CN1923827A - Eremophilone lactones acid natural product and application thereof - Google Patents
Eremophilone lactones acid natural product and application thereof Download PDFInfo
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- CN1923827A CN1923827A CN 200610053575 CN200610053575A CN1923827A CN 1923827 A CN1923827 A CN 1923827A CN 200610053575 CN200610053575 CN 200610053575 CN 200610053575 A CN200610053575 A CN 200610053575A CN 1923827 A CN1923827 A CN 1923827A
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- -1 Eremophilone lactones Chemical class 0.000 title claims abstract description 23
- 239000002253 acid Substances 0.000 title claims abstract description 23
- BSUGIIZTULADOL-YWPYICTPSA-N eremophilone Natural products O=C1C[C@@H](C(C)=C)C[C@]2(C)[C@@H](C)CCC=C21 BSUGIIZTULADOL-YWPYICTPSA-N 0.000 title claims description 17
- 229930014626 natural product Natural products 0.000 title description 8
- 210000004027 cell Anatomy 0.000 claims description 62
- 150000001875 compounds Chemical class 0.000 claims description 48
- 239000003814 drug Substances 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 18
- 210000004881 tumor cell Anatomy 0.000 claims description 18
- 230000012010 growth Effects 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 230000005764 inhibitory process Effects 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 7
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 6
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 6
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 6
- 208000019065 cervical carcinoma Diseases 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 6
- 210000002751 lymph Anatomy 0.000 claims description 6
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 5
- 239000000443 aerosol Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 238000013270 controlled release Methods 0.000 claims description 3
- 239000010408 film Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 239000000865 liniment Substances 0.000 claims description 3
- 229940040145 liniment Drugs 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- LKBQARGGDFBGFF-UHFFFAOYSA-N eremophilane Natural products CC1C(O)CCC2C(=O)CC(CC12C)C(=C)C LKBQARGGDFBGFF-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 8
- 125000004423 acyloxy group Chemical group 0.000 abstract 1
- 230000004071 biological effect Effects 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 230000003013 cytotoxicity Effects 0.000 description 9
- 231100000135 cytotoxicity Toxicity 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 241001113317 Farfugium Species 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 230000001472 cytotoxic effect Effects 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- 229910052697 platinum Inorganic materials 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- 229930182555 Penicillin Natural products 0.000 description 5
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 5
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- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 5
- 229920002554 vinyl polymer Polymers 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000208827 Ligularia Species 0.000 description 2
- 241001479578 Packera contermina Species 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
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- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 2
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- AJWBFJHTFGRNDG-GBJTYRQASA-N eremophilane Chemical compound C1CC[C@H](C)[C@@]2(C)C[C@H](C(C)C)CC[C@H]21 AJWBFJHTFGRNDG-GBJTYRQASA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
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- 229960001592 paclitaxel Drugs 0.000 description 2
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 235000004385 Conyza canadensis Nutrition 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- 241000409198 Packera aurea Species 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
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- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- 150000004526 eremophilane derivatives Chemical class 0.000 description 1
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- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an eremophilane lactone compound with chemical name as 3beta-chiretta acyloxy group-eremophile-7(11)-alkylene-12, 8beta-lactone-14-acid, which can inhibit the biological activity of HL-60, CNE, KB, Hela and P338D1.
Description
Technical field
The invention belongs to Natural Medicine Chemistry and pharmacology technical field.In particular to a kind of Eremophilone lactones acid natural product and medicinal use thereof.
Background technology
At present, because the problems such as environmental pollution that industrial development brings, the existent environment of people quality constantly descends, and the sickness rate of tumor disease and lethality rate also constantly rise.Yet the selectivity of at present clinical used cytotoxicity antitumor drug is not high, causes Normocellular pernicious killing and wounding limited the general usability of such medicine.Therefore, seek and find that the high cytotoxicity antitumor drug of new selectivity is worldwide research focus.We also are devoted to the research of this class medicine.
Black purple Farfugium kaemferi Ligularia atroviblacea (Franch.) Hand.-Mazz. is a composite family Farfugium kaemferi platymiscium, and Yunnan is among the people to be used for clearing heat and detoxicating and treatment flu, cough are used.The inventor is in extraction and chemical constitution study to composite family Farfugium kaemferi platymiscium and composite family Senecio, once found wherein to contain a large amount of eremophilane lactones, find that as contriver in recent years the eremophilane lactone in the Senecio wightii has tumour cell HL-60, A549 and KB strain all have certain cytotoxicity (Zhao Yu etc., Chinese Chemical Letters, 2002,13 the 4th phases of volume, 333-334 page or leaf).In addition, the inventor has reported that also several eremophilane lactones of chicken foot squaw weed also have certain cytotoxicity (Zhao Yu etc., Chinese Chemical Letters,, 13 the 8th phases of volume, 754-757 page or leaf in 2002 to KB cell strain and A-549 cell strain; Zhao Yu etc., Chinese Chemical Letters,, 16 the 3rd phases of volume, 362-364 page or leaf in 2005).But, do not appear in the newspapers as yet for the chemical constitution study and the bioactivity research of black purple Farfugium kaemferi.In view of the above, the inventor identifies chemical separation and structure that this kind of plant has been carried out biological tracking, has obtained the Eremophilone lactones acid compounds that described in the present invention has novel structure; And according to the whole world especially susceptibility of often swell the knurl spectrum of disease and the tumour cell of China, selected people's promyelocytic leukemia cell (HL-60), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell (KB), human cervical carcinoma cell (Hela) and mouse lymph sample oncocyte (P388D1), totally five strain tumor cell lines are as the index of cell in vitro cytotoxic activity pharmacology evaluation.The result demonstrates it the effect that suppresses above-mentioned growth of tumour cell, finishes the present invention thus.
Summary of the invention
The purpose of this invention is to provide a kind of eremophilane lactonic acid compound, its chemical name is: 3 β-Radix Angelicae Sinensis acyloxy-Airy Mo Fen-7 (11)-alkene-12,8 β-lactone-14-acid have following array structure:
Another object of the present invention provides compound (A) and salt thereof are used for suppressing the medicine of tumor cell growth activity in preparation application.
The application in the medicine of preparation inhibition people's promyelocytic leukemia cell (HL-60), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell (KB), human cervical carcinoma cell (Hela) and mouse lymph sample oncocyte (P388D1) growth activity of compound provided by the invention (A) and salt thereof.
Generally be rich in the eremophilane lactone in the Farfugium kaemferi platymiscium, its extracting method mostly is organic solvent and soaks extracting or refluxing extraction, and behind the recovery solvent, gained medicinal extract carries out solvent and distributes and/or various chromatography method, gets in conjunction with the recrystallization technology purifying.
The preparation method of compound among the present invention (A) is as follows: by the underground part of black purple Farfugium kaemferi through pure water or the extraction of ketone water system, organic solvent column chromatography, preparation of lamina chromatography and recrystallization method purifying.Specifically comprise the following steps:
A. extract medicinal material through pulverizing with pure water or ketone water mixed solvent, concentrated extracting solution reclaims alcoholic solvent or ketone solvent;
B. the medicinal extract that step a is obtained carries out the solvent distribution through sherwood oil, vinyl acetic monomer, propyl carbinol; The ethyl acetate extract that obtains is carried out column chromatography, use the organic solvent wash-out, thin-layer chromatography detects, collect stream part of containing compound (A) respectively, again through preparation thin layer or dextrane gel Sephadex LH-20 column chromatography, gradient elution, thin-layer chromatography detects, the stream part that contains compound (A) is reduced pressure respectively and is volatilized solvent, selects for use suitable organic solvent to carry out recrystallization, obtains pure product.
Among the preparation method among the present invention, alcohol can be methyl alcohol, ethanol, propyl alcohol, butanols, ethylene glycol or their mixture.Preferred alcohol.The alcohol water mixed solvent can be alcohol and water with arbitrary proportion blended solvent, the mixed solvent of preferred alcohol and water, the aqueous ethanolic solution of especially preferred 60-95%.Ketone can be acetone, methylethylketone, butanone or their mixture, the ketone water mixed solvent can be ketone and water with arbitrary proportion blended solvent, the mixed solvent of preferred acetone and water, especially preferred acetone content is greater than 60% ketone solution.
Recrystallization solvent can be straight or branched ester class, ethers, alcohols, ketone or their mixture of 1 to 6 carbon among the step b.Preferred acetone and vinyl acetic monomer.The column chromatography used medium can be silica gel, diatomite, reverse phase silica gel, macroporous resin, aluminum oxide, dextrane gel (Sephadex) class among the step b.Preferred silica gel.Eluting solvent can be ether, ester, ketone, chloroform, methylene dichloride, alcohol or they the two or three's a mixture.The preferred sherwood oil and the mixed solvent of acetone or sherwood oil and vinyl acetic monomer or the mixed solvent of chloroform and methyl alcohol carry out gradient elution.
Medicinal material among the present invention can be arbitrary position of black purple Farfugium kaemferi Ligularia atroviblacea (Franch.) Hand.-Mazz., promptly can be its root, stem, leaf, seed, skin, fruit, also can be their mixture.Preferred its underground part.
Compound of the present invention (A) or its pharmacologically acceptable salt and solvate thereof can combine with auxiliary material or carrier pharmaceutically commonly used, have the active pharmaceutical composition that can be used for anti-curing oncoma of growth of tumour cell inhibition thereby prepare.Above-mentioned various kinds of drug composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
Compound of the present invention (A) or its pharmacologically acceptable salt and solvate thereof can with the antitumor drug that has now gone on the market such as platinum medicine cis-platinum (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, NVB, nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), etoposide (Etoposide), taxol (Paclitaxel) wait and unite use, prepare and prevent and treat tumor disease class pharmaceutical composition.Such pharmaceutical composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
Compound of the present invention (A) has important biological, external to five strain tumour cells, the cytotoxic activity test that comprises people's promyelocytic leukemia cell (HL-60), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell (KB), human cervical carcinoma cell (Hela) and mouse lymph sample oncocyte (P388D1) shows that this type of eremophilane lactonic acid compound (specifically seeing embodiment) is inhibited to human body tumour cell growth, might develop into new control tumour medicine.
Embodiment
In order to understand essence of the present invention better, at first use the process of formal specification compound (A) preparation of embodiment below, embodiment has provided part physics and the chemistry and the Wave Spectrum data of representative compounds.Mandatory declaration, embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Secondly respectively with the inhibiting The pharmacological results of this eremophilane lactonic acid compound, its new purposes in the antitumor drug research field is described to five kinds of tumor cell line growths.Pharmacology embodiment has provided the part activity data of this compound.Mandatory declaration, pharmacology embodiment of the present invention is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: the preparation of compound (A)
Get the black purple Farfugium kaemferi underground part of 5.0 kilograms of exsiccant and be ground into powder, add 50 liter of 95% alcohol immersion.At room temperature soak each 7 days 3 times.Ethanol extract merges, and decompression and solvent recovery disperses with 3 literss of water to the dried 462 gram medicinal extract that obtain, and uses 60-90 ° of sherwood oil, vinyl acetic monomer, n-butanol extraction more successively.Reclaim under reduced pressure ethyl acetate extraction liquid obtains 89.0 gram medicinal extract.This medicinal extract restrains 100-200 order silica gel column chromatographies, chloroform-methanol (50: 0-0: 1) gradient elution with 800.Thin-layer chromatography detect to merge same stream part, stream part of containing compound (A) concentrate on 20: 1 and 10: 1 elutriants in.Decompression volatilizes solvent and gets medicinal extract 6.9 gram, again through column chromatography (200-300 order) with prepare thin layer (60-90 ° sherwood oil-vinyl acetic monomer 8: 1) purifying, finally obtains compound (A) (120mg).
The physics and the spectroscopic data of compound (A): colourless powder; Fusing point: 200-202 ℃ (acetone); [α]
D 20:-136.5 (c 0.30, methyl alcohol); Ultraviolet λ
Max(methyl alcohol) nm:224; IR v
Max KBr(cm
-1): 2985,1768,1714,1706,1654; Electrospray ionization mass spectrum ESI-MS (m/z): 361[M-H]
-High resolution electrospray ionization mass spectrum HR-ESI-MS (m/z): 361.1742 (calculated value [C
20H
26O
6+ H]
+361.1729);
13C and
1H NMR spectral data sees Table 1.
Table 1. compound (A)
13C-NMR and
1H-NMR spectrum data *
Carbon number | δC | δH |
1 2 3 4 5 6 7 | 22.7 secondary carbon 35.7 secondary carbon 71.6 tertiary carbons 45.6 tertiary carbons 39.7 quaternary carbons 25.4 secondary carbon 163.2 quaternary carbons | 1.89 multiplet 1.39 multiplets 1.74 multiplets 5.58 (quartets, J=3.0Hz) 2.64 is (bimodal, J=3.0Hz)-2.07 (bimodal, J=14.4Hz) 1.68 (double doublets, J=14.4,1.2Hz)- |
8 9 10 11 12 13 14 15 1′ 2′ 3′ 4′ 5′ | 81.8 tertiary carbon 38.4 secondary carbon 41.1 tertiary carbons 122.1 quaternary carbons 168.3 quaternary carbons 8.1 primary carbons 177.2 quaternary carbons 25.8 primary carbons 174.2 quaternary carbons 129.3 quaternary carbons 138.9 tertiary carbons 20.9 primary carbons 15.8 primary carbons | 4.87 (double doublet, J=9.6,4.2Hz) 2.23 multiplets, 1.85 multiplet 2.17 multiplets--1.77 are (bimodal, J=1.2Hz)-1.64 unimodal 6.11 (four quartets, J=7.2,1.6Hz) 1.98 (two quartets, J=7.2,1.6Hz), 1.92 (wide unimodal) |
* (in deuterated methanol, measure).
Embodiment 2: compound (A) is to the cytotoxic activity of KB cell
KB (oral epithelium cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 24 hours hatch, and the dimethyl sulfoxide solution of the compound that will newly join (A) joins in each hole with concentration gradient respectively, makes compound in the hole (A) ultimate density be respectively 100 μ g/mL, 33.3 μ g/mL, 11.1 μ g/mL and 3.7 μ g/mL.After 72 hours, the phosphate buffered saline buffer that adds 10 μ L MTT (5mg/mL), continue 37 ℃ of cultivations after 4 hours again, removed unconverted MTT in centrifugal 5 minutes, add 200 μ L methyl-sulphoxides in every hole, with the MTT crystal Jia Za (formazan) of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.Wherein compound (A) is to KB cell 503nhibiting concentration (IC
50) obtain by dose effect curve.
The IC of compound (A)
50For: 9.97 * 10
-5M; The positive control cis-platinum is to the IC of KB cell
50Be 5.67 * 10
-6M.
Experiment conclusion: the KB cell is Cytotoxic effective tool and the evaluation index of test compounds to tumour cell.This experiment shows that this Eremophilone lactones acid natural product has stronger cytotoxicity to the KB cell, might develop into the new medicine with antitumor action.
Embodiment 3: compound (A) is to the cytotoxic activity of HL-60 cell
HL-60 (people's promyelocytic leukemia cell) contains 10% calf serum, 100U/mL penicillin and 100U/mL Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 1 * 10
4Individual density is inoculated in 96 orifice plates, contains 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, and concrete grammar is with embodiment 2.Wherein compound (A) is to HL-60 cell 503nhibiting concentration (IC
50) obtain by dose effect curve.
The IC of compound (A)
50For: 2.08 * 10
-4M; And the positive control cis-platinum is to the IC of HL-60 cell
50Be 2.07 * 10
-5M.
Experiment conclusion: this experiment shows that this Eremophilone lactones acid natural product has stronger cytotoxicity to the HL-60 cell, might develop into the new medicine with treatment leukemia and related neoplasms effect.
Embodiment 4: compound (A) is to the cytotoxic activity of CNE cell
CNE (nasopharyngeal carcinoma) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.With every hole 5 * 10
3The concentration of cell joins in 96 orifice plates, contains 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, and concrete grammar is with embodiment 2.Wherein compound (A) is to CNE cell 503nhibiting concentration (IC
50) obtain by dose effect curve.
The IC of compound (A)
50For: 1.67 * 10
-4M; And the positive control cis-platinum is to the IC of CNE cell
50Be 4.62 * 10
-6M.
Experiment conclusion: this experiment shows that this Eremophilone lactones acid natural product has more weak cytotoxicity to the CNE cell.
Embodiment 5: compound (A) is to the cytotoxic activity of Hela cell
Hela (human cervical carcinoma) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, and concrete grammar is with embodiment 2.Wherein compound (A) is to Hela cell 503nhibiting concentration (IC
50) obtain by dose effect curve.
The IC of compound (A)
50For: 8.89 * 10
-5M; And the positive control cis-platinum is to the IC of Hela cell
50Be 4.20 * 10
-6M.
Experiment conclusion: this experiment shows that this Eremophilone lactones acid natural product has stronger cytotoxicity to the Hela cell, might develop into the new medicine with anti-cervical cancer and related neoplasms effect.
Embodiment 6: compound (A) is to the cytotoxic activity of P388D1
P388D1 (mouse lymph sample knurl) cell contains 10% calf serum, 100U/mL penicillin and 100U/mL Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Individual density is inoculated in 96 orifice plates, contains 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The measuring method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the compound that will newly join (A) joins in each hole with concentration gradient respectively, makes that the ultimate density of compound is respectively 100 μ g/mL, 50 μ g/mL, 25 μ g/mL, 5 μ g/mL in the hole.After 72 hours, add the normal saline solution of 10 μ L MTT (5mg/mL), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of damp atmosphere, add 150 μ L methyl-sulphoxides in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein compound (A) is to the half-inhibition concentration (IC of P388D1 cell
50) obtain by dose effect curve.
The IC of compound (A)
50For: 6.15 * 10
-5M; And the positive control cis-platinum is to the IC of P388D1 cell
50Be 1.03 * 10
-6M.
Experiment conclusion: this experiment shows that this Eremophilone lactones acid natural product has stronger cytotoxicity to the P388D1 cell, might develop into the new medicine with anti-cervical cancer and related neoplasms effect.
Claims (7)
2. the application of Eremophilone lactones acid compound according to claim 1 in the medicine of preparation inhibition growth of tumour cell.
3. the application of the salt of Eremophilone lactones acid compound according to claim 1 in the medicine of preparation inhibition growth of tumour cell.
4. the application of Eremophilone lactones acid compound according to claim 2 in the medicine of preparation inhibition growth of tumour cell is characterized in that: the application in preparation inhibition people promyelocytic leukemia cell, nasopharyngeal carcinoma cell, oral squamous carcinoma cell, human cervical carcinoma cell and mouse lymph sample oncocyte in the medicine of any growth of tumour cell.
5. the application of the salt of Eremophilone lactones acid compound according to claim 3 in the medicine of preparation inhibition growth of tumour cell is characterized in that: the application in preparation inhibition people promyelocytic leukemia cell, nasopharyngeal carcinoma cell, oral squamous carcinoma cell, human cervical carcinoma cell and mouse lymph sample oncocyte in the medicine of any growth of tumour cell.
6. the application in the medicine of preparation inhibition growth of tumour cell according to claim 2 or 3 described Eremophilone lactones acid compounds, it is characterized in that: described Eremophilone lactones acid compound or and salt, vehicle that allows with preparation or pharmaceutical excipient are combined in preparation and suppress application in the medicine of growth of tumour cell.
7. the application of Eremophilone lactones acid compound according to claim 6 in the medicine of preparation inhibition growth of tumour cell, it is characterized in that: described dosage form is drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
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CN106035372A (en) * | 2016-05-28 | 2016-10-26 | 淄博夸克医药技术有限公司 | Composition for preventing and controlling wheat blossom midges and preparation method thereof |
CN114107233A (en) * | 2021-10-27 | 2022-03-01 | 武汉臻智生物科技有限公司 | Phosetrene synthetase gene, high-yield strain and application |
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2006
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CN106035372A (en) * | 2016-05-28 | 2016-10-26 | 淄博夸克医药技术有限公司 | Composition for preventing and controlling wheat blossom midges and preparation method thereof |
CN114107233A (en) * | 2021-10-27 | 2022-03-01 | 武汉臻智生物科技有限公司 | Phosetrene synthetase gene, high-yield strain and application |
CN114107233B (en) * | 2021-10-27 | 2024-01-09 | 武汉合生科技有限公司 | Synthetase gene of phorene, high-yield strain and application |
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