc as formula shown in (I), compound 7:R
1=(R)-MTPA, R
2=R
3=H; Compound 8:R
1=(S)-MTPA, R
2=R
3=H.
Compound 7 and 8 hydrogen spectrum data are as follows.
Compound 7:
1h NMR (500MHz, CDCl
3) δ 2.42 (3H, s, H-18), 2.80 (1H, dd, J=8.4,17.3Hz, H-7a), 2.75 (1H, dd, J=8.3,17.3Hz, H-7b), 3.03 (1H, dd, J=4.1,15.1Hz, H-12a), 2.98 (1H, dd, J=7.1,15.1Hz, H-12b), 3.82 (3H, s, H-16), 3.88 (3H, s, H-17), 3.83 (1H, dd, J=8.0,8.5Hz, H-6), 5.40 (1H, dd, J=4.5,7.2Hz, H-13), 6.65 (1H, s, H-2), (6.74 1H, s, H-4), 12.05 (OH-1).
Compound 8:
1h NMR (500MHz, CDCl
3) δ 2.41 (3H, s, H-18), 3.08 (1H, dd, J=8.5,17.5Hz, H-7a), 3.22 (1H, dd, J=8.0,17.5Hz, H-7b), 3.16 (1H, dd, J=3.5,15.0Hz, H-12a), 3.02 (1H, dd, J=8.5,15.0Hz, H-12b), 3.77 (3H, s, H-17), 3.85 (3H, s, H-16), 3.94 (1H, dd, J=8.5,8.0Hz, H-6), 5.40 (1H, dd, J=3.5,8.5Hz, H-13), 6.65 (1H, s, H-2), (6.74 1H, s, H-4), 12.05 (OH-1).
Embodiment 4: suc as formula shown in (I) containing Thiochromone compound 1,2,3,4,5,6 and 7 anti tumor activity in vitro screening experiment:
Collect respectively malignant melanoma cell strain A375, lung cancer cell line A549, cervical cancer cell strain HeLa, breast cancer cell line mcf-7, laryngeal cancer cell strain Hep-2, hepatoma cell strain HepG2 and the colon-cancer cell strain SW-620 of logarithmic phase, make its suspension with 10% serum 1640 substratum, be inoculated in 96 well culture plates, every porocyte number is 5000/80 μ L, is placed in 5%CO
237 ℃ of cultivations of incubator.To be diluted to concentration containing Thiochromone compound (compound 1,2,3,4,5,6 or 7) with 10% serum 1640 substratum is 3.125 μ g/mL, 6.25 μ g/mL, 12.5 μ g/mL, 25 μ g/mL, 50 μ g/mL, 100 μ g/mL, the experimental solutions of 200 μ g/mL.Adding respectively concentration next day in the culture plate of different experimental group is 3.125 μ g/mL, 6.25 μ g/mL, 12.5 μ g/mL, 25 μ g/mL, 50 μ g/mL, 100 μ g/mL, the experimental solutions 20 μ L of 200 μ g/mL, and make the final concentration in every hole reach test (experimental group concentration adopts the two-fold dilution).10% serum 1640 substratum that add in addition equivalent in negative control group.After 48h, inhale and abandon the nutrient solution in experimental group and control group, every hole adds MTT20 μ L (2.5mg/mL), continue to cultivate 4h, more every hole adds DMSO 100 μ L termination reactions, 37 ℃ of placement 20min, detect the absorbance A value of each hole at the 570nm place by microplate reader, calculate inhibitory rate of cell growth.Cell growth rate=(experimental group OD ÷ control group OD) * 100%.
Experimental result shows, can suppress the growth of malignant melanoma cell strain A375, lung cancer cell line A549, cervical cancer cell strain HeLa, breast cancer cell line mcf-7, laryngeal cancer cell strain Hep-2, hepatoma cell strain HepG2, colon-cancer cell strain SW-620 containing Thiochromone compound 1-7 shown in formula (I), their IC50 value is as shown in table 3.Therefore of the present invention suc as formula shown in (I) can be for the preparation of antitumor drug containing Thiochromone compound.
The cytotoxic activity of table 3 compound 1-7 to 7 kinds of tumour cells
Annotate: "-" means because of the not enough not test of sample size.
Claims (9)
- Shown in formula I containing Thiochromone compound:
Compound 1:R wherein 1=R 2=R 3=H; Compound 2:R 1=R 3=H, R 2=CH 3; Compound 3:R 1=R 3=Ac, R 2=H; Compound 4:R 1=R 2=R 3=Ac; Compound 5:R 1=R 2=Ac, R 3=H; Compound 6:R 1=Ac, R 2=R 3=H; Compound 7:R 1=(R)-MTPA, R 2=R 3=H; Compound 8:R 1=(S)-MTPA, R 2=R 3=H. - 2. the preparation method containing Thiochromone compound claimed in claim 1, is characterized in that, comprises the following steps:(1) prepare the fermented liquid of fungi Penicillium oxalicum CCTCC AF 93256;(2) ethyl acetate, methylene dichloride or the chloroform solvent extraction for fermented liquid that step (1) are obtained, concentrated ethyl acetate extract, dichloromethane extract or the chloroform extract of obtaining;(3) by the described ethyl acetate extract of step (2), dichloromethane extract or chloroform extract process normal pressure silica gel column chromatography, take chloroform-methanol, chloroform-acetone, chloroform-ethyl acetate, sherwood oil-acetone or petroleum ether-ethyl acetate solvent systems is eluent, carry out gradient elution from volume ratio 100:0 to 0:100, follow the trail of and merge component with thin-layer chromatography, to on thin-layer chromatography, can use the component that chloroform-the acetone solvent system is launched of volume ratio 8:2, obtain crude product through gel filtration chromatography, purified, obtain compound 1 claimed in claim 1 and 2;(4) compound 1 is dissolved in anhydrous pyridine and reacts with acetic anhydride as catalyzer and prepare compound 3-6 claimed in claim 1 with DMAP in room temperature;(5) compound 1 is dissolved in anhydrous pyridine and prepares compound 7 claimed in claim 1 and 8 with (S)-2-methoxyl group-2-trifluoromethyl phenyllacetyl chloride and (R)-2-methoxyl group-2-trifluoromethylbenzene excess acetyl chloride respectively in room temperature;The preparation method of the fermented liquid of the fungi Penicillium oxalicum CCTCC AF 93256 described in step (1) is inoculated in fungi Penicillium oxalicum CCTCC AF 93256 in the PDA nutrient agar, cultivate 3 days for 28 ℃, obtain cultivating the flat board that bacterial classification is arranged, then bacterial classification in flat board is inoculated in the PDA substratum, in rotating speed 200r/min shaking table, 28 ℃ of cultivations of temperature 3 days, obtain seed liquor, seed liquor is inoculated in the PDA substratum again, in the standing cultivation of room temperature 30 days, obtain fermented liquid, every liter of described PDA nutrient agar contains potato 200g, glucose 20g, sea salt 30g, agar 20g, surplus is water, every liter of described PDA substratum contains potato 200g, glucose 20g, sea salt 30g, surplus is water, the described extraction ethyl acetate of step (2), described concentrated employing concentrating under reduced pressure, the described purifying of step (3) adopts chromatographic column to separate or recrystallization.
- 3. claimed in claim 1 containing the application of Thiochromone compound in preparing antitumor drug.
- 4. application according to claim 3, is characterized in that, described is compound 1 claimed in claim 1 containing Thiochromone compound, and described antitumor drug is melanoma, lung cancer, cervical cancer, mammary cancer, laryngocarcinoma, liver cancer or bowelcancer medicine.
- 5. application according to claim 3, is characterized in that, described is compound 2 claimed in claim 1, compound 3 or compound 4 containing Thiochromone compound, and described antitumor drug is melanoma, lung cancer, cervical cancer or bowelcancer medicine.
- 6. application according to claim 3, is characterized in that, described is compound 5 claimed in claim 1 containing Thiochromone compound, and described antitumor drug is melanoma, cervical cancer or bowelcancer medicine.
- 7. application according to claim 3, is characterized in that, described is compound 6 claimed in claim 1 containing Thiochromone compound, and described antitumor drug is melanoma or bowelcancer medicine.
- 8. application according to claim 3, is characterized in that, described is compound 7 claimed in claim 1 containing Thiochromone compound, and described antitumor drug is melanoma, lung cancer, cervical cancer or bowelcancer medicine.
- 9. an antitumor drug, is characterized in that, comprises claimed in claim 1 containing Thiochromone compound and acceptable carrier pharmaceutically as activeconstituents of significant quantity.
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