CN103070875A - Composition with anticancer effect - Google Patents
Composition with anticancer effect Download PDFInfo
- Publication number
- CN103070875A CN103070875A CN2013100536673A CN201310053667A CN103070875A CN 103070875 A CN103070875 A CN 103070875A CN 2013100536673 A CN2013100536673 A CN 2013100536673A CN 201310053667 A CN201310053667 A CN 201310053667A CN 103070875 A CN103070875 A CN 103070875A
- Authority
- CN
- China
- Prior art keywords
- ursolic acid
- formula
- compositions
- acid derivative
- anticancer effect
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a composition with an anticancer effect, and the composition mainly comprises the following active components: 2-eeoxy-D-glucose and ursolic acid derivatives. The composition can effectively increase the concentration of active drugs on a tumor site, effectively kill hepatoma carcinoma cells and reduce the toxicity and side effect on normal cells, so that the integral effect for treating the tumor can be improved, and a promising application prospect in treating the solid tumor can be realized.
Description
Technical field
The present invention relates to a kind of compositions with anticancer effect, be specifically related to have the use in conjunction of deoxyglucose and the antitumoral compounds of cancer target.
Background technology
Selective killing tumor cell and the damage that alleviates normal tissue is to treat at present the significant challenge that the tumor strategy faces.Be different from normal cell, even tumor cell under aerobic conditions, also mainly pass through the capacitation of glycolysis mode decomposition glucose, and the grade malignancy of tumor is higher, the glycolysis feature is just more obvious.Therefore, the tumor cell of targeting abnormal carbohydrate metabolism may become a New Policy of selective killing tumor cell.Utilize glycolytic inhibitor etc. blocking-up is glucolytic and carry out, thereby so that tumor cell is dead because energy supply lacks, but normal cell is unaffected.
Ursolic acid (Ursolic acid, UA), terpenoid, its relative molecular weight are 456.68, molecular formula is C
30H
48O
3, at the occurring in nature aboundresources, mainly the form with free or glucosides exists.Research is found, ursolic acid has widely biological effect, such as anticancer, anti-liver injury, malaria, anti-HIV, antiinflammatory sterilization etc., wherein remarkable with active anticancer, its anticancer spectrum is wide, not only multiple carcinogen is had resistant function, and to kinds of tumor cells in vivo, outer inhibitory action arranged all.Little because of its side effect, toxicity is low, demonstrates larger clinical practice potentiality.A large amount of research work has been done to the structure of modification aspect of ursolic acid in recent years by inventor's seminar, improving its bioavailability and to improve its active anticancer, and delivers Patents.But the ursolic acid derivative activity after the modification increases, but to Normocellular toxicity also corresponding raising.
Zymolysis inhibitor and chemotherapy drugs in combination are used, chemotherapeutics plays lethal effect for the active tumor cell of propagation on the one hand, and the slow hypoxic tumor cells of glycolytic inhibitor targeted therapy propagation, thereby improve the whole structure of oncotherapy, have great application prospect in the treatment of entity tumor.
Therefore, the inventor selects to block glycolytic pathway as the target spot of selective killing tumor cell, with Hep G2 hepatoma carcinoma cell as object of study, drug combination by glycolytic inhibitor 2-deoxy-D-glucose and ursolic acid and derivant thereof, analog, Hep G2 cell is carried out the Anticancer Activity in vitro test, the result shows, ursolic acid and derivant thereof and glycolytic inhibitor 2-deoxy-D-glucose are united use can the selective killing tumor cell, and lower to Normocellular toxic action.
Summary of the invention
The present invention seeks under the prerequisite that overcomes the prior art deficiency, a kind of effectively compositions of killing hepatoma cell is provided.
The invention provides a kind of compositions with anticancer effect, it is characterized in that described compositions has mainly comprised following active component: 2-deoxy-D-glucose and ursolic acid derivative, described ursolic acid derivative be a kind of as shown in the formula (I) chemical compound or multiple as shown in the formula (I) the mixture of chemical compound, R in the formula (I)
1Be hydroxyl or acetoxyl group, R
2For hydroxyl ,-NH (CH
2)
nNH
2Or with one of following formula (II) ~ formula (IV), wherein-NH (CH
2)
nNH
2Middle n is the even number of 2-12.Ursolic acid derivative is preferably N-[3 β-acetoxyl group-Folium Vaccinii vitis-idaeae alkane-12-alkene-28-acyl]-amino hexamethylene diamine (below be abbreviated as " USW-006 "), its structural formula is shown in formula V.
Wherein ursolic acid derivative is 1-10:4000-80000 with the ratio of the amount of substance of 2-deoxy-D-glucose, and preferred ratio is 4:20000.
Be more specifically a kind of compositions with anticancer effect, it is characterized in that described compositions is comprised of 2-deoxy-D-glucose and ursolic acid derivative.
Described compositions with anticancer effect is characterized in that it is in the application of the medicine of preparation treatment tumor and neoplasm metastasis.
The activity test in vitro of this anti-cancer composition to Hep G2 cell is provided among the present invention, and provides normal hepatocytes cancerous cell L02 to test in contrast.
Wherein as shown in the formula (I) chemical compound, R in formula (I)
1Be hydroxyl or acetoxyl group, R
2For-NH (CH
2)
nNH
2The time preparation method be:
The ursolic acid stirring and dissolving of (1) 1 weight portion is added dropwise to the acetic anhydride of 2-3 weight portion in the pyridine of 40-50 weight portion, add a small amount of DMAP, stir 16-18 h under the room temperature, after reaction finishes, transfer pH 3-4 with 2 mol/L HCl, steaming desolventizes, sucking filtration, and the washing filter cake is to neutral, dry, dried product dry method loading, column chromatography purification, dehydrated alcohol thermosol, cool off recrystallization, get the 3-O-acetyl group ursolic acid of white powder;
(2) 1 weight portion 3-O-acetyl group ursolic acids are dissolved in 30-35 weight portion CH
2Cl
2In, in batches, dropwise adding the oxalyl chloride of 1-2 weight portion, stirring reaction 12-24 h under the room temperature steams the gas that desolventizes and react generation, gets the crude product of 3-O-acetyl group UA acyl chlorides intermediate, directly enters next step reaction; The CH that in above-mentioned intermediate, adds the 20-30 weight portion
2Cl
2, triethylamine regulator solution pH 8-9, the NH of adding 1-2 weight portion
2(CH
2)
nNH
2(n=4,6,8,10 or 12), stirring reaction 12-24 h under the room temperature is after reaction finishes, the water that adds the 5-10 weight portion in the reactant liquor is transferred pH3-4 with 2 mol/L HCl, filters, the washing filter cake is neutral to filtrate pH, drying, dried product dry method loading, column chromatography purification, the dehydrated alcohol thermosol, the cooling recrystallization gets white powder, is the R that works as shown in the formula (I)
1R during for acetoxyl group
2For-NH (CH
2)
nNH
2The chemical compound of (n=4,6,8,10 or 12);
(3) take by weighing the 1-2 weight portion as shown in the formula (I) work as R
1During for acetoxyl group, R
2For-NH (CH
2)
nNH
2The chemical compound of (n=4,6,8,10 or 12); Be dissolved among the CH3OH-THF of 20-30 weight portion, the volume ratio of described CH3OH and THF is 1: 1.5-2.5; The 4mol/LNaOH that adds the 4-8 weight portion, stirring reaction 3-5h under the room temperature adds the water of 5-10 weight portion in the reactant liquor, and 2mol/L HCl regulates pH 3-4, removes solvent under reduced pressure, and water washing and precipitating is to neutral, drying; Dried product dry method loading, column chromatography purification, the dehydrated alcohol thermosol, the cooling recrystallization must be the R that works as shown in the formula (I)
1R during for hydroxyl
2For-NH (CH
2)
nNH
2The chemical compound of (n=4,6,8,10 or 12).
As shown in the formula (I) work as R
1R during for acetoxyl group
2For-NH (CH
2)
2NH
2The time the preparation of chemical compound at patent " a kind of ursolic acid derivative with active anticancer and preparation method thereof " application number: disclose in 201110373561.2.
When as shown in the formula (I), R in formula (I)
2As with the preparation method of the chemical compound shown in following formula (II) ~ formula (IV) at patent " ursolic acid nitrogen heterocyclic ring class formation trim of anti-tumor activity and preparation method thereof " application number: disclose in 201210180483.9.
Description of drawings
Fig. 1 is that ursolic acid derivative USW-006,2DG use separately and unite the impact of using hepatoma carcinoma cell HepG2 survival rate
Fig. 2 is that ursolic acid derivative USW-006 and 2DG use separately and unite the impact of using normal liver cell L02 survival rate
The specific embodiment
Now in conjunction with the embodiments, the present invention done further specifying, but scope of the present invention is not limited to following examples.
Embodiment 1
The activity test in vitro of this anti-cancer composition to Hep G2 cell is provided, and provides normal hepatocytes cancerous cell L02 to test in contrast.
Ursolic acid derivative USW-006,2-DG and compositions Anticancer Activity in vitro thereof--the mtt assay detection of drugs is to the inhibited proliferation of Hep G2 cell
1. get one bottle in the Hep G2 cell that is in the exponential phase state, use trypsinization, make 1 * 10
4The cell suspension of individual/mL.
2. cell suspension is moved into 96 orifice plates, every hole 100 L make a circle and use the PBS shrouding in week, put 37 ℃, 5% CO
2Cultivate 24 h in the incubator.
3. 2-DG is divided into 5 groups of 10mmol/L, 20mmol/L, 40mmol/L, 60mmol/L and 80mmol/L according to concentration; USW-006 is divided into 5 groups of 1 μ mol/L, 2 μ mol/L, 4 μ mol/L, 6 μ mol/L, 8 μ mol/L and 10 μ mol/L according to concentration; The drug combination group is divided into 10mmol/L 2-DG according to concentration and unites 2 μ mol/L USW-006,20mmol/L 2-DG and unite 4 μ mol/L USW-006,40mmol/L 2-DG and unite 6 μ mol/L USW-006,60mmol/L 2-DG and unite 8 μ mol/L USW-006,80mmol/L 2-DG and unite 10 μ mol/L UA5 group.
4. remove culture medium, add tested compositions according to Concentraton gradient, every hole 100 L, other establishes the blank group.Establish 4 multiple holes for every group.Behind drug effect 24 h, remove the pastille culture medium, in every hole, add serum-free, without phenol red 1640 culture medium, 90 L, add again MTT solution 10 L, continue to hatch 4 h after, stop cultivation.
5. discard supernatant in 96 orifice bores, every hole adds 100 L DMSO, 20 min that vibrate measure each hole absorbance value (OD value) in 570 nm wavelength places, calculate the survival rate of cell: survival rate (%)=(the average OD value of the average OD value of medication group ÷ blank group) * 100%.Experimental result is used GraphPad Prism software and is carried out the experimental result processing, as depicted in figs. 1 and 2 as shown in Table 1 and Table 2.
Table 1. ursolic acid derivative USW-006,2DG use separately and unite use to the impact of hepatoma carcinoma cell HepG2 survival rate
Table 2. ursolic acid derivative USW-006 and 2DG use separately and unite use to the impact of normal liver cell L02 survival rate
Among Fig. 1, white legend be the HepG2 cell through USW-006(2,4,6,8,10 M) survival rate behind the processing 24h, the Lycoperdon polymorphum Vitt legend is that the HepG2 cell is through 2DG (10,20,40,60,80 mM) survival rate behind the processing 24h, black legend are the survival rate of HepG2 cell behind USW-006 and 2DG synergy processing 24h.
Among Fig. 2, white legend be the L02 cell through USW-006(2,4,6,8,10 M) survival rate behind the processing 24h, the Lycoperdon polymorphum Vitt legend is that the L02 cell is through 2DG (10,20,40,60,80 mM) survival rate behind the processing 24h, black legend are the survival rate of L02 cell behind USW-006 and 2DG synergy processing 24h.
Such as table 1, table 2, illustrated in figures 1 and 2, when 2-DG and USW-006 use separately, HepG2 hepatoma carcinoma cell and normal cell lines of human liver L02 are all had in various degree inhibited proliferation, and be dose dependent.When USW-006 and 2-DG unite when using, it has significant inhibited proliferation to hepatoma carcinoma cell HepG2, and is collaborative additive effect, and drug combination is not obvious to normal cell lines of human liver L02 cooperative effect.
Claims (6)
1. compositions with anticancer effect, it is characterized in that described compositions has mainly comprised following active component: 2-deoxy-D-glucose and ursolic acid derivative, described ursolic acid derivative be a kind of as shown in the formula (I) chemical compound or multiple as shown in the formula (I) the mixture of chemical compound, R in the formula (I)
1Be hydroxyl or acetoxyl group, R
2For hydroxyl ,-NH (CH
2)
nNH
2Or with one of following formula (II) ~ formula (IV), wherein-NH (CH
2)
nNH
2Middle n is the even number of 2-12
2. a kind of compositions with anticancer effect as claimed in claim 1 is characterized in that its ursolic acid derivative and the ratio of the amount of substance of 2-deoxy-D-glucose are 1-10:4000-80000.
3. a kind of compositions with anticancer effect as claimed in claim 1 is characterized in that its ursolic acid derivative and the ratio of the amount of substance of 2-deoxy-D-glucose are preferably 4:20000.
4. such as claim 1,2 or 3 described a kind of compositionss with anticancer effect, it is characterized in that described compositions is comprised of 2-deoxy-D-glucose and ursolic acid derivative.
6. a kind of compositions with anticancer effect as claimed in claim 1 is characterized in that the application of described compositions in the medicine of preparation treatment tumor and neoplasm metastasis.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310053667.3A CN103070875B (en) | 2013-02-19 | 2013-02-19 | Composition with anticancer effect |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310053667.3A CN103070875B (en) | 2013-02-19 | 2013-02-19 | Composition with anticancer effect |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103070875A true CN103070875A (en) | 2013-05-01 |
CN103070875B CN103070875B (en) | 2015-01-28 |
Family
ID=48147722
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310053667.3A Expired - Fee Related CN103070875B (en) | 2013-02-19 | 2013-02-19 | Composition with anticancer effect |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103070875B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106074565A (en) * | 2016-07-05 | 2016-11-09 | 福州大学 | A kind of containing Sorafenib and the pharmaceutical composition of micromolecular compound and the application in preparing antitumor drug |
CN108136066A (en) * | 2015-08-14 | 2018-06-08 | 伊西康公司 | Use the method for glycolysis dependence compound treatment disease |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080300147A1 (en) * | 2004-03-26 | 2008-12-04 | Nasser Chegini | Detection and Treatment of Fibrotic Disorders |
-
2013
- 2013-02-19 CN CN201310053667.3A patent/CN103070875B/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080300147A1 (en) * | 2004-03-26 | 2008-12-04 | Nasser Chegini | Detection and Treatment of Fibrotic Disorders |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108136066A (en) * | 2015-08-14 | 2018-06-08 | 伊西康公司 | Use the method for glycolysis dependence compound treatment disease |
US11986489B2 (en) | 2015-08-14 | 2024-05-21 | Ethicon, Inc. | Method of treating a disease using a glycolytic dependent compound |
CN106074565A (en) * | 2016-07-05 | 2016-11-09 | 福州大学 | A kind of containing Sorafenib and the pharmaceutical composition of micromolecular compound and the application in preparing antitumor drug |
CN106074565B (en) * | 2016-07-05 | 2018-08-17 | 福州大学 | A kind of pharmaceutical composition and its application in preparation of anti-tumor drugs containing Sorafenib and micromolecular compound |
Also Published As
Publication number | Publication date |
---|---|
CN103070875B (en) | 2015-01-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102212008B (en) | Tanshinol ligustrazine derivative and preparation method and application thereof | |
EP2787002B1 (en) | Oleanolic acid amidate derivatives, preparation methods and uses thereof | |
CN108440583B (en) | Boric acid derivative and its medicinal composition | |
WO2021139395A1 (en) | High-efficiency low-toxicity anti-cancer compound synthesized by autocatalysis in cells and living bodies and synthesis method for anti-cancer compound | |
CN104163823B (en) | A kind of camptothecine and Artesunate conjugate and preparation method thereof and application | |
PT727430E (en) | PLATINUM COMPLEXES | |
Ivanović et al. | Ruthenium (II)–arene complexes with substituted picolinato ligands: Synthesis, structure, spectroscopic properties and antiproliferative activity | |
CN102241674A (en) | Synthesis method and antitumor activity evaluation of 1,1-dimethyl-beta-carboline-3-formacyl amino acid benzyl ester | |
CA2950305A1 (en) | Texaphyrin-pt(iv) conjugates and compositions for use in overcoming platinum resistance | |
CN103070875B (en) | Composition with anticancer effect | |
CN113072595B (en) | Low-toxicity Pt complex and preparation method and application thereof | |
CN102241726A (en) | Glycyrrhetinic acid derivative and application thereof as antitumor medicament | |
CN104151391A (en) | Oleanolic acid derivative having antineoplastic effect, preparation method and purpose thereof | |
CN107141284B (en) | Coptisine analog derivative, preparation method, pharmaceutical composition and anticancer usage | |
WO2023155688A1 (en) | Oral pt (iv) anti-cancer prodrug axially containing 3-bromopyruvic acid ligand | |
CN101029034B (en) | Polyenic taxol soluble derivative, its preparation and use | |
WO2015064764A1 (en) | Aryloyl(oxy or amino)pentafluorosulfanylbenzene compound, pharmaceutically acceptable salt thereof, and prodrugs thereof | |
CN106432076B (en) | A kind of Ciprofloxacin C3 amide derivatives and its preparation method and application | |
Shirvani et al. | Design, synthesis, in silico studies, and antiproliferative evaluations of novel indolin-2-one derivatives containing 3-hydroxy-4-pyridinone fragment | |
CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
CN103965202B (en) | Bicyclic-fused heterogeneous ring compound, Preparation Method And The Use | |
CN104926804A (en) | Compounds with anti-tumor effect, and preparation method and application of compounds | |
CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
CN104230913A (en) | Piperazine-substituted quinazoline compound and use thereof | |
CN103351383A (en) | 5-fluorouracil nitroxyl-free-radical anti-tumor drug |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150128 Termination date: 20170219 |