CN101156865A - Antineoplastic new usage of cardiac glycoside compound in antiar - Google Patents
Antineoplastic new usage of cardiac glycoside compound in antiar Download PDFInfo
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- CN101156865A CN101156865A CNA2007101812783A CN200710181278A CN101156865A CN 101156865 A CN101156865 A CN 101156865A CN A2007101812783 A CNA2007101812783 A CN A2007101812783A CN 200710181278 A CN200710181278 A CN 200710181278A CN 101156865 A CN101156865 A CN 101156865A
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- cardiac glycoside
- antiarin
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Abstract
The invention relates to the medicine technology field, in particular relates to a new application of cardiac glycoside chemical compound having general formula (I) in preparing oncotherapy drug, wherein, R equals to 2-O-methyl-Beta-D-mycose, 6-deoxidation-Beta-D-gulose or 6-deoxidation-2-O-methyl-Beta-D-allose. The cardiac glycoside chemical compound can be obtained through a separation from upas in various conventional separation methods or be obtained through a synthesis or semisynthesis method.
Description
Technical field:
The present invention relates to medical technical field, specifically is the new purposes of a class cardiac glycoside chemical compound in the preparation anti-tumor medicine.
Background technology:
Radix aconiti hemsleyani [Antiaris toxicaria (Pers.) Lesch.] is Moraceae Antiaris (Antiaris) plant.Another name: add cloth, shears tree, curare wood.The Radix aconiti hemsleyani platymiscium whole world has 3 mutation of 4 kinds approximately, is distributed in Southeast Asia.China only produces a kind, and promptly Radix aconiti hemsleyani is distributed in ground such as Hainan, Yunnan, Guangdong and Guangxi.It is said one of seeds the most malicious in the xylophyta in the world, grow in the mountain region evergreen broad-leaved rainforest and monsoon rainforest of height above sea level 300-1000m.The bright myron milky of Radix aconiti hemsleyani has severe toxicity, and being used as medicine is used to have loose bowels, emetic, and heart tonifying also can be used as anesthetis; Seed is also poisonous, and the analgesic antidiarrheal of being used as medicine is used for dysentery.
The main component of Radix aconiti hemsleyani milk and seed is a cardiac glycoside compounds.Cardiac glycoside compounds is the indispensable important drugs of treatment heart failure, clinically in order to heart diseases such as treatment heart failure and dysrhythmias.To the existing report of the cardiotonic that separates the cardiac glycoside that obtains in the Radix aconiti hemsleyani, but do not see that the report that suppresses the activity of tumor cells aspect is arranged.The inventor has carried out separation and anti-tumor activity test to the cardiac glycoside compounds in the Radix aconiti hemsleyani, has found to have in the Radix aconiti hemsleyani the new purposes of the cardiac glycoside compounds of general formula (I) at anti-tumor aspect.
Summary of the invention:
The objective of the invention is to disclose the new purposes of cardiac glycoside compounds in the preparation anti-tumor medicine that a class has general formula (I).
Cardiac glycoside compounds with general formula (I) can utilize and comprise adsorbent resin column chromatography, silica gel column chromatography, reversed-phase silica gel column chromatography, multiple conventional separation means such as decompression column chromatography obtain from Radix aconiti hemsleyani, perhaps obtain by synthetic and semi-synthetic means.Employing is with monomeric compound or select wherein any two or more monomers with the compound recipe form that arbitrary proportion makes up, and makes it to combine with suitable excipient, makes various dosage forms according to conventional method.Be used to prepare the medicine that treatment comprises multiple Cancerous diseases such as pulmonary carcinoma, renal carcinoma, gastric cancer, nasopharyngeal carcinoma, bladder cancer, colorectal cancer, bone tumor, breast carcinoma, uterus carcinoma, oral cancer, gallbladder cancer, cancer of bile ducts, cancer of biliary duct, cancer of pancreas, ovarian cancer, acute leukemia, malignant lymphoma, cerebroma.
The structure of the cardiac glycoside compounds in its formula of (I) is as follows:
(1) R=2-O-methyl-β-D-trehalose (2-O-methyl-β-D-fucose): malicious antiarin A (toxiearioside A)
(2) R=6-deoxidation-β-D-gulose (6-deoxy-β-D-gulose): α-antiarin (α-antiarin)
(3) R=6-deoxidation-2-O-methyl-β-D-allose (6-deoxy-2-O-methyl-β-D-allose (javose)): Radix aconiti hemsleyani Java glucosides (antiarojavoside)
Chemical compound in the mutual-through type of the present invention (I) has carried out the anti-tumor activity test, and the result shows that this compounds has stronger inhibitory action to various tumor cell strains.
The specific embodiment
The present invention is further elaborated below in conjunction with instantiation, but do not limit the present invention.
Embodiment 1: cardiac glycoside compounds poison antiarin A (toxicarioside A), α-antiarin (α-antiarin), the extraction separation of Radix aconiti hemsleyani Java glucosides (antiarojavoside):
Radix aconiti hemsleyani milk (4L) is with 95% ethanol room temperature lixiviate 3 times, and decompression recycling ethanol is to there not being the alcohol flavor.Ethanol extraction is scattered in becomes suspension in the water, obtain petroleum ether part (6.87g) through petroleum ether extraction, obtain ethyl acetate part (8.69g) with ethyl acetate extraction then, remaining water liquid is gone up macroporous adsorbent resin (D-101) column chromatography after filtering, priority water and methanol-eluted fractions, collect meoh eluate, obtain methanol part (228.4g) through concentrating.Ethyl acetate part that obtains and methanol part are crossed the decompression post respectively and are divided into some fractions, again through silicagel column, reverse phase silica gel post and sephadex column repeatedly column chromatography obtain chemical compound poison antiarin A (14.2g), α-antiarin (7.96g) and Radix aconiti hemsleyani Java glucosides (8.46g).
Embodiment 2: cardiac glycoside compounds poison antiarin A (toxicarioside A), α-antiarin (α-antiarin), the structure of Radix aconiti hemsleyani Java glucosides (antiarojavoside) is identified:
Utilize spectral technique, comprise ultraviolet, infrared, nuclear magnetic resonance, NMR and high resolution mass spectrum analysis, identified the cardiac glycoside compounds poison antiarin among the embodiment 1, α-antiarin, the structure of Radix aconiti hemsleyani Java glucosides.Use the 2D-NMR technology to some chemical compound first, on sugar such as Radix aconiti hemsleyani Java glucosides
13C-NMR,
1The H-NMR data belong to.(seeing attached list 1,2)
Embodiment 3: cardiac glycoside compounds poison antiarin A (toxicarioside A), α-antiarin (α-antiarin), the external tumor that presses down of Radix aconiti hemsleyani Java glucosides (antiarojavoside) is tested:
Adopt mtt assay to test cardiac glycoside compounds poison antiarin A, α-antiarin, Radix aconiti hemsleyani Java glucosides is to hepatoma carcinoma cell SMMC-7721, the stomach cancer cell SGC-7901 of human body, the external antitumor activity (the results are shown in subordinate list 3) of breast cancer cell MCF-7, chronic myeloid leukemia cells K562.Activity test method is as follows: the testing sample of negative control group (water), DMSO solvent control group, positive controls (ametycin) and 8 variable concentrations (0.8,1.6,3.2,6.3,12.5,25,50,100) is established in experiment, each concentration establish 2 parallel.Collect the exponential phase cell, the blood counting chamber counting is inoculated in the flat Tissue Culture Plate in 96 holes by 4500 the cancerous cell amounts in every hole, places 5%CO
2, humidity more than 90%, cultivate in 37 ℃ of incubators.Take out behind the 24h and add a certain amount of testing sample, taking-up places microscopically to observe every porocyte form after continuing to cultivate 3 d, record cellular morphology situation of change, follow MTT solution (being dissolved in balanced salt solution PBS) the 50 μ L that every hole adds 5mg/mL, behind 37 ℃ of reaction 4 h, with the cell culture fluid sucking-off, every hole adds 100 μ L DMSO Formazane is fully dissolved, Tissue Culture Plate is placed on the MK3 microplate reader, survey the absorbance (A) in each hole with the 570nm wavelength, by the following formula long suppression ratio of seeking survival.
With the sample concentration is abscissa, is vertical coordinate with the suppression ratio, maps and obtains the concentration (IC that suppression ratio is 50% o'clock sample
50), the active result of sample is promptly with half-inhibition concentration (IC
50) expression.
Embodiment 4: cardiac glycoside compounds poison antiarin A (toxicarioside A) 10g mixes with microcrystalline Cellulose 80g and magnesium stearate 10g, and mixture breaks into diameter 5mm with single punch tablet machine, the tablet of weight 200mg.Every toxic antiarin A20mg in this tablet.In conjunction with disease, each 1-2 sheet, take 2-3 every day.
Embodiment 5: cardiac glycoside compounds α-antiarin (α-antiarin) mix with lactose 110g and magnesium stearate 10g with each 40g of Radix aconiti hemsleyani Java glucosides (antiarojavoside), with every 500mg filled capsules.In this capsule, each capsule contains α-antiarin and Radix aconiti hemsleyani Java each 100mg of glucosides.In conjunction with disease, each 1-2, take 3-4 every day.
Malicious antiarin A among subordinate list 1, the embodiment 2, α-antiarin, the physicochemical constant poison antiarin A of Radix aconiti hemsleyani Java glucosides: white, needle-shaped crystals, [α]
D 25+ 0.24 (c 0.23, MeOH), and UV (MeOH) λ
Max216,296nm
-1IR (KBr) 3401,2943,2890,1734,1638,1066cm
-1HRMS (CI, ammonia, 140eV) m/z ([M+1])
+581.2953 calc ' d for C
30H
45O
11581.2949.
α-antiarin: white solid, [α]
D 25-4.0 (MeOH), Mp 238-240 °, HRMS (CI, ammonia, 140eV) m/z ([M+1])
+566.644 calc ' d for C
30H
44O
11566.273.
Radix aconiti hemsleyani Java glucosides: colourless colloid substance, [α]
D 25+ 5.4 (c, 0.9in 80%MeOH.), Mp 206-212 °, HRMS (CI, ammonia, 140eV) m/z ([M+1])
+580.671 calc ' d for C
30H
44O
11580.288.
Malicious antiarin A among subordinate list 2, the embodiment 2, α-antiarin, Radix aconiti hemsleyani Java glucosides
13The C-NMR data
| Position | Poison antiarin A (in CD 3OD) | α-antiarin (in CD 3OD) | Radix aconiti hemsleyani Java glucosides (in CD 3OD) |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 1′ 2′ 3′ 4′ 5′ 6′ OMe | 19.1 25.9 75.3 37.6 75.1 35.8 25.4 42.1 37.3 57.0 31.5 75.2 55.8 85.9 32.6 28.3 46.8 9.8 209.8 178.3 75.4 118.0 177.3 102.1 82.5 75.4 73.4 72.1 16.7 61.3 | 17.8 24.6 72.0 36.1 73.3 31.6 24.0 40.6 35.1 55.2 34.5 72.7 54.0 83.9 30.5 26.6 44.9 9.2 208.6 176.9 73.3 116.2 173.8 99.4 69.2 70.71 71.96 72.7 17.8 | 19.2 26.0 74.7 37.9 75.0 35.3 25.4 42.1 37.2 55.8 31.5 74.2 57.0 86.2 32.6 28.3 46.8 10.0 209.8 177.3 75.4 117.9 178.3 98.2 81.8 75.2 70.8 68.7 19.6 57.0 |
Malicious antiarin A among subordinate list 3, the embodiment 1-3, α-antiarin, the external tumor result that presses down of Radix aconiti hemsleyani Java glucosides
| Chemical compound | IC 50(μg ml -1) | |||
| Poison antiarin A α-antiarin Radix aconiti hemsleyani Java glucosides | SMMC-7721 5.6 8.7 6.3 | SGC-7901 4.2 4.5 5.7 | MCF-7 9.8 8.2 12.4 | K562 2.4 3.2 7.5 |
Claims (3)
1. the purposes of cardiac glycoside compounds in the preparation anti-tumor medicine that has general formula (I).
The structural formula of the cardiac glycoside compounds of general formula (I):
(1) R=2-O-methyl-β-D-trehalose (2-O-methyl-β-D-fucose): malicious antiarin A (toxicarioside A)
(2) R=6-deoxidation-β-D-gulose (6-deoxy-β-D-gulose): α-antiarin (α-antiarin)
(3) R=6-deoxidation-2-O-methyl-β-D-allose (6-deoxy-2-O-methyl-β-D-allose (javose)): Radix aconiti hemsleyani Java glucosides (antiarojavoside)
2. the purposes of cardiac glycoside compounds as claimed in claim 1 in the preparation anti-tumor medicine, it is characterized in that: the cardiac glycoside compounds that adopts general formula (I), with monomeric compound or the compound recipe form of selecting wherein two or more monomers arbitrarily to make up with arbitrary proportion, make it to combine, make the application of various dosage forms in the preparation anti-tumor medicine according to conventional method with suitable excipient.
3. the purposes of cardiac glycoside compounds as claimed in claim 1 in the preparation anti-tumor medicine, it is characterized in that: adopt with monomeric compound or the made preparation of compound recipe form, can be used for preparing the medicine that treatment comprises multiple Cancerous diseases such as hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, nasopharyngeal carcinoma, bladder cancer, colorectal cancer, bone tumor, breast carcinoma, uterus carcinoma, oral cancer, gallbladder cancer, cancer of bile ducts, cancer of biliary duct, cancer of pancreas, ovarian cancer, acute leukemia, malignant lymphoma, cerebroma.
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| CN2007101812783A CN101156865B (en) | 2007-10-26 | 2007-10-26 | Antineoplastic new usage of cardiac glycoside compound in antiar |
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| CN2007101812783A CN101156865B (en) | 2007-10-26 | 2007-10-26 | Antineoplastic new usage of cardiac glycoside compound in antiar |
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| CN101156865A true CN101156865A (en) | 2008-04-09 |
| CN101156865B CN101156865B (en) | 2010-04-21 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101323634B (en) * | 2008-04-29 | 2010-12-15 | 暨南大学 | Induced nuclear receptor TR3 expressed cardiac glycoside compounds and use thereof |
| CN104324043A (en) * | 2013-04-11 | 2015-02-04 | 中国热带农业科学院热带作物品种资源研究所 | Use of cardiac glycoside compound |
| CN104398532A (en) * | 2013-04-11 | 2015-03-11 | 中国热带农业科学院热带作物品种资源研究所 | Application of cardiac glycoside compound 12beta-hydroxycalotropin |
| CN108558980A (en) * | 2018-03-14 | 2018-09-21 | 中国药科大学 | The cardiac glycoside compounds with anti-tumor activity detached from streblus asper root and its application |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050026849A1 (en) * | 2003-03-28 | 2005-02-03 | Singh Chandra U. | Water soluble formulations of digitalis glycosides for treating cell-proliferative and other diseases |
| US20060205679A1 (en) * | 2004-10-22 | 2006-09-14 | Azaya Therapeutics, Inc. | Topical and oral formulations of cardiac glycosides for treating skin diseases |
-
2007
- 2007-10-26 CN CN2007101812783A patent/CN101156865B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101323634B (en) * | 2008-04-29 | 2010-12-15 | 暨南大学 | Induced nuclear receptor TR3 expressed cardiac glycoside compounds and use thereof |
| CN104324043A (en) * | 2013-04-11 | 2015-02-04 | 中国热带农业科学院热带作物品种资源研究所 | Use of cardiac glycoside compound |
| CN104398532A (en) * | 2013-04-11 | 2015-03-11 | 中国热带农业科学院热带作物品种资源研究所 | Application of cardiac glycoside compound 12beta-hydroxycalotropin |
| CN104398532B (en) * | 2013-04-11 | 2017-02-22 | 中国热带农业科学院热带作物品种资源研究所 | Application of cardiac glycoside compound 12beta-hydroxycalotropin |
| CN104324043B (en) * | 2013-04-11 | 2017-06-23 | 中国热带农业科学院热带作物品种资源研究所 | A kind of purposes of cardiac glycoside compound |
| CN108558980A (en) * | 2018-03-14 | 2018-09-21 | 中国药科大学 | The cardiac glycoside compounds with anti-tumor activity detached from streblus asper root and its application |
| CN108558980B (en) * | 2018-03-14 | 2020-11-03 | 中国药科大学 | Cardiac glycoside compound separated from streblus streblumea root and having antitumor activity and application thereof |
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| CN101156865B (en) | 2010-04-21 |
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