CN101244048A - Chalcone compounds and uses of the composition - Google Patents
Chalcone compounds and uses of the composition Download PDFInfo
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- CN101244048A CN101244048A CNA2007100375708A CN200710037570A CN101244048A CN 101244048 A CN101244048 A CN 101244048A CN A2007100375708 A CNA2007100375708 A CN A2007100375708A CN 200710037570 A CN200710037570 A CN 200710037570A CN 101244048 A CN101244048 A CN 101244048A
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Abstract
The invention discloses the application of chalcone ketones compound and the salt as shown in formula I in inhibiting cell mitosis; wherein, the application can produce the efficacy of inhibiting tumor or inhibiting over proliferation of cell. The invention also discloses the application of the compounds and the salt in treating tumor; the usage can play the role of inhibiting over proliferation of cell through inhibiting cell mitosis; in the formula (as shown in the figure), R1, R2, R3 and R4 can be independently selected from hydrogen, hydroxy, C1-C8 alkoxy, C1-C4 acyl and halogen.
Description
Technical field
The present invention relates to plant extract, relate in particular to a kind of chalcone compounds that from leguminous plant, extracts, perhaps contain the purposes of the pharmaceutical composition of this chemical compound.
Background technology
As everyone knows, human beings'health in the malignant tumor serious threat, and its treatment also becomes the focus that people pay close attention to, and traditional chemotherapy and radiation also often brings bigger toxic and side effects to the patient owing to lack specificity when obtaining curative effect.Therefore, the micromolecule antitumor drug of searching targeting becomes an emphasis in new drug research field gradually.Because the Chinese medicine of China has long history aspect oncotherapy, therefore, screening has the new purposes of the noval chemical compound or the known native compound of brand-new molecular structure from natural plants, also becomes one of main path of new drug development.Import along with molecular biology method in oncology's the research, the antitumor Chinese medicine screening platform on the cellular elements biology level has been gradually improved and is ripe.
Known compound 1,3-diphenyl-2-propylene-1-ketone (popular name " chalcone ") is the flavonoid class material, finds some flavonoid class recently, comprises those that are categorized as chalcone, has active anticancer, but its concrete anticancer mechanism is still unknown at present.
Think that now the interior effect of body of these materials is complicated especially.Chinese patent ZL00812303.9 claims to find some new chalcones, chalcone derivative and chalcone analog, and particularly phenyl ring wherein is substituted in the 1-position or is contained the metathetical chemical compound of one or more heteroatomic rings to responsive cancerous cell with to the conventional chemotherapy medicine, the antitumor agent that comprises latest generation, handkerchief Seeley Ta Keer (paclitaxel) and the resistive cell of many Xi Takeer (docetaxel) have stronger antiproliferative activity.
In addition, we know, cell is finished to finish to division next time by division once, and (be G1 → S → G2 → M) carry out activity again and again, this growth of cell, division circulation promptly are called cell cycle (cell cycle) all will to experience identical changes phase.Various cancerigenic factors take place by making the not normal tumor that causes of mitotic regulation and control.Therefore, the medicine that influences cell cycle can be used for treating tumor.Especially in the G2 phase, chromosome begins spiralization and shortens, and tubulin is synthetic in a large number, and polymerization forms spindle.Found that at present some medicines (as paclitaxel, vincristine etc.) can be used for the treatment of tumor by destroying the spindle structure or by influencing the microtubule assembling, destroying the normal function of microtubule, thereby stop cell mitogen.
But, also do not have report to show the chalcones material at present, thereby performance suppresses mitotic effect by the inhibition tubulin polymerization.
Therefore, there is a need in the field to provide chalcones material new purposes in this respect.
Summary of the invention
The present invention aims to provide the purposes of chalcone compounds aspect inhibition mitosis, treatment tumor.
In a first aspect of the present invention, chalcone compounds or its pharmaceutically acceptable salt of a kind of formula I is provided, perhaps contain the purposes of the plant extract of this chemical compound,
In the formula,
R1, R2, R3 and R4 are selected from hydrogen, hydroxyl, C1-C8 alkoxyl, C1-C4 acyl group, halogen independently of one another;
It is used to preparation or is used as mitotic inhibitor.
In another preference, described inhibitor can be used for treating tumor, and/or the caused disease of treatment cell hyperproliferation.
In another preference, R1 among the formula I, R2, R3 and R4 are selected from the alkoxyl of the straight or branched of hydroxyl, a 1-4 carbon atom independently of one another.
In another preference, described chemical compound is suc as formula shown in the II:
In another preference, described formula I chemical compound or described extract extract from leguminous plant.
In another preference, described leguminous plant is the heartwood position of Lignum Sappan, especially Lignum Sappan.
In another preference, described pharmaceutically acceptable salt is formula I chemical compound and the alkali metal or the formed salt of alkaline-earth metal that are selected from down group: sodium, potassium, calcium, magnesium etc.
In another preference, described inhibitor comprises pharmaceutical composition, food compositions or Halth-care composition.
In another preference, comprise the additional component that is selected from down group in the described inhibitor: paclitaxel (taxol), Colchicine (colchicine), vincaleucoblastine, vinblastine, vincristine, vindesine, vinorelbine, colchicine, Demecolcine, Colchiceinamidum.
In another preference, described inhibitor is selected from injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder spray or suppository.
In a second aspect of the present invention, chalcone compounds or its pharmaceutically acceptable salt of a kind of formula I is provided, perhaps contain the purposes of the plant extract of this chemical compound,
In the formula,
R1, R2, R3 and R4 are selected from hydrogen, hydroxyl, C1-C8 alkoxyl, C1-C4 acyl group, halogen independently of one another;
It is used to prepare the compositions for the treatment of tumor.
In another preference, described tumor is selected from down group: renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia.
In another preference, described compositions is as mitotic inhibitor, and/or the caused disease of treatment cell hyperproliferation.
In another preference, R1 among the formula I, R2, R3 and R4 are selected from the alkoxyl of the straight or branched of 1-4 carbon atom independently of one another.
In another preference, described chemical compound is suc as formula shown in the II:
In another preference, described formula I chemical compound or described extract extract from leguminous plant.
In another preference, described leguminous plant is the heartwood position of Lignum Sappan, especially Lignum Sappan.
In another preference, described pharmaceutically acceptable salt is formula I chemical compound and the alkali metal or the formed salt of alkaline-earth metal that are selected from down group: sodium, potassium, calcium, magnesium etc.
In another preference, described compositions comprises pharmaceutical composition, food compositions or Halth-care composition.
In another preference, comprise the additional component that is selected from down group in the described compositions: paclitaxel, vincaleucoblastine, camptothecine, teniposide, colchicine, homoharringtonine, etoposide, procarbazine, asparaginase, cisplatin, carboplatin, mitoxantrone, tamoxifen, cyclophosphamide, mustine hydrochlcride, lomustine, semustine, plug is for group, busulfan, formylmerphalan, chlorambucil, fluorouracil, tegafur, excellent fluorine pyridine, carmofur, mercaptopurine, methotrexate, cytosine arabinoside, ancitabine, the mercapto guanine, altretamine, hydroxyurea, mitomycin, amycin, epirubicin, bleomycin, training Lay mycin, acrivastine, Trastuzumab, imatinib mesylate, gemcitabine, hycamtin, docetaxel, and/or leuprorelin.
In another preference, described compositions is selected from injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder spray or suppository.
In a third aspect of the present invention, a kind of pharmaceutical composition is provided, it contains
(a) formula II chemical compound or its pharmaceutically acceptable salt as active component of effective dose perhaps contain the plant extract of this chemical compound or its pharmaceutically acceptable salt;
(b) pharmaceutically acceptable carrier.
In another preference, described pharmaceutical composition also contains one or more auxiliary activity compositions that (c) is selected from down group: the mitotic inhibitor, the antitumor drug that do not comprise formula II chemical compound or its pharmaceutically acceptable salt; Immunosuppressant; The cell hyperproliferation inhibitor.
In a fourth aspect of the present invention, provide a kind of vitro inhibition mitotic method, it comprises step: with concentration is chalcone compounds or its pharmaceutically acceptable salt suc as formula I of 0.1-50 μ M, and the plant extract that perhaps contains this chemical compound mixes with dimethyl sulfoxide (DMSO) solution;
In the formula,
R1, R2, R3 and R4 are selected from hydrogen, hydroxyl, C1-C8 alkoxyl, C1-C4 acyl group, halogen independently of one another.
In another preference, R1 among the formula I, R2, R3 and R4 are selected from the alkoxyl of the straight or branched of hydroxyl, a 1-4 carbon atom independently of one another.
In another preference, described chemical compound is suc as formula shown in the II:
In view of the above, the invention provides the chalcones material by the inhibition tubulin polymerization, thereby performance suppresses mitotic effect.
Description of drawings
Fig. 1 has shown that the Lignum Sappan chalcone is to gastric carcinoma cells HGC cell cycle sketch map; Wherein
The negative matched group gastric carcinoma cells of A HGC cell cycle sketch map;
B is a Lignum Sappan chalcone group gastric carcinoma cells HGC cell cycle sketch map.
Fig. 2 has shown the tubulin polymerization curve.
The specific embodiment
The inventor is surprised to find the chemical compound with formula I through extensive and deep research, has the effect of good inhibition cell mitogen and/or inhibition cell hyperproliferation, and can be by these approach treatment tumors.Therefore be to have the novel substance that suppresses cell mitogen and antitumor action:
In the formula,
R1, R2, R3 and R4 are selected from hydrogen, hydroxyl, C1-C8 alkoxyl, C1-C4 acyl group or halogen independently of one another.
As used herein, described " inhibitor " or " compositions " all are a kind of compositionss that contains formula I compound or its salt, the weight of wherein contained formula I compound or its salt is the 0.1-99% of composition total weight, preferably is 30-95%, more preferably is 50-90%.It comprises (a) mitotic inhibitor, (b) compositions of treatment tumor.
Among the formula I, R1 is preferably from hydroxyl or have the alkoxyl of the straight or branched of 1-4 carbon atom; More preferably, hydroxyl or methoxyl group; Hydroxyl most preferably.
R2 is preferably from hydroxyl or have the alkoxyl of the straight or branched of 1-4 carbon atom; More preferably, hydroxyl or methoxyl group; Hydroxyl most preferably.
R3 is preferably from hydroxyl or have the alkoxyl of the straight or branched of 1-4 carbon atom; More preferably, hydroxyl or methoxyl group; Hydroxyl most preferably.
R4 is preferably from hydroxyl or have the alkoxyl of the straight or branched of 1-4 carbon atom; More preferably, hydroxyl and methoxyl group; Methoxyl group most preferably.
Chemical compound of the present invention is preferably suc as formula II:
It is to extract from pulse family (Leguminosae) Semen Caesalpiniae platymiscium Lignum Sappan (Caesal pinia sappan L.), especially the heartwood position of Lignum Sappan.
Chemical compound of the present invention can be gone up the form use of acceptable salt with pharmacy or physiology.These salt comprise: the salt that forms with alkali metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium), and the salt (when with this form administration, can change into active part in vivo) that exists with " prodrug " forms of other routines.
The extract that contains formula I chemical compound also can be used for the present invention.A kind of preferred extracting method as mentioned above.Usually, the purity at extract Chinese style I chemical compound should more preferably be 50-98% at 40%-99.9% by weight.
Purposes
Chalcone compounds of the present invention or its salt, or the plant extract that contains this chemical compound can be used for preparation or as mitotic inhibitor.Described microtubule inhibitor can be used for treating tumor, and/or suppresses cell hyperproliferation.
Chalcone compounds of the present invention or its salt, or the plant extract that contains this chemical compound can be used for treating tumor, described purposes can be by suppressing mitosis, and/or suppress cell hyperproliferation and realize.The representational example of the tumor of being treated comprises (but being not limited to): renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia.
Chalcone compounds of the present invention or its salt, or the plant extract that contains this chemical compound can be used as or be used to prepare the cell hyperproliferation inhibitor.Described inhibitor can be used for treating tumor, suppresses mitosis, and/or treats other because the disease that cell hyperproliferation causes.
Described because the disease (being selected from down group) that cell hyperproliferation causes:
Atopy such as allergic asthma, atopic dermatitis (eczema) and allergic rhinitis;
Cell-mediated anaphylaxis such as contact dermatitis, hypersensitivity pneumonitis;
Autoimmune disease such as systemic lupus erythematosus (sle), psoriasis, type i diabetes, autoimmune thyroid disease, Alzheimer, glomerulonephritis;
Tumor such as renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia etc.
The effective dose of used active component can change with the order of severity of mode of administration and disease to be treated.Yet, when chemical compound of the present invention every day gives with the dosage of about 0.5-500mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 2-4 time every day, or with the slow release form administration.For most of large mammal, the accumulated dose of every day is about 1-100mg.Be applicable to dosage form for oral administration, comprise reactive compound with the blended about 0.5-500mg of solid-state or liquid pharmaceutically acceptable carrier.This therapeutic scheme of scalable is to reach optimum therapeuticing effect.For example, can be according to the needs of treatment situation, every day, the several times separate administration or reduced dosage in proportion.Usually, becoming the scope of human oral clinical dosage is 1-1000mg/ day, is preferably 10-200mg/ day, and the non-oral dosage of being grown up is 0.1-100mg/ day, preferred 1-100mg/ day.
At the plant extract that uses The compounds of this invention or contain this chemical compound during as mitotic inhibitor, also can with other treatment agent coupling.For example (but being not limited to) and be selected from down the group one or more mitotic inhibitor couplings: vinblastine, vincristine, vindesine, vinorelbine, colchicine, Demecolcine, Colchiceinamidum, paclitaxel etc.
When using The compounds of this invention treatment tumor, also can with other treatment agent coupling.For example with one or more auxiliary activity composition couplings that are selected from down group: paclitaxel, vincaleucoblastine, camptothecine, teniposide, colchicine, homoharringtonine, etoposide, procarbazine, asparaginase, cisplatin, carboplatin, mitoxantrone, tamoxifen, cyclophosphamide, mustine hydrochlcride, lomustine, semustine, plug is for group, busulfan, formylmerphalan, chlorambucil, fluorouracil, tegafur, excellent fluorine pyridine, carmofur, mercaptopurine, methotrexate, cytosine arabinoside, ancitabine, the mercapto guanine, altretamine, hydroxyurea, mitomycin, amycin, epirubicin, bleomycin, training Lay mycin, acrivastine, Trastuzumab, imatinib mesylate, gemcitabine, hycamtin, docetaxel, leuprorelin.
The present invention also comprises pharmaceutical composition and suppresses mitotic method that it comprises the The compounds of this invention to the administration medicine effective quantity.
The present invention also comprises the method for pharmaceutical composition and treatment tumor, and it comprises the The compounds of this invention to the administration medicine effective quantity.
The present invention also comprises the method for the treatment of the disease that causes owing to cell hyperproliferation, and it comprises the The compounds of this invention to the administration medicine effective quantity.
Usually, when The compounds of this invention is used for such use, they can make the pharmaceutical dosage form of different way of administration with one or more pharmaceutically acceptable carriers or mixed with excipients, as injection, injectable sterile powder, tablet, capsule, spirit, powder, granule, syrup, solution, tincture, aerosol, powder spray, suppository etc.
Chemical compound of the present invention can be through oral, intravenous, intramuscular or subcutaneous route administration.
But the dosage form of oral administration administration is in the above-mentioned dosage form: tablet, capsule, powder, granule, syrup, solution, spirit.Solid-state carrier comprises: starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose, kaolin, micropowder silica gel, Pulvis Talci, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, polyvinylpyrrolidone.And liquid carrier comprises: sterilized water, ethanol, Polyethylene Glycol, nonionic surfactant and edible oil (as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami).Normally used adjuvant comprises in the process of pharmaceutical compositions: flavoring agent, coloring agent, antiseptic (as oxybenzene alkyl butyl ester, sodium benzoate, sorbic acid) and antioxidant (as vitamin E, vitamin C, sodium pyrosulfite and dibenzylatiooluene).
The dosage form that can be used for injection administration in the above-mentioned dosage form comprises: injection, injectable sterile powder, they are that medicine and one or more pharmaceutically acceptable mixed with excipients are made form for drug administration by injection.Solvent comprises: sterilized water, ethanol, glycerol, propylene glycol, Polyethylene Glycol.In addition, also need add antibacterial (as benzyl alcohol, butyl hydroxybenzoate, thimerosal), isoosmotic adjusting agent (as sodium chloride, glucose), suspending agent (as sodium carboxymethyl cellulose, methylcellulose), solubilizing agent (tween 80, lecithin), antioxidant (as vitamin E, vitamin C, sodium pyrosulfite) and filler (as lactose, mannitol).
From being easy to prepare the position with administration, preferred pharmaceutical composition is a solid-state composition, and especially tablet and solid are filled or the capsule of liquid filling.The preferred oral administration.
Major advantage of the present invention is:
1, chalcone compounds of the present invention can be used for preparing effective mitotic inhibitor.
2, chalcone compounds of the present invention can effectively be treated tumor.
3, chalcone compounds of the present invention also can effectively be treated because the disease that cell hyperproliferation causes.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio and umber by weight.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Preparation embodiment 1
Extract chemical compound Lignum Sappan chalcone in the Lignum Sappan
Get Lignum Sappan medical material 100g, extracted 1 hour with 1000ml 95% alcohol heat reflux, medicinal residues reuse 1000ml95% ethanol extraction once.Merge above extracted twice liquid, extracting solution is concentrated into 100ml water liquid, use the 100ml ethyl acetate extraction, above extraction step is repeated once again.Shift out ethyl acetate layer, be concentrated into driedly, obtain crude product.Get crude product 10g, mix sample in 30g 100-200 order silica gel, carry out silicagel column (400g, 200-300 order) and just be separated, use the chloroform of following ratio successively: methanol mixed solution (200: 1,100: 1,50: 1,25: 1,10: 1) 5000ml gradient elution, at last with methanol towards post.Collect 116 streams part altogether, according to the TLC testing result, merge stream part, Fr.62-90 obtains the orange powder chemical compound through after purification by silica gel column chromatography is handled repeatedly, detects (purity is more than 90%) through TLC and HPLC, is a monomeric compound, its molecular formula, UV,
1H-NMR and
13The C-NMR data are as follows:
Molecular formula: C
16H
14O
5
UVλmax(MeOH，nm)：361，250
1H-NMR(400MHz，δppm，CD
3OD)：7.58(1H-6’，d，J＝8.4Hz)，7.50(1H-β，d，J＝15.8Hz)，7.36(1H-α，d，J＝15.8Hz)，7.11(1H-2，d，J＝2.0Hz)，6.98(1H-6，dd，J＝8.2、2.0Hz)，6.79(1H-5，d，J＝8.3Hz)，6.51(1H-3’，d，J＝2.3Hz)，6.45(1H-5’，dd，J＝8.5、2.1Hz)，3.88(3H-OCH
3，s)
13C-NMR(100MHz，δppm，CD
3OD)：193.6(C＝O)，164.9(C-2’)，162.9(C-4’)，150.0(C-4)，147.3(C-3)，145.0(C-β)，134.2(C-6’)，129.1(C-1)，125.6(C-6)，123.8(C-α)，122.2(C-1’)，117.1(C-5)，115.7(C-2)，109.4(C-5’)，100.6(C-3’)，56.6(OCH
3)
The result shows that the chemical compound of acquisition is the Lignum Sappan chalcone with formula II:
Effect embodiment 1
The Lignum Sappan chalcone is to the influence of microtubule polymerization
Experimental apparatus: the multi-functional microplate reader of GENios Pro, available from Tecan company.
Experiment reagent: tubulin polymerization test kit (Tubul in Polymerization Assay Kit), available from Cytoskeleton company (Cat.#CDS03andBK006).
Experimental technique (being as the criterion) with tubulin polymerization test kit description:
1,37 ℃ of preheating 96 orifice plates, 30 minutes;
2,4 ℃ of pre-cooling tubulin polymerization solution (Tubulin Polymerization Buffer):
General tubulin buffer (General Tubulin Buffer) (750 μ l): 80mM piperazine-N, N '-two (2-ethanesulfonic acid) is (pH6.9) (PIPES), 2mM Mgcl2,0.5mM ethyleneglycolbis(2-aminoethylether)tetraacetic acid (EGTA);
Tubulin glycerol buffer (Tubulin Glycerol Buffer) (250 μ l): 15% glycerol (glycerol) is dissolved in the general tubulin buffer;
GTP (guanosine triphosphate) (GTP Stock) (200mM, 10 μ l): 1mM GTP (guanosine triphosphate) (GTP);
3, preheating 500 μ l General Tubulin Buffer are to room temperature;
4, be divided into 2 groups at random: (1) matched group: every hole adds 5 μ l General Tubulin Buffer; (2) Lignum Sappan chalcone group: every hole adds 10 μ l and prepares the Lignum Sappan chalcone (formula II) that embodiment 1 makes, and final concentration is 50 μ g/ml, hatches 2 minutes for 37 ℃; More than 2 experimental grouies, establish 3 multiple holes for every group;
5, get the tubulin of a pipe 200 μ l packing,, again it is positioned on ice as for dissolving 1 minute fast under the room temperature;
6, tubulin dilution is dissolved in the tubulin polymerization solution of 420 μ l pre-coolings, to final concentration be 3mg/ml;
7, every hole adds 100 μ l tubulins, immediately 96 orifice plates is put into microplate reader, the dynamic curve of record tubulin polymerization.
Experimental result: see Fig. 2.
The result shows that the Lignum Sappan chalcone can significantly suppress the polymerization of tubulin, compares with matched group, has significant difference.Infer that the Lignum Sappan chalcone may influence the formation and the function of spindle by suppressing tubulin polymerization, stops mitosis.
Effect embodiment 2
The Lignum Sappan chalcone is to the influence of people's gastric cancer HGC cell cycle
In vitro culture HGC cell when growth conditions is good, digests and inoculates 1 * 10
5Individual cell is in the 6cm culture dish, and it is adherent to spend the night.Deng cell state good after, inhale and go culture medium, add the Lignum Sappan chalcone (formula II) that the preparation embodiment 1 with the culture medium dilution makes, final concentration is 2 μ g/ml, negative control hole adds culture medium, cultivates 24h for 37 ℃.Observation of cell metamorphosis under the mirror.(0.25% pancreatin/0.02%EDTA), blow down gently moves into centrifuge tube, the centrifugal 5min of 2000rpm, PBS washing 2 times, the centrifugal 5min of 1000rpm with trypsin digestion cell.Slowly add 75% ethanol (20 ℃ of pre-coolings), 800 μ l in cell precipitation, vibration (Vortex) makes it to form unicellular as far as possible while dripping.4 ℃ fixedly spend the night after, the centrifugal 5min of 1000rpm, the PBS washed twice, centrifugal.Be resuspended in 300 μ l PBS, add the RNase (final concentration is 50 μ g/ml) that boiled in advance, hatch 30min for 37 ℃.300 order nylon net filters add propidium iodide (PI) (final concentration is 25 μ g/ml), 4 ℃ of lucifuge 1h, and flow cytometer detects cell cycle.
After the Lignum Sappan chalcone (formula II) that preparation embodiment 1 makes acted on HGC cell 24h, it is round that cell all becomes, and part is floating, and collecting cell carries out flow cytometer and detects.
The results are shown in Figure (as Fig. 1, A and B)
The result shows that after the effect of Lignum Sappan chalcone, G1, S phase cell obviously reduce, and G2 phase cell obviously increases, and the Lignum Sappan chalcone is described under 2 μ g/ml dosage, makes people's gastric cancer HGC cell stagnate the phase in G2-M, stops tumor cell to carry out normal mitosis.
Effect embodiment 3
Lignum Sappan chalcone and isoliquiritigenin are to the inhibitory action of kinds of tumor cells growth in the in vitro tests
In vitro culture murine sarcoma S180 cell, human embryo kidney (HEK) cancer 293 cells, human hepatoma HepG2 cell, people's pulmonary carcinoma A549 and CRL-5895 cell, people's gastric cancer HGC cell, human breast carcinoma MCF-7 cell, human leukemia HL-60 cell, human lymphoma U937 cell, human colon carcinoma HT-29 cell, human osteosarcoma MG-63 cell.Cell grows to the logarithmic growth after date, uses trypsin digestion cell, and centrifugal 5 minutes of 1000rpm abandons supernatant, and an amount of culture medium suspends, and adjusts cell concentration to 8 * 10
4/ ml.With cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ l, place (37 ℃ of cell culture incubators, 5%) after cultivating 24h in, Lignum Sappan chalcone (formula II) the 100 μ l that the preparation embodiment 1 of the every hole adding of Lignum Sappan chalcone group cell culture medium dilution makes, final concentration is 0.5 μ g/ml, the every hole of isoliquiritigenin group adds isoliquiritigenin (this prepared in laboratory) the 100 μ l of cell culture medium dilution, final concentration is 0.5 μ g/ml, the blank group adds the cell culture medium of equivalent, and each group is all established 6 multiple holes.After cultivating 66h in the incubator, every hole adds the MTT 20 μ l of 5mg/ml, places 4h for 37 ℃.Every hole adds three liquid (5%SDS, 10mM HCl, 5% isopropyl alcohol), and 37 ℃ are spent the night.492nm/620nm surveys absorbance (OD).The OD value is carried out the t check, and calculates the suppression ratio of medicine each growth of tumour cell:
Suppression ratio=(matched group OD value-administration group OD value)/matched group OD value * 100%.
The structure of isoliquiritigenin (Isoliquiritigenin) is shown in formula III:
Table 1 Lignum Sappan chalcone and isoliquiritigenin are to the inhibitory action of kinds of tumor cells growth
| The cell title | Lignum Sappan chalcone group OD value | Isoliquiritigenin group OD value | Matched group OD value | Lignum Sappan chalcone suppression ratio (%) | Isoliquiritigenin suppression ratio (%) |
| S180 | 0.0103±0.002* | 0.0204±0.001* | 0.3095±0.01 | 96.67％ | 93.41％ |
| 293 | 0.0027±0.005* | 0.0156±0.009* | 0.2578±0.03 | 98.95％ | 93.95％ |
| HepG2 | 0.0410±0.002* | 0.0365±0.005* | 0.2488±0.01 | 83.52％ | 85.33％ |
| A549 | 0.0275±0.00* | 0.102±0.01* | 0.1889±0.03 | 85.44％ | 46.00％ |
| CRL-5895 | 0.1268±0.001* | 0.116±0.03* | 0.2354±0.01 | 46.13％ | 50.72％ |
| HGC | 0.1082±0.003* | 0.189±0.05* | 0.4526±0.05 | 76.09％ | 58.24％ |
| MCF-7 | 0.0388±0.002* | 0.0523±0.009* | 0.1508±0.01 | 74.27％ | 65.31％ |
| HL-60 | 0.0256±0.00* | 0.0985±0.01* | 0.2315±0.03 | 88.94％ | 57.45％ |
| HT-29 | 0.0568±0.01* | 0.0756±0.01* | 0.1325±0.02 | 57.13％ | 42.94％ |
| MG-63 | 0.0258±0.00* | 0.0542±0.008* | 0.1456±0.01 | 82.28％ | 62.77％ |
| U937 | 0.1458±0.03* | 0.254±0.05* | 0.4789±0.02 | 69.56％ | 46.96％ |
* represent p＜0.01, compare to have significant difference with matched group
Experimental result is as shown in table 1, in various tumor cell culture liquid, add Lignum Sappan chalcone and isoliquiritigenin respectively after, the OD value of administration group all is lower than the blank group, difference has significance (p＜0.01).
The result shows, when Lignum Sappan chalcone and isoliquiritigenin dosage are respectively 0.5 μ g/ml, external murine sarcoma cell, human embryo kidney (HEK) cancerous cell, hepatoma carcinoma cell, lung carcinoma cell, stomach cancer cell, breast cancer cell, leukaemia, colon cancer cell, osteosarcoma cell, lymphoma cell are all had the effect of very strong its growth of inhibition, antitumor spectra is wide.
Effect embodiment 4
Lignum Sappan chalcone and isoliquiritigenin are to the inhibitory action of S180 tumor-bearing mice tumor growth
Laboratory animal: female, male SPF level KM mice, available from (credit number: SCXK (Shanghai) 2003-0003 of Shanghai Slac Experimental Animal Co., Ltd.; Certification of fitness numbering: 0023568), body weight is 18-22g, and SPF level Animal House is raised, and feedstuff and water are freely absorbed in 12h illumination/12h dark.
Experimental technique: get 7 days S180 ascites mice of inoculation, aseptic condition extracts ascites down, adjusts cell concentration to 5 * 10 with normal saline
6/ ml.It is subcutaneous that S180 cell suspension is seeded in mice right fore armpit with 0.2ml/ amount only.Behind the inoculation 24h, the male and female mice is divided into 3 groups (10 every group) respectively at random: Lignum Sappan chalcone group, prepare the Lignum Sappan chalcone (formula II) that embodiment 1 makes with dissolved in distilled water, dosage is 1mg/kg; The isoliquiritigenin group, with dissolved in distilled water isoliquiritigenin (this prepared in laboratory), dosage is 1mg/kg; Matched group gives distilled water, and the administration volume is 0.1ml/10g, and every day, gastric infusion was 1 time, continuous 10 days.Next day is put to death mice in drug withdrawal, strips the tumor piece and weighs, and calculates every cell mean, carries out the t check.Calculate tumour inhibiting rate:
Tumour inhibiting rate=(matched group tumor weight-administration group tumor is heavy)/matched group tumor heavy * 100%.
Table 2 Lignum Sappan chalcone and isoliquiritigenin are to the inhibitory action of S180 tumor-bearing mice tumor growth
* represent p＜0.01, compare to have significant difference with matched group
The results are shown in Table 2, Lignum Sappan chalcone and isoliquiritigenin be successive administration after 10 days respectively, the administration group is female, male mouse tumor weigh less than matched group, difference has significance (p＜0.01).
The result shows that Lignum Sappan chalcone and isoliquiritigenin can obviously suppress S180 tumor-bearing mice growth of tumor when 1mg/kg dosage.Simultaneously, the body weight of Lignum Sappan chalcone group and isoliquiritigenin group mice does not obviously descend, and compares with matched group, and difference does not have significance, illustrates that medicine is nontoxic substantially.
Embodiment 5
The preparation of tablet
Utilize routine techniques, mix following component, direct compression then, the pharmaceutical composition of preparation tablet form, its prescription is as follows:
| Composition | Recipe quantity (g/1000 sheet) |
| The Lignum Sappan chalcone (suc as formula II) that preparation embodiment 1 makes | 100 |
| |
50 |
| Microcrystalline Cellulose | 40 |
| Corn starch | 6 |
| Carboxymethyl starch sodium | 3 |
| Magnesium stearate | 1 |
| |
200 |
Embodiment 6
The preparation of injection
| Composition | Recipe quantity (g/1000ml) |
| The Lignum Sappan chalcone (suc as formula II) that preparation embodiment 1 makes | 10 |
| Sodium sulfite | 0.2 |
| Sodium carboxymethyl cellulose | 5 |
| Tween 80 | 1.5 |
| Water for injection | Add to 1000ml |
1. sodium sulfite is added in the 500ml water for injection, adds sodium carboxymethyl cellulose, mixing, soaked overnight (24 hours), complete molten after, filter with 210 order nylon cloths;
2. with 1. heating in water bath of solution, add tween 80, mixing;
3. to the water-bath boiling, add the Lignum Sappan chalcone, mixing continues heating 30 minutes, takes out and is cooled to room temperature, G
3Sintered glass funnel filters;
4. add the injection water to 1000ml, mixing, embedding is with 100 ℃ of sterilizations in 30 minutes.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. the chalcone compounds of a formula I or its pharmaceutically acceptable salt perhaps contain the purposes of the plant extract of this chemical compound,
In the formula,
R1, R2, R3 and R4 are selected from hydrogen, hydroxyl, C1-C8 alkoxyl, C1-C4 acyl group, halogen independently of one another;
It is characterized in that, be used to preparation or be used as mitotic inhibitor.
2. purposes as claimed in claim 1 is characterized in that described inhibitor can be used for suppressing tumor, and/or suppresses cell hyperproliferation.
3. purposes as claimed in claim 1 is characterized in that, R1 among the formula I, R2, R3 and R4 are selected from the alkoxyl of the straight or branched of hydroxyl, a 1-4 carbon atom independently of one another.
4. purposes as claimed in claim 1 is characterized in that, described chemical compound is suc as formula shown in the II:
5. the chalcone compounds of a formula I or its pharmaceutically acceptable salt perhaps contain the purposes of the plant extract of this chemical compound,
In the formula,
R1, R2, R3 and R4 are selected from hydrogen, hydroxyl, C1-C8 alkoxyl, C1-C4 acyl group, halogen independently of one another;
It is characterized in that, be used to prepare the compositions for the treatment of tumor.
6. purposes as claimed in claim 5 is characterized in that, described compositions is as mitotic inhibitor, and/or the cell hyperproliferation inhibitor.
7. purposes as claimed in claim 5 is characterized in that, R1 among the formula I, and R2, R3 and R4 are selected from the alkoxyl of the straight or branched of 1-4 carbon atom independently of one another.
8. purposes as claimed in claim 5 is characterized in that, described chemical compound is suc as formula shown in the II:
9. a pharmaceutical composition is characterized in that it contains
(a) formula II chemical compound or its pharmaceutically acceptable salt as active component of effective dose perhaps contain the plant extract of this chemical compound or its pharmaceutically acceptable salt;
(b) pharmaceutically acceptable carrier.
10. mitotic method of vitro inhibition, it is characterized in that, it comprises step: with concentration is chalcone compounds or its pharmaceutically acceptable salt suc as formula I of 0.1-50 μ M, and the plant extract that perhaps contains this chemical compound mixes with dimethyl sulphoxide solution;
In the formula,
R1, R2, R3 and R4 are selected from hydrogen, hydroxyl, C1-C8 alkoxyl, C1-C4 acyl group, halogen independently of one another.
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| CN102070429A (en) * | 2010-12-15 | 2011-05-25 | 厦门大学 | Chalcone derivative, and preparing method and application thereof |
| CN101580510B (en) * | 2009-05-27 | 2014-07-23 | 沈阳药科大学 | Artemisinin derivatives and application thereof |
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| CN105380931A (en) * | 2015-11-26 | 2016-03-09 | 成都中医药大学 | Anti-tumor application of chalcone compounds |
| CN106831376A (en) * | 2017-01-24 | 2017-06-13 | 昆药集团股份有限公司 | A kind of chalcone compound with active anticancer and preparation method thereof, preparation and application |
| CN107973708A (en) * | 2017-12-05 | 2018-05-01 | 王艳艳 | A kind of new chalcone compounds and its application |
| CN115990147A (en) * | 2022-12-07 | 2023-04-21 | 四川大学 | Application of metochalcone in preparation of tumor metastasis inhibiting drugs |
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- 2007-02-15 CN CN200710037570A patent/CN101244048B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101580510B (en) * | 2009-05-27 | 2014-07-23 | 沈阳药科大学 | Artemisinin derivatives and application thereof |
| CN102070429A (en) * | 2010-12-15 | 2011-05-25 | 厦门大学 | Chalcone derivative, and preparing method and application thereof |
| CN102070429B (en) * | 2010-12-15 | 2013-03-13 | 厦门大学 | Chalcone derivative, and preparing method and application thereof |
| CN105017056A (en) * | 2014-04-30 | 2015-11-04 | 中国医学科学院药物研究所 | Phenyl acrylketone derivative and preparation method, drug composition and application thereof |
| CN105017056B (en) * | 2014-04-30 | 2019-02-01 | 中国医学科学院药物研究所 | Phenylpropen ketone derivatives and its preparation method and pharmaceutical composition and purposes |
| CN105380931A (en) * | 2015-11-26 | 2016-03-09 | 成都中医药大学 | Anti-tumor application of chalcone compounds |
| CN106831376A (en) * | 2017-01-24 | 2017-06-13 | 昆药集团股份有限公司 | A kind of chalcone compound with active anticancer and preparation method thereof, preparation and application |
| CN107973708A (en) * | 2017-12-05 | 2018-05-01 | 王艳艳 | A kind of new chalcone compounds and its application |
| CN115990147A (en) * | 2022-12-07 | 2023-04-21 | 四川大学 | Application of metochalcone in preparation of tumor metastasis inhibiting drugs |
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|---|---|
| CN101244048B (en) | 2012-09-05 |
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