CN101502506B - Medical use of 3-(3,4-dihydroxyphenyl)-acrylic acid 2-(3,4-dihydroxyphenyl)-ethyl ester - Google Patents
Medical use of 3-(3,4-dihydroxyphenyl)-acrylic acid 2-(3,4-dihydroxyphenyl)-ethyl ester Download PDFInfo
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- CN101502506B CN101502506B CN200910114960XA CN200910114960A CN101502506B CN 101502506 B CN101502506 B CN 101502506B CN 200910114960X A CN200910114960X A CN 200910114960XA CN 200910114960 A CN200910114960 A CN 200910114960A CN 101502506 B CN101502506 B CN 101502506B
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- ethyl ester
- dihydroxy benzenes
- caffeic acid
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Abstract
The invention discloses the application of caffeic acid 3,4-dihydroxy-phenethyl ester, prodrug or pharmaceutically acceptable salts thereof in the preparation of anti-tumor medicaments, the tumor is selected from digestive system tumors, lung cancer, mammary cancer, ovarian cancer, prostatic cancer, central nervous system tumors, melanoma or leukemia, wherein, the digestive system tumor particularly represents gastric cancer, colon cancer, liver cancer or pancreatic cancer tumors.
Description
Technical field
The invention belongs to pharmaceutical field, relate to caffeic acid 3, the medical usage of 4-dihydroxy benzenes ethyl ester, particularly caffeic acid 3, the application of 4-dihydroxy benzenes ethyl ester in the preparation antitumor drug.
Background technology
Phytochemistry, 2000; 55:927-931 obtains noval chemical compound caffeic acid 3 open first the separation from plant, 4-dihydroxy benzenes ethyl ester and chemical constitution thereof, but do not disclose its biological activity.
Chinese patent application (publication number CN 1879672A) discloses caffeic acid 3, anti-mice S in 4-dihydroxy benzenes ethyl ester vitro inhibition human colon cancer cell (HCT-8), gastric carcinoma cells (BGC-823), Proliferation of Human Ovarian Cell (A-2780) growth and the body
180Effect.But the tumor kind and the tumor line that disclose are comprehensive inadequately, for better predicting the clinical antitumor action of this chemical compound, be necessary further to disclose its activity, thereby further disclose caffeic acid 3,4-dihydroxy benzenes ethyl ester antineoplastic medical usage other tumor kind and more tumor strain.
Summary of the invention
The technical problem to be solved in the present invention provides caffeic acid 3, the application of 4-dihydroxy benzenes ethyl ester in the preparation antitumor drug, and a kind of caffeic acid 3 that contains, the antineoplastic pharmaceutical compositions of 4-dihydroxy benzenes ethyl ester.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
A kind of antineoplastic pharmaceutical compositions, comprise the caffeic acid 3 for the treatment of effective dose, 4-dihydroxy benzenes ethyl ester, its prodrug or acceptable salt pharmaceutically, and pharmaceutically acceptable excipient or carrier is characterized in that described tumor is selected from digestive system tumor, pulmonary carcinoma, breast carcinoma, ovarian cancer, carcinoma of prostate, central nerve neuroma, melanoma or leukemia; Described digestive system tumor is selected from gastric cancer, colon cancer, hepatocarcinoma or cancer of pancreas.
Treatment effective dose defined herein is meant and can produces function or active and can be by the amount of people and/or animals received to people and/or animal.Pharmaceutically acceptable excipient or carrier defined herein are meant the excipient or the carrier that are used for the treatment of administration, and they itself are not necessary active component, and do not have undue toxicity after using.The caffeic acid 3 of treatment effective dose, 4-dihydroxy benzenes ethyl ester, its prodrug or pharmaceutically the consumption of acceptable salt is between the 0.001-500mg/kg body weight/day, any consumption in above-mentioned scope is all effective dose of the present invention.Preferably, the consumption of chemical compound of the present invention is between the 0.05-300mg/kg body weight/day; Preferred, the consumption of chemical compound of the present invention is between the 0.01-100mg/kg body weight/day.Described " caffeic acid 3 of treatment effective dose, 4-dihydroxy benzenes ethyl ester, its prodrug or acceptable salt pharmaceutically " can be used for the single drug or the drug combination treatment of tumor.It will be appreciated by those skilled in the art that the consumption when actual administration can be higher than or be lower than above-mentioned dosage range.Can be subjected to all multifactor influences at " the treatment effective dose " of a certain object (as mammal or people) and concrete therapeutic scheme, the judgement etc. that comprises age, body weight, ordinary circumstance, sex, diet, administration time, the disease process of administration object and accept the doctor for medical treatment.
Pharmaceutical composition of the present invention can be dosage form for example tablet or the capsule that is fit to oral administration, also can be for example to be used for parenteral injection (comprising in intravenous, subcutaneous, intramuscular, the blood vessel or infusion) with sterile solution, suspension or emulsion, also can be for example to be used for topical with ointment or emulsifiable paste, also can be for example with the suppository rectally, can also be to advance in the tumor or through the administration of location input by direct injection.Pharmaceutical composition of the present invention can also be in endoscope, trachea, damage location, percutaneous, intravenous, subcutaneous or intraperitoneal infusion.Common pharmaceutical composition of the present invention can use conventional excipients known in the art or preparing carriers with conventional method.
Pharmaceutically acceptable solid excipient or carrier comprise: starch, corn starch, lactose, sucrose, sodium carbonate, calcium phosphate, phosphoric acid glycol, calcium carbonate, alginic acid, microcrystalline Cellulose, gelatin; Pharmaceutically the acceptable liquid-carrier for example comprises sterilized water, Polyethylene Glycol, non-ionic surface active agent (as hydroxypropyl cellulose) and oil for example Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum sesami, olive oil or liquid paraffin; As long as be fit to the characteristic and the needed specific administration mode of active component.Normally used adjuvant also can be comprised in the described pharmaceutical composition of preparation, for example for example vitamin E, vitamin C, BHT and BHA of flavoring agent, pigment, antiseptic (as ethyl or propyl group-hydroxybenzoate) and antioxidant.
Tablet not coating or coating with the disintegrate that changes them and subsequently active component in gastrointestinal tract absorption or strengthen their stability and/or outward appearance, under described back two kinds of situations, can use conventional coating materials known in the art and method.
Be used for the form that oral pharmaceutical composition can also be a hard capsule, for example calcium carbonate, calcium phosphate, microcrystalline cellulose or Kaolin of active component and inert solid excipient wherein, or the form of soft capsule, wherein for example Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum sesami, olive oil or liquid paraffin mix for active component and water or oil.The pharmaceutical compositions that is suitable for injecting comprises aseptic aqueous solution, dispersion liquid or aseptic powder (being used for preparing aseptic parenteral solution or dispersion liquid) temporarily.In all cases, these forms must be aseptic and must be that fluid is easy to discharge from syringe.Under preparation and condition of storage must be stable, and must be able to prevent pollution and the influence of microorganism such as antibacterial and fungus.Carrier can be solvent or disperse medium, for example water, alcohol, their suitable mixture and vegetable oil.
Chinese patent application (publication number CN 1879672A) discloses mtt assay and has measured caffeic acid 3,4-dihydroxy benzenes ethyl ester (CADPE) is to human colon cancer cell (HCT-8), gastric carcinoma cells (BGC-823), the effect of Proliferation of Human Ovarian Cell (A-2780) growth inhibited, the result proves caffeic acid 3, and 4-dihydroxy benzenes ethyl ester can significantly suppress the growth of above-mentioned three kinds of tumor cells.To S
180The ascitic type mice with tumor, caffeic acid 3,4-dihydroxy benzenes ethyl ester has obvious antineoplastic, and tumour inhibiting rate is between 30% and 85%.Above-mentioned experiment in vitro and mouse tumor model result of experiment can only be pointed out caffeic acid 3, and 4-dihydroxy benzenes ethyl ester has the prospect that is developed to antitumor drug.But, people's tumor invasion mechanism is very complicated, there is greatest differences between people and Mus species, caffeic acid 3,4-dihydroxy benzenes ethyl ester to other tumor cell whether inhibitory action is arranged, whether it have activity, its antineoplastic selectivity of anti-people's tumor in the body, these problems can't predict that all a large amount of creationary experiments of needs prove one by one and answer by the disclosed content of above-mentioned patent application (publication number CN 1879672A).
The cell in vitro screening platform (IVCLSP) that chemical compound of the present invention is set up through research and development in 5 years at national cancer institute (NCI) is gone up comprising that 60 kinds of tumor strains of 9 kinds of people's tumors such as leukemia, melanotic tumor, pulmonary carcinoma, colon cancer, renal carcinoma, ovarian cancer, breast carcinoma, cerebroma and carcinoma of prostate carry out screening active ingredients, the result proves caffeic acid 3,4-dihydroxy benzenes ethyl ester all has significant growth inhibited effect, IC to the tumor strain of all tests
50Concentration is 10
-5-10
-7Between the M, the IC of most tumor strains
50Concentration is 10
-6-10
-7M proves caffeic acid 3, and 4-dihydroxy benzenes ethyl ester has comparison broad-spectrum antitumor action.And experiment in vitro shows that also this chemical compound does not have toxicity to normal cell.
The present invention utilizes tumor cell in vitro to cultivate and human tumor bare mouse different species transplantation model proof caffeic acid 3,4-dihydroxy benzenes ethyl ester body is interior to human digestive system's malignant tumor, pasting is not the inhibitory action that gastric cancer, colon cancer, hepatocarcinoma have highly significant, is better than the chemotherapeutics cisplatin.
The present invention proves caffeic acid 3 with a large amount of creationary experiments and competent experimental data, 4-dihydroxy benzenes ethyl ester all has inhibitory action to the tumor of being screened, and the alimentary system malignant tumour high to Chinese's sickness rate, as gastric cancer, colon cancer certain anti-tumor in vivo effect is arranged.Contain caffeic acid 3,4-dihydroxy benzenes ethyl ester or its prodrug, pharmaceutically the antineoplastic pharmaceutical compositions of acceptable salt is very likely brought into play the positive therapeutic effect separately or with other cancer therapy drugs clinically.
Description of drawings
Fig. 1 is a caffeic acid 3, the chemosynthesis flow chart of 4-dihydroxy benzenes ethyl ester;
Fig. 2 is a caffeic acid 3, the hydrogen spectrogram of 4-dihydroxy benzenes ethyl ester;
Fig. 3 is a caffeic acid 3, the carbon spectrogram of 4-dihydroxy benzenes ethyl ester;
Fig. 4 is a caffeic acid 3, the structural representation of 4-dihydroxy benzenes ethyl ester;
Fig. 5 is a caffeic acid 3, the high-efficient liquid phase chromatogram of 4-dihydroxy benzenes ethyl ester;
Fig. 6 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the inhibitory action of the cell growth of 57 tumor strains of 9 kinds of people's tumors;
Fig. 7 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of people's gastric cancer HGC27, living cells (green)/dead cell (redness);
Fig. 8 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of people's gastric cancer AGS, living cells (green)/dead cell (redness);
Fig. 9 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of people's Gastric Cancer MGC 803;
Figure 10 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of people's gastric cancer SGC-7901;
Figure 11 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of people's gastric cancer BGC-823;
Figure 12 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of people's hepatocarcinoma QGY7701;
Figure 13 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of people's hepatocarcinoma SMMC7721, living cells (green)/dead cell (redness);
Figure 14 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of people's hepatocarcinoma Bel-7402, living cells (green)/dead cell (redness);
Figure 15 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of people's hepatocarcinoma HepG2, living cells (green)/dead cell (redness);
Figure 16 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of human colon carcinoma HCT116, living cells (green)/dead cell (redness);
Figure 17 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is to the toxicity of human colon carcinoma SW-620, living cells (green)/dead cell (redness);
Figure 18 is a caffeic acid 3, and 4-dihydroxy benzenes ethyl ester is in the inhibitory action of human tumor bare mouse different species model to the colon cancer growth;
Figure 19 is a caffeic acid 3, the inhibitory action that 4-dihydroxy benzenes ethyl ester (CADPE) transmitted the human liver cancer cell cycle
Below in conjunction with accompanying drawing the present invention is described in further detail.Should be understood to, these embodiment only are used to the present invention is described and are not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, the perhaps condition that provides or advise according to manufacturer.Removing other has definition or explanation, the same meaning that employed all specialties of this paper and scientific terminology and those skilled in the art are familiar with.Any in addition method similar or impartial to described content and material all can be used among the present invention.
Embodiment 1 caffeic acid 3,4-dihydroxy benzenes ethyl ester synthetic
1, reagent: 3,4-dihydroxyphenyl acetic acid, caffeic acid, thionyl chloride (SOCl
2), tetrahydrochysene calorize lithium (LiAlH
4), dicyclohexylcarbodiimide (DCC), absolute methanol, anhydrous tetrahydro furan (THF), tartaric acid, anhydrous sodium sulfate.
2, caffeic acid 3, the chemosynthesis flow process of 4-dihydroxy benzenes ethyl ester: with reference to accompanying drawing 1.
3, method:
Synthesizing of (1) 3,4-dihydroxyphenyl ethanol: with 3, the 4-dihydroxyphenyl acetic acid is dissolved in the absolute methanol, after dropwise adding thionyl chloride under 0 ℃ of condition and stirring 15 minutes, places under room temperature and does not stop in 16 hours to stir.Reactant is behind concentrating under reduced pressure, and its residue is dissolved in the anhydrous tetrahydro furan, after substep adds tetrahydrochysene calorize lithium, places under room temperature and does not stop in 16 hours to stir.Reactant is poured in 5% tartaric acid solution, uses ethyl acetate extraction.Acetic acid ethyl acetate extract after the merging reclaims ethyl acetate and obtains acetic acid ethyl ester extract behind anhydrous sodium sulfate dehydration.Acetic acid ethyl ester extract is through silica gel column chromatography, mixed solution with cyclohexane extraction and ethyl acetate is made eluent, the Fractional Collections eluent, under uviol lamp, detect each stream part with thin layer chromatography (TLC), to contain 3, the eluent of 4-dihydroxyphenyl ethanol merges back recovery organic solvent and obtains 3, the 4-dihydroxyphenyl ethanol.
(2) caffeic acid 3,4-dihydroxy benzenes ethyl ester synthetic: with caffeic acid and 3, the 4-dihydroxyphenyl ethanol is dissolved in the anhydrous tetrahydro furan, adds dicyclohexylcarbodiimide then.Its mixture at room temperature stirred 8 hours, added microdistillation water and continued to stir 15 minutes.Filter, filtrate gets brown thick shape solution at 60 ℃ of following concentrating under reduced pressure.This brown thick shape solution is through silica gel column chromatography, make eluent with ethyl acetate and alcoholic acid mixed solution, the Fractional Collections eluent, under uviol lamp, detect each stream part with TLC, to contain caffeic acid 3, each stream of 4-dihydroxy benzenes ethyl ester part merging back is reclaimed organic solvent and is got chemical compound caffeic acid 3,4-dihydroxy benzenes ethyl ester.
Synthetic caffeic acid 3,4-dihydroxy benzenes ethyl ester is an amorphous powder, is dissolved in methanol and the ethanol ferric chloride reaction positive; Apparent blue-fluorescence under the uviol lamp.
UV (MeOH, λ max) 212,223,251 (acromions), 293,326nm;
IR(KBr，cm-1)3429，1693，1606，1524，1448，1384，1263，1162，1116，1056；
HRESIMS：m/z?339.08408[M+Na]
+(calcd?for?C
17H
16NaO
6，339.08446)。
1H (accompanying drawing 2) and
13C-NMR (accompanying drawing 3): data see Table 1.
Table 1, caffeic acid 3, the hydrogen of 4-dihydroxy benzenes ethyl ester and carbon spectrum data (δ ppm, in MeOD-d4)
1, instrument: high performance liquid chromatograph.
2, reagent: caffeic acid 3,4-dihydroxy benzenes ethyl ester reference substance (self-control); Methanol (chromatographically pure), acetic acid (analytical pure).
3, chromatographic condition: chromatographic column:: Hypersil C18 performance liquid chromatographic column (250 * 4.6mm, 5 μ m); Column temperature: 25C; Detect wavelength: 326nm; Flow velocity: 1.5mL/min; Mobile phase: see Table 2.
Table 2 caffeic acid 3,4-dihydroxy benzenes ethyl ester RP-HPLC eluent gradient condition
4, the preparation of reference substance solution: precision takes by weighing the caffeic acid 3 behind 60 ℃ of vacuum dryings, and 4-dihydroxy benzenes ethyl ester reference substance 25.0mg puts in the 25ml volumetric flask, add 70% ethanol 20ml, put slight fever dissolving in the water-bath, put cold, add 70% ethanol dilution to scale, shake up, promptly.
5, the preparation of need testing solution: precision take by weighing behind 60 ℃ of vacuum dryings as synthetic caffeic acid 3 as described in the embodiment 1,4-dihydroxy benzenes ethyl ester sample 50mg, put in the 50ml volumetric flask, add 70% ethanol 35ml, put in the water-bath slight fever dissolving, put coldly, add 70% ethanol dilution to scale, shake up, promptly.
6, sample determination: getting concentration is the caffeic acid 3 of 1.0mg/mL, and 4-dihydroxy benzenes ethyl ester need testing solution 10 μ L sample introductions are measured caffeic acid 3 under aforementioned chromatographic condition, the peak area of 4-dihydroxy benzenes ethyl ester, and calculate caffeic acid 3, and the content of 4-dihydroxy benzenes ethyl ester, the HPLC spectrogram is seen accompanying drawing 5.The present invention is with the described method of embodiment synthetic caffeic acid 3, the content of 4-dihydroxy benzenes ethyl ester be 93.2% (n=3, SD=0.22).Embodiment 3 caffeic acids 3, the external growth inhibited effect of 4-dihydroxy benzenes ethyl ester (CADPE) to human malignant lesion's leukemia, melanotic tumor, pulmonary carcinoma, renal carcinoma, colon cancer, ovarian cancer, breast carcinoma, cerebroma and carcinoma of prostate
Table 3 caffeic acid 3, the external active anticancer of 4-dihydroxy benzenes ethyl ester
Embodiment 4 caffeic acids 3,4-dihydroxy benzenes ethyl ester (CADPE) is to the inhibitory action of the pernicious stomach cancer cell of people
Cultivate 24 hours human stomach cancer cell line HGC27, AGS, MGC 803, and SGC-7901 (low differentiation) and BGC-823 (low differentiation) at the caffeic acid 3 that contains variable concentrations, cultivated 72 hours in the culture medium of 4-dihydroxy benzenes ethyl ester again.(Sulforhodamine B, SRB) staining analysis method is measured cell viability, detects dead cell with Live and Dead assay with the sulfo group rhodamine B.Experimental result shows: caffeic acid 3, and 4-dihydroxy benzenes ethyl ester low concentration can significantly suppress the propagation of above 4 kinds of tumor cells; Along with the increase of concentration, caffeic acid 3,4-dihydroxy benzenes ethyl ester be kill tumor cell (seeing accompanying drawing 7-11) directly, and to the normal cell avirulence.
Measured caffeic acid 3 with embodiment 4 same methods, 4-dihydroxy benzenes ethyl ester is to the cytotoxicity of human hepatoma cell strain QGY-7701, SMMC-7721, Bel-7402 and HepG2.Result of the test confirms caffeic acid 3, and 4-dihydroxy benzenes ethyl ester all has the toxicity (seeing accompanying drawing 12-15) of highly significant to the 4 strain human liver cancer cells of being measured.
Measured caffeic acid 3 with embodiment 4 same methods, 4-dihydroxy benzenes ethyl ester is to the cytotoxicity of human colon cancer cell strain HCT-116 and SW-620.Result of the test and NCI test are in full accord, and (10 μ M) can suppress growth of tumour cell fully in mental retardation concentration.Along with the increase caffeic acid 3 of concentration, 4-dihydroxy benzenes ethyl ester is kill tumor cell (seeing accompanying drawing 16-17) directly.
Human colon carcinoma (5 * 10
6SW-620) be inoculated in 6 week nude mice in age (male and female half and half) backs subcutaneous, (this moment, tumor was grown to 100-200mm after 10 days
3) animal is divided into following 3 groups: DMSO solvent control group, cisplatin (CDDP) treatment group (5mg/kg, ip) and CADPE treatment group (5mg/kg, ip), every group of 5 animals, be administered once every day, measured tumor size, continuous 24 days with measuring the diameter device in per 2 days.Cisplatin can partly suppress the growth of human colon carcinoma SW-620; And caffeic acid 3,4-dihydroxy benzenes ethyl ester can suppress the growth (seeing accompanying drawing 18) of human colon carcinoma very significantly, and effect obviously is better than the chemotherapeutics cisplatin.
Claims (1)
1. caffeic acid 3, and 4-dihydroxy benzenes ethyl ester or the pharmaceutically application of acceptable salt in the preparation antitumor drug is characterized in that described tumor is selected from hepatocarcinoma, pulmonary carcinoma, breast carcinoma, carcinoma of prostate, central nerve neuroma, melanoma or leukemia.
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|---|---|---|---|---|
| WO2011097797A1 (en) * | 2010-02-10 | 2011-08-18 | Peng Jinlian | Polyphenol acrylic acid derivative, preparation and use in preparing medicine thereof |
| CN102949384A (en) * | 2012-10-29 | 2013-03-06 | 浙江大学 | Application of coffee acid 3, 4-dihydroxy benzene ethyl ester to preparation of antitumor drug |
| JP6444984B2 (en) * | 2013-04-05 | 2018-12-26 | マヌカ ヘルス ニュージーランド リミテッド | Therapeutic compositions comprising propolis extract and uses thereof |
| CN108992434A (en) * | 2018-07-06 | 2018-12-14 | 浙江大学 | Purposes of the caffeic acid 3,4- dihydroxy benzenes ethyl ester in preparation prevention colorectal cancer drug |
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| CN1879672A (en) * | 2006-05-17 | 2006-12-20 | 连晓媛 | A medicament containing effective components of glabrous sarcandra herb, its preparation method and application |
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| CN1879672A (en) * | 2006-05-17 | 2006-12-20 | 连晓媛 | A medicament containing effective components of glabrous sarcandra herb, its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| Jung et al.Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by.《Carcinogenesis》.2007,第28卷(第8期),1780–1787. * |
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