CN1686109A - Application of cantharidin derivative as anti-tumour medicine - Google Patents
Application of cantharidin derivative as anti-tumour medicine Download PDFInfo
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- CN1686109A CN1686109A CN 200510033897 CN200510033897A CN1686109A CN 1686109 A CN1686109 A CN 1686109A CN 200510033897 CN200510033897 CN 200510033897 CN 200510033897 A CN200510033897 A CN 200510033897A CN 1686109 A CN1686109 A CN 1686109A
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- DHZBEENLJMYSHQ-XCVPVQRUSA-N cantharidin Chemical class C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O DHZBEENLJMYSHQ-XCVPVQRUSA-N 0.000 title claims abstract description 56
- 239000003814 drug Substances 0.000 title claims abstract description 17
- 230000000259 anti-tumor effect Effects 0.000 title description 4
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 10
- 208000032839 leukemia Diseases 0.000 claims abstract description 7
- 229940095758 cantharidin Drugs 0.000 claims description 39
- 229930008397 cantharidin Natural products 0.000 claims description 39
- DHZBEENLJMYSHQ-UHFFFAOYSA-N cantharidine Natural products O1C2CCC1C1(C)C2(C)C(=O)OC1=O DHZBEENLJMYSHQ-UHFFFAOYSA-N 0.000 claims description 39
- 210000004027 cell Anatomy 0.000 claims description 20
- 241000534944 Thia Species 0.000 claims description 11
- 230000012010 growth Effects 0.000 claims description 8
- 229930008399 cantharidic acid Natural products 0.000 claims description 7
- ZZDBMDNRQQDSKG-UHFFFAOYSA-N methyl 5-bromo-1-benzofuran-2-carboxylate Chemical compound BrC1=CC=C2OC(C(=O)OC)=CC2=C1 ZZDBMDNRQQDSKG-UHFFFAOYSA-N 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 claims description 5
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 claims description 5
- 102000011195 Profilin Human genes 0.000 claims description 5
- 108050001408 Profilin Proteins 0.000 claims description 5
- 201000005296 lung carcinoma Diseases 0.000 claims description 4
- 201000009030 Carcinoma Diseases 0.000 claims description 3
- 201000006585 gastric adenocarcinoma Diseases 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 230000004614 tumor growth Effects 0.000 abstract description 3
- 210000000214 mouth Anatomy 0.000 abstract description 2
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 1
- 210000001072 colon Anatomy 0.000 abstract 1
- 210000004185 liver Anatomy 0.000 abstract 1
- 210000004072 lung Anatomy 0.000 abstract 1
- 210000002784 stomach Anatomy 0.000 abstract 1
- 238000002474 experimental method Methods 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 229940041181 antineoplastic drug Drugs 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- JAABVEXCGCXWRR-FBXFSONDSA-N rel-norcantharidin Chemical compound C1C[C@H]2[C@@H]3C(=O)OC(=O)[C@@H]3[C@@H]1O2 JAABVEXCGCXWRR-FBXFSONDSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 238000011275 oncology therapy Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
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- 208000005718 Stomach Neoplasms Diseases 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000022131 cell cycle Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 206010017758 gastric cancer Diseases 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 201000011549 stomach cancer Diseases 0.000 description 4
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 3
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 3
- 229940122454 Protein phosphatase 2A inhibitor Drugs 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
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- 230000006870 function Effects 0.000 description 2
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- 229940107698 malachite green Drugs 0.000 description 2
- FDZZZRQASAIRJF-UHFFFAOYSA-M malachite green Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC=CC=1)=C1C=CC(=[N+](C)C)C=C1 FDZZZRQASAIRJF-UHFFFAOYSA-M 0.000 description 2
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- 208000010655 oral cavity squamous cell carcinoma Diseases 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
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- 208000024172 Cardiovascular disease Diseases 0.000 description 1
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- 102000016736 Cyclin Human genes 0.000 description 1
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- 230000004543 DNA replication Effects 0.000 description 1
- 101100457919 Drosophila melanogaster stg gene Proteins 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 241000124079 Mylabris Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- RFCWHQNNCOJYTR-UHFFFAOYSA-N Tautomycin Natural products CC=1C(=O)OC(=O)C=1C(O)CC(=O)OC(C(C)C)C(OC)C(O)CC(=O)C(C)C(O)CCC(C)C(C(CC1)C)OC21CCC(C)C(CCC(C)C(C)=O)O2 RFCWHQNNCOJYTR-UHFFFAOYSA-N 0.000 description 1
- -1 Wang Guangsheng Chemical compound 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
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- VYQQEQBNIXINLS-KFJLSGOXSA-N cantharidin cantharidic acid Chemical compound C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O.C1CC2C(C(O)=O)(C)C(C)(C(O)=O)C1O2 VYQQEQBNIXINLS-KFJLSGOXSA-N 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 101150069072 cdc25 gene Proteins 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000011960 computer-aided design Methods 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
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- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
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- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An application of the cantharidin derivative which can suppress the growth of tumor cells and the activity of proteophosphotase 2A (PP2A) in preparing the antineoplastic medicines for treating the cancers of oral cavity, stomach, liver, lung and colon and leukemia is disclosed.
Description
Technical field
The present invention relates to the pharmaceutical compound field, relate to the application of a compounds specifically as antitumor drug.
Background technology
Malignant tumor is the chronic disease that mortality rate is only second to cardiovascular and cerebrovascular disease.Existing antitumor drug curative effect is unsatisfactory, and toxic and side effects is also bigger.The progress learned of molecular weight tumor provides new treatment approach for oncotherapy in recent years, and the discovery of novel targets makes the development of cancer therapy drug go on the road of targeted therapy.Yet, develop a kind of brand-new medicine both expensive, the cycle is long.Along with the development of the modernization of Chinese medicine, increasing in the discovery of pharmaceutically active ingredient and the mechanism of action thereof clear and definite, provide many potential affluent resources for effectively seeking cancer therapy drug.The development of modern molecule structure activity relationship theory is also for providing strong support with certain molecule for target spot designs synthetic drug.Therefore, utilize computer-aided design, the natural inhibitor of known action target spot is carried out structure of modification,, become one of strategy of seeking antitumor drug to seek effective cancer therapy drug.
The reversible phosphorylation of albumen is the most important regulatory mechanism of fundamental sum of vital movement, belongs to post translational modification, affects the many critical functions of cell, for example: gene expression, carbohydrate metabolism, cell cycle, apoptosis, the conduction of cell signal neurotransmitter and dna replication dna or the like.Swelling and ache is that polygenes changes and to cause the cell cycle disorder, the class disease due to the growth of cell property out of control.Phosphoprotein phosphatase 2A (PP2A) by regulating proteic reversible phosphorylation function, plays an important factor of negative regulation effect just in cell cycle.PP2A can suppress the activation of cdk/cyclin complex by the activity of the inhibition activatory kinases of CDK (CAK) or the dephosphorylation of cdc25, thereby plays negative regulatory function in cell cycle.
Have only the PP2A inhibitor of minority to be found so far, as okadaic acid, microcystinLR, (list of references McCluskey A. such as tautomycin, et al.J Med Chem 200245 (6): 1151-75), but, do not have clinical value, and unique PP2A inhibitor that shows clinical value is cantharidin ex hoc genus anne thing all because of toxicity is big." core Ji directly side opinion " of Song dynasty well-known doctor Yang Shiying in but the Mylabris curing oncoma is proposed.Nineteen fifty-three at the U.S.'s synthetic cantharidin, China studies show that to this medicine it can have antitumor action, but urinary system and liver toxicity are big, can not be used for clinical.The eighties, synthetic norcantharidin such as Wang Guangsheng, toxicity reduces to some extent, the clinical auxiliary treatment that is used for tumors such as hepatocarcinoma, gastric cancer, colon cancer.But since less to its Study on mechanism, intellectual property protection also lacked, fail to become the main flow cancer therapy drug always.
The bright discovery cantharidin of Chinese scholar Li Yan residing in American was PP2A at intracellular action target spot in 1992.Cantharidin and homologue thereof act on this discovery of PP2A and have opened the gate of reappraising cantharidin effect and application.Because it is simple in structure, be easy to transform, Australian McCluskey and Sakoff etc. have begun the work of synthetic new cantharidin homologue.Its work concentrates on explores series compound to the inhibiting structure activity relationship of the PP2A of purification, find also that wherein part of compounds has inhibitory action to the growth of tumor cell, but present work is in the laboratory research still.
Summary of the invention
The objective of the invention is problem, provide a class cantharidin derivative preparing as the application in the antitumor drug at above-mentioned antitumor drug existence.This cantharidin derivative can suppress the growth of tumor cell and the activity of Profilin phosphatase 2A.
Research worker is through a large amount of scientific researches, confirmed that cantharidin derivative can suppress growth of tumour cell and Profilin phosphatase 2A activity, be used for suppressing growth of tumour cell and the active medicine of Profilin phosphatase 2A has very important application in preparation, the general structure of cantharidin derivative is shown in (I):
Wherein,
R
1Be H, R
2Be CH, X is O, and Y is O;
Or R
1Be H, R
2Be CH
2, X is O, Y is H
2
Or R
1Be CH
3, R
2Be CH
2, X is (OH)
2, Y is O;
Or R
1Be CH
3, R
2Be CH
2, X is S, Y is O.
Above-mentioned cantharidin analog is dehydronorcantharidiimide element, nor-deoxidation cantharidin, Cantharidic acid. or thia cantharidin.
Above-mentioned tumor cell behaviour oral squamous carcinoma cell, people's adenocarcinoma of stomach cell, hepatoma carcinoma cell, colon cancer cell, leukaemia or lung carcinoma cell.
The plain nor-deoxidation cantharidin Cantharidic acid. thia cantharidin of dehydronorcantharidiimide
Beneficial effect of the present invention: the present invention can suppress growth of tumour cell through a large amount of cantharidin derivatives that experimental studies have found that, and the activity of Profilin phosphatase 2A (PP2A).It has the potential that is developed at the cancer therapy drug of novel targets phosphoprotein phosphatase 2A, has important development prospect aspect the malignant tumor medicines such as preparation treatment human mouth cancer, gastric cancer, hepatocarcinoma, colon cancer, leukemia and pulmonary carcinoma.
Description of drawings
Fig. 1 is the influence figure of chemical compound thia cantharidin to the PP2A enzyme kinetics;
Fig. 2 is the influence figure of cantharidin to the PP2A enzyme kinetics.
The specific embodiment
Embodiment 1: dehydronorcantharidiimide element (ZWN-01) synthetic
In round-bottomed flask, add and make the dissolved absolute ether 20.0mL of 1.45g (15.0mmol) maleic anhydride just, add furan 8.10g (120.0mmol) again, sealing, room temperature was placed 2～3 hours, adularescent prism-shaped crystal is separated out, and continue to place about 15 hours, treat that white solid is no longer separated out till.Cross filtering liquid, dry under the room temperature after crystal washs 5～6 times with absolute ether, obtain the 2.32g white solid, productive rate 96.6%.Product through IR spectrum,
1H NMR spectrum, MS compose mensuration.Analysis result is as follows:
IR composes (KBr): 3144.8,3095.6,3065.6,3032.8,2296.9,1860.3,1788.9,1597.3,1568.8, and 1227.5cm
-1.
1H NMR composes (300MHz, d
6-Acetone), d:3.38 (s, 2H), 5.36 (s, 2H), 6.63 (s, 2H)
FAB-MS composes m/z:166 ([M]
+, 10%).
Embodiment 2: nor-deoxidation cantharidin (CH-06) synthetic
20.1mg under the ice bath (0.5mmol) NaBH
4Add among the 10.0mL THF.Stir.In the above-mentioned system during 80.2mg (0.5mmol) norcantharidin that is dissolved in 5.0mL dropwise stirs, remove ice bath after dropwising, stirred 10 minutes under the room temperature.Add the hydrochloric acid 2.0mL of 1N again, add water then, through absolute ether extraction, concentrate, column chromatography purification gets the 40.2mg white solid.Productive rate is 54.8%.Product through IR spectrum,
1H NMR spectrum, MS compose mensuration.
Analysis result is as follows:
IR composes (KBr): 3224.7,2989.7,2958.3,2920.5,2881.1,1763.5,1198.1, and 816cm
-1.
1H NMR composes (300MHz, CDCl
3), d:4.88 (d, J=4.5Hz 1H), 4.54 (d, J=4.8Hz 1H), 4.43 (dd, J=9.0,4.2Hz, 1H), 4.11 (dd, J=9.3,4.2Hz 1H), 2.81～2.69 (m, 2H), 1.88～1.72 (m, 2H), 1.62～1.47 (m, 2H).
FAB-MS composes m/z:154 ([M]
+, 100%)
Embodiment 3: Cantharidic acid. (LY-07) synthetic
In the 50mL round-bottomed flask, place cantharidin 196.2mg (1.0mmol), add distilled water 20.0mL, be heated to and refluxed 0.5 hour, filtration, washing, vacuum drying, column chromatography purification get the 172.4mg white solid.Productive rate is 80.5%.The product warp
1H NMR composes mensuration.Analysis result is as follows:
1H NMR composes (300MHz, CDCl
3), d:1.24 (s, 6H), 1.73～1.82 (m, 4H), 4.71 (t, J=2.4Hz, 2H).
Embodiment 4: thia cantharidin (LY-08) synthetic
Exsiccant cantharidin 196.2mg (1.0mmol) and Na
2S9H
2O 480.0mg (2.0mmol) at room temperature is woven in the mortar and grinds, and is absinthe-green dope up to mixture, and the gas that is attended by rotten-egg odour is simultaneously emitted.Carefully reactant mixture is added in the 10% ice-cold hydrochloric acid, through chloroform extraction, cold water washing, concentrated organic facies, column chromatography purification get the 76.4mg white solid.Productive rate is 36%.The product warp
1H NMR composes mensuration.Analysis result is as follows:
1H NMR composes (300MHz, CDCl
3), d:1.24 (s, 6H), 1.69～1.85 (m, 4H), 4.74 (t, J=2.4Hz, 2H)
Embodiment 5: the extracorporeal anti-tumor cell proliferation experiment of cantharidin derivative
Selected cell strain comprises: human oral cavity epithelial cancer KB-3-1, people's adenocarcinoma of stomach MGC803, hepatocarcinoma HepG2, colon cancer LoVo, leukemia HL-60 and pulmonary carcinoma Glc82 cell strain etc.The trophophase tumor cell of taking the logarithm is made certain density cell suspension inoculation in 96 orifice plates, and every hole adds certain density medicine to be measured, and control wells does not add medicine, and each concentration is established 4 parallel holes.Cultivate 68 hours adding MTT100ug/ holes, continue to cultivate 4 hours, discard culture fluid, add the 200ul dimethyl sulfoxide, shake 15 minutes fully after the dissolving, measure 570/630nm dual wavelength absorption photometric value, calculate drug level (IC when suppressing the growth of 50% cell with the Logit method with microplate reader
50).Experiment repeats 3 times, the results are shown in Table 1.The dehydronorcantharidiimide element is to stomach cancer cell, and the growth of leukaemia and lung carcinoma cell has inhibitory action; Nor-deoxidation cantharidin oral cavity squamous cell carcinoma cell has inhibitory action; Cantharidic acid. and thia cantharidin oral cavity squamous cell carcinoma, gastric cancer, hepatocarcinoma, colon cancer, the growth of leukemia and lung carcinoma cell all has inhibitory action, IC
50Value is similar with the positive control cantharidin.
Table 1 is the extracorporeal anti-tumor cells growth activity (IC of cantharidin derivative
50, μ M)
Sample KB-3-1 MGC803 HepG2 LoVo HL-60 Glc82
Cantharidin
* 2.7 5.4±0.4 19.1 - 2.7 1.2
Norcantharidin
* 69.5±8.5 161.9±56.9 212.9±26.2?- 15.7 5.3
Dehydronorcantharidiimide element-53.4 ± 10.8--159.3 17.5
Nor-deoxidation cantharidin 112.0 ± 5.5＞200＞200＞200＞200＞200
Cantharidic acid. 0.8 ± 0.2 2.2 ± 0.7 3.0 ± 2.2 14.7 0.8 1.6
Thia cantharidin 1.8 ± 0.2 1.3 ± 0.1 14.7 ± 7.0 98.3 1.1 2.0
*Cantharidin (Cantharidin), the positive contrast of norcantharidin (Norcanthafidin)
Embodiment 6: the pure PP2A enzymatic activity experiment of the vitro inhibition of cantharidin derivative
Vitro inhibition PP2A enzyme assay (malachite green oxalate method): every hole 5 μ l protein phosphatase zymolytes are added to 96 half orifice plates (substrate final concentration 250 μ M), add 3 μ l (i.e. 0.03 unit) the pure product of PP2A (or PP1) again, every then hole adds the candidate compound 10 μ l of variable concentrations, last arranges not dosing, add equal-volume and removed the phosphate radical pure water as blank, hatch 30min for 37 ℃, every hole adds AB mixed liquor 80 μ l colour developing 10min, measures OD
630nmWith the half-inhibition concentration IC of Logit method computerized compound to PP2A
50The results are shown in Table 2.Nor-deoxidation cantharidin has certain inhibitory action to PP2A; Cantharidic acid. is better than PP1 to the inhibition of PP2A, IC
50Value is very approaching with cantharidin; The thia cantharidin has stronger inhibitory action to PP2A and PP1.
Table 2 is the activity inhibition experiment (IC of part cantharidin derivative to PP2A and PP1
50, μ M)
Sample P P2A PP1
Cantharidin
* 0.28 1.98
Norcantharidin
* 0.56 1.89
Nor-deoxidation cantharidin 61.85 N-
Cantharidic acid. 0.31 1.87
Thia cantharidin 2.85 3.05
*Cantharidin, norcantharidin is as the positive control of PP2A inhibitor
Embodiment 7: cantharidin derivative is to PP2A enzyme kinetics influence experiment
Utilizing Malachite Green method to measure in the experiment of PP2A enzymatic activity, set 4 groups for thia cantharidin (LY-8), final concentration is respectively 2.5uM, 1.25uM, 0.625uM, 0uM; Positive control cantharidin final concentration is 0.25uM, 0.125uM, 0.0625uM, 0uM.Substrate pentapeptide (Lys-Arg-pThr-Ile-Arg) final concentration in every group of inherent every reacting hole is 100,150,225,325,450uM.The PP2A in every hole is 0.03U.Total reaction volume is the 20ul/ hole, places 37 ℃, adds Malachite Green reagent (80ul/ hole) colour developing 10min behind the reaction 1hr, and independent experiment repeats 4 times.The OD value that records is converted into response speed, draws the suppressor mode of sample the PP2A enzyme according to the double-reciprocal plot method of rice-Man equation.Independent experiment repeats 4 times, the results are shown in Figure 1 and Fig. 2.As seen from the figure, thia cantharidin and cantharidin all belong to the noncompetitive suppressor mode to the inhibition of PP2A.
In sum, above-mentioned cantharidin analog has potentiality and the prospect that develops into antitumor drug.
Claims (3)
1, cantharidin derivative is used for suppressing the application of growth of tumour cell or the active medicine of Profilin phosphatase 2A in preparation, and the general structure of described cantharidin derivative is shown in (I):
Wherein,
R
1Be H, R
2Be CH, X is O, and Y is O;
Or R
1Be H, R
2Be CH
2, X is O, Y is H
2
Or R
1Be CH
3, R
2Be CH
2, X is (OH)
2, Y is O;
Or R
1Be CH
3, R
2Be CH
2, X is S, Y is O.
2, application as claimed in claim 1 is characterized in that described cantharidin derivative is dehydronorcantharidiimide element, nor-deoxidation cantharidin, Cantharidic acid. or thia cantharidin.
3, application as claimed in claim 1 or 2 is characterized in that described tumor cell behaviour oral squamous carcinoma cell, people's adenocarcinoma of stomach cell, hepatoma carcinoma cell, colon cancer cell, leukaemia or lung carcinoma cell.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510033897 CN1686109A (en) | 2005-04-01 | 2005-04-01 | Application of cantharidin derivative as anti-tumour medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510033897 CN1686109A (en) | 2005-04-01 | 2005-04-01 | Application of cantharidin derivative as anti-tumour medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1686109A true CN1686109A (en) | 2005-10-26 |
Family
ID=35304150
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510033897 Pending CN1686109A (en) | 2005-04-01 | 2005-04-01 | Application of cantharidin derivative as anti-tumour medicine |
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| Country | Link |
|---|---|
| CN (1) | CN1686109A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101073564B (en) * | 2006-05-19 | 2010-10-13 | 山东轩竹医药科技有限公司 | Medicinal composition containing L-glutamine |
| CN102796794A (en) * | 2012-08-31 | 2012-11-28 | 哈尔滨工业大学 | Preparation method of cantharis toxin |
-
2005
- 2005-04-01 CN CN 200510033897 patent/CN1686109A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101073564B (en) * | 2006-05-19 | 2010-10-13 | 山东轩竹医药科技有限公司 | Medicinal composition containing L-glutamine |
| CN102796794A (en) * | 2012-08-31 | 2012-11-28 | 哈尔滨工业大学 | Preparation method of cantharis toxin |
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