CN1686102A - Application of cantharidin derivative in preparation of antitumour medicine - Google Patents
Application of cantharidin derivative in preparation of antitumour medicine Download PDFInfo
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- CN1686102A CN1686102A CN 200510034017 CN200510034017A CN1686102A CN 1686102 A CN1686102 A CN 1686102A CN 200510034017 CN200510034017 CN 200510034017 CN 200510034017 A CN200510034017 A CN 200510034017A CN 1686102 A CN1686102 A CN 1686102A
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Abstract
An application of the cantharidin derivative (C11H16O5 or C10H16O4) which can suppress the growth of tumor cells and the activity of proteophosphotase 2A (PP2A) in preparing antineoplastic medicines is disclosed.
Description
Affiliated technical field
The present invention relates to the cantharidin derivative field, the particularly application of cantharidin derivative in the preparation antitumor drug.
Background technology
(cantharidin is extensively to be present in more than the 1500 kind of intravital a kind of natural defensive toxin of Mylabris CA) to cantharidin.Mylabris Meloidae insecticide, acrid in the mouth cold in nature for hypertoxic Chinese crude drug, except that having active anticancer, still has various active such as antiviral, tonifying YANG, leukocyte increasing.China is the country of being familiar with the Mylabris medical value in the world the earliest, is documented with regard to its form, habit and usage in Compendium of Material Medica.1810, French medicine scholar Robiquet extracted the cantharidin crude extract first from the Mylabris kind.1914, Gadamer confirmed the chemical constitution of cantharidin.Nineteen fifty-three, Gilbert stork has synthesized cantharidin at laboratory first, but because the harsh conditions of 16kbar pressure, and does not have medical value, so far mass production not as yet.
Cantharidin itself is a kind of half obedient alkene toxin, and its toxicity is strong.For oral administration can cause gastrointestinal inflammation, mucosal necrosis, can make glomerular epithelium cell major injury, occur albuminuria, cylinderuria, hematuria, and serum albumin nitrogen raise.The clinical consumption that cantharidin is used for the treatment of hepatocarcinoma is 0.5mg/day, and its LD
50Be 30mg/kg, toxic dose is about 1.0g, and lethal dose is about 3.0g, and inappropriate medication easily makes the people poison even be dead, fails clinical use so far.
Thereby the more synthetic selectivitys of design suppress tumor cell, and the cantharidin derivative little to body toxicity is significant.The eighties, synthetic norcantharidin such as Wang Guangsheng and N-hydroxycantharidin, N-methylcantharidimide and disodium cantharidinate, wherein norcantharidin toxicity reduces to some extent, the clinical auxiliary treatment that is used for tumors such as hepatocarcinoma, gastric cancer, colon cancer.But because less to its Study on mechanism, fail becomes the main flow cancer therapy drug always, and the inscience property right.Bright discovery cantharidin of Chinese scholar Li Yan residing in American in 1992 and homologue thereof are PP2A at intracellular action target spot.The gate of reappraising cantharidin effect and application has been opened in this discovery.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 to be explored in the discussion of series compound to the inhibiting structure activity relationship of PP2A of purification.
Summary of the invention
The object of the present invention is to provide the application of cantharidin derivative in the preparation antitumor drug.
The object of the present invention is achieved like this: the cantharidin derivative shown in the following structural formula CH-03: (2S, 3R)-3-(carboxymethyl)-2,3-dimethyl-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid, the application in the preparation antitumor drug.
The object of the present invention is achieved like this: the cantharidin derivative shown in the following structural formula LY-09: (2S, 3R)-3-(methylol)-2,3-dimethyl-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid, the application in the preparation antitumor drug.
External pharmacological evaluation shows that Compound C H-03 and LY-09 comprise human oral cavity epithelial cancer KB-3-1 to kinds of tumor cells, people's adenocarcinoma of stomach MGC803, and hepatocarcinoma HepG2, leukemia HL-60 and pulmonary carcinoma Glc82 cell strain etc. have certain growth inhibited effect.Simultaneously, the active experimental result of phosphoprotein phosphatase 2A is shown that Compound C H-03 and LY-09 have obvious inhibitory action to the PP2A enzymatic activity.Therefore, above-claimed cpd can be used for antitumor drug.
The specific embodiment
The invention provides 3 novel cantharidin derivatives, wherein 2 chemical compounds have inhibitory action to growth and the PP2A enzymatic activity of malignant cell.
Compound C H-02 provided by the present invention, Chinese be (2S, 3R)-3-(cyano methyl)-2,3-dimethyl-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid; English name be (2S, 3R)-3-(cyanomethyl)-2,3-dimethyl-7-oxa-bicyclo[2.2.1] heptane-2-carboxylic acid; Molecular formula C
11H
15NO
3Molecular weight is 209.24; Fusing point is 148.1～151.7 ℃; White solid.Structural formula is as follows:
The synthetic route of CH-02 is:
The processing step of its synthetic method is:
Compound C H-01 is dissolved among the DMSO of new steaming, and evenly mixed with KCN, and the mol ratio of Compound C H-01 and KCN is 1.0: 1.0～3.0.Reflux is 4～8 hours under constantly stirring.Reaction system is cooled to room temperature, with an amount of 20%H
2SO
4Be acidified to pH=3, use ethyl acetate extraction then, extract is through saturated common salt water washing, MgSO
4Dry, concentrated, column chromatography purification gets Compound C H-02.
Compound C H-03 provided by the present invention, Chinese be (2S, 3R)-3-(carboxymethyl)-2,3-dimethyl-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid; English name be (2S, 3R)-3-(carboxymethyl)-2,3-dimethyl-7-oxa-bicyclo[2.2.1] heptane-2-carboxylic acid; Molecule is C
11H
16O
5Molecular weight is 228.24; Fusing point is 232.2～232.3 ℃; White solid.Structure is as follows:
The synthetic route of CH-03 is:
The processing step of its synthetic method is:
Under the room temperature, Compound C H-02 is dissolved in the excessive concentrated hydrochloric acid, slowly is warming up to backflow, reacted 5～8 hours, the adularescent solid is separated out gradually in the system, and reactant mixture is filtered.Solid is through washing, vacuum drying; Filtrate is used ethyl acetate extraction, the concentrated white solid that also gets.Twice gained solid merging got Compound C H-03 through column chromatography purification.
Compound L Y-09 provided by the present invention, Chinese is: (2S, 3R)-3-(methylol)-2,3-dimethyl-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid; English name be (2S, 3R)-3-(hydroxymethyl)-2,3-dimethyl-7-oxa-bicyclo[2.2.1] heptane-2-carboxylic acid; Molecular formula is C
10H
16O
4Molecular weight is 200.23; White or faint yellow solid.Its structural formula is:
The synthetic route of LY-09 is:
The processing step of its synthetic method is:
Under the room temperature, Compound C H-01 and excessive 20%NaOH is mixed, slowly be heated to backflow, reacted 6～8 hours.Through chloroform extraction, concentrate, column chromatography purification gets compound L Y-09.
External pharmacological evaluation shows that Compound C H-03 and LY-09 comprise human oral cavity epithelial cancer KB-3-1 to kinds of tumor cells, people's adenocarcinoma of stomach MGC803, hepatocarcinoma HepG2, leukemia HL-60 and pulmonary carcinoma Glc82 cell strain etc. have the long inhibitory action (the results are shown in Table 1) of certain dirt.Simultaneously, the active experimental result of phosphoprotein phosphatase 2A is shown that Compound C H-03 and LY-09 have obvious inhibitory action to the PP2A enzymatic activity.(the results are shown in Table 2).Therefore, above-claimed cpd can be used for antitumor drug.
Table 1 extracorporeal suppression tumor cell growth activity experiment (IC
50, μ M)
| Sample | ??KB-3-1 | ????MGC803 | ????HepG2 | ????HL-60 | ??Glc82 |
| ??Cantharidin *??Norcantharidin *??CH-03 ??LY-09 | ??2.7 ??69.5±8.5 ??56.2 ??79.2 | ????5.4±0.4 ????161.9±56.9 ????94.9 ????123.6 | ????19.1 ????212.9±26.2 ????155.8 ????218.5 | ????2.7 ????15.7 ????＞200 ????103.2 | ??1.2 ??5.3 ??＞200 ??92.1 |
*Cantharidin, the positive contrast of norcantharidin, IC
50It is 50% inhibition concentration
Table 2 PP2A and PP1 enzymatic activity suppress experiment (IC
50, μ M)
| Sample | ????PP2A | ????PP1 |
| ????Cantharidin *????Norcantharidin *????CH-03 ????LY-09 | ????0.28 ????0.56 ????29.91 ????23.44 | ????1.98 ????1.89 ????- ????39.43 |
*Cantharidin, norcantharidin is as the positive control (with bibliographical information value basically identical, list of references J.A.Sakoff, et al.Investigational New Drugs 20:1-11,2002) of PP2A inhibitor
Embodiment 1
Compound C H-02 and synthetic
CH-01 91.0mg (5.0mmol) is dissolved in the DMSO (10.0mL) of new steaming and mixed evenly with KCN 97.5mg (15.0mmol), under continuous condition of stirring in oil bath reflux 5 hours.Reaction system is at room temperature cooled off, and adds 20%H
2SO
4Be acidified to pH=3, use ethyl acetate extraction then, organic facies is through saturated common salt water washing, MgSO
4Dry, concentrated, column chromatography purification obtains the 30.9mg white solid.Productive rate is 29.6%.Product through elementary analysis, IR spectrum,
1H NMR spectrum, MS compose mensuration.Analysis result is as follows:
Elementary analysis (value of calculation/measured value) is (%): C63.14/63.05, H7.23/7.48, N6.69/6.58;
IR composes (KBr): 2982.4,2235.7,1709.9,1689.2,1481.1,1446.1,1266.6,1164.3,1126.2,1006.9,932.4,879.1,817.3,588.4, and 469.2cm
-1
1H NMR composes (300MHz, CDCl
3), δ: 1.24 (s, 3H), 1.25 (s, 3H), 1.53～1.76 (m, 2H), 1.77～1.85 (m, 2H), 2.54 (d, J=15.9Hz, 1H), 2.71 (d, J=15.0Hz, 1H), 4.41 (d, J=4.8Hz, 1H), 4.91 (d, J=4.5Hz, 1H);
FAB-MS composes m/z:210 ([M+H]
+, 30%).
Embodiment 2
Compound C H-03 and synthetic
In the round-bottomed flask of 25mL, place CH-02 209.2mg (1.0mmol), add concentrated hydrochloric acid 10.0mL under the room temperature and make it dissolving, oil bath slowly heats up, back flow reaction 8 hours, the adularescent solid is separated out gradually in the system, and reactant mixture is filtered.Solid is through washing, vacuum drying; Filtrate is used ethyl acetate extraction, the concentrated white solid that also gets.Twice gained solid merging got the 134.0mg white solid through column chromatography purification.Productive rate is 58.7%.Product through IR spectrum,
1H NMR spectrum, MS compose mensuration.Analysis result is as follows:
IR composes (KBr): 3065.9,2975.6,1754.9,1722.6,1348.6,1279.1,1200.5,1160.6,1085.8,992.3,928.5,853.8,742.1,653.8,552.4 cm
-1
1H NMR composes (300MHz, d
6-Acetone), δ: 1.19 (s, 3H), 1.41 (s, 3H), 1.95 (d, J=16.8Hz, 1H), 1.62～2.31 (m, 4H), 3.27 (d, J=16.8Hz, 1H), 4.39 (dd, J=10.5,6.9 Hz, 1H), 4.94 (dd, J=11.7,4.8Hz, 1H);
MS (ESI) composes m/z:227.3 ([M-H]
+, 100), 228.3 (M
+, 11%).
Embodiment 3
Compound L Y-09 and synthetic
In the 25mL round-bottomed flask, place Compound C H-01 54.6mg (0.3mmol) and 20%NaOH 10mL, slowly be heated to backflow.Reacted 8 hours.Through chloroform extraction, concentrate, column chromatography purification gets the 34.6mg white solid.Productive rate is 57.7%.The product warp
1H NMR spectrum, MS compose mensuration.Analysis result is as follows:
1H NMR composes (300MHz, CDCl
3), δ: 1.08 (s, 3H), 1.14 (s, 3H), 1.58～1.85 (m, 4H), 3.96 (d, J=8.7Hz, 1H), 4.22 (d, J=8.7Hz, 1H), 4.28 (d, J=5.4Hz, 1H), 3.95 (d, J=4.5Hz, 1H);
MS (ESI) composes m/z:199.3 ([M-H]
+, 100), 200.3 (M
+, 16%).
Embodiment 4
Invent the experiment in vitro of described chemical compound
(1) chemical compound extracorporeal anti-tumor cell proliferation experiment
Selected cell strain comprises: human oral cavity epithelial cancer KB-3-1, people's adenocarcinoma of stomach MGC803, hepatocarcinoma HepG2, 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.
(2) the pure PP2A enzymatic activity experiment of chemical compound vitro inhibition
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.
Claims (2)
1. the cantharidin derivative shown in the following structural formula CH-03: (2S, 3R)-3-(carboxymethyl)-2,3-dimethyl-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid, the application in the preparation antitumor drug.
2. the cantharidin derivative shown in the following structural formula LY-09: (2S, 3R)-3-(methylol)-2,3-dimethyl-7-oxabicyclo [2.2.1] heptane-2-carboxylic acid, the application in the preparation antitumor drug.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552274A (en) * | 2010-11-12 | 2012-07-11 | 姚雪彪 | Application of moving point motor protein small molecular inhibitor to inhibition of tumor cell proliferation |
| CN102775429A (en) * | 2012-08-10 | 2012-11-14 | 山东轻工业学院 | Preparation and application of unsaturation demethylation cantharides acid silver polymer |
| CN104447782A (en) * | 2014-12-30 | 2015-03-25 | 贵州柏强制药有限公司 | Bromo-norcantharidin acid-benzyl ester, and synthetic method and application thereof |
| CN104478892A (en) * | 2014-12-30 | 2015-04-01 | 贵州柏强制药有限公司 | Bromo-norcantharidin ethyl gallate as well as preparation method and application thereof |
| CN104530072A (en) * | 2014-12-30 | 2015-04-22 | 贵州柏强制药有限公司 | Bromo-norcantharidin mono-methyl ester, as well as synthesizing method and application thereof |
| CN102775429B (en) * | 2012-08-10 | 2016-11-30 | 齐鲁工业大学 | Unsaturated demethyl Cantharidic acid. silver joins preparation and the purposes of polymers |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1385154A (en) * | 2001-05-15 | 2002-12-18 | 中国人民解放军第二军医大学 | Slow-releasing injection type demehylcantharidin for antitumor |
-
2005
- 2005-04-08 CN CNB200510034017XA patent/CN100391451C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552274A (en) * | 2010-11-12 | 2012-07-11 | 姚雪彪 | Application of moving point motor protein small molecular inhibitor to inhibition of tumor cell proliferation |
| CN102552274B (en) * | 2010-11-12 | 2013-10-23 | 姚雪彪 | Application of moving point motor protein small molecular inhibitor to inhibition of tumor cell proliferation |
| CN102775429A (en) * | 2012-08-10 | 2012-11-14 | 山东轻工业学院 | Preparation and application of unsaturation demethylation cantharides acid silver polymer |
| CN102775429B (en) * | 2012-08-10 | 2016-11-30 | 齐鲁工业大学 | Unsaturated demethyl Cantharidic acid. silver joins preparation and the purposes of polymers |
| CN104447782A (en) * | 2014-12-30 | 2015-03-25 | 贵州柏强制药有限公司 | Bromo-norcantharidin acid-benzyl ester, and synthetic method and application thereof |
| CN104478892A (en) * | 2014-12-30 | 2015-04-01 | 贵州柏强制药有限公司 | Bromo-norcantharidin ethyl gallate as well as preparation method and application thereof |
| CN104530072A (en) * | 2014-12-30 | 2015-04-22 | 贵州柏强制药有限公司 | Bromo-norcantharidin mono-methyl ester, as well as synthesizing method and application thereof |
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|---|---|
| CN100391451C (en) | 2008-06-04 |
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