CN101810608A - Anti-tumor small molecule compound targeting at human phosphatidylethanolamine-bindingprotein-4 - Google Patents
Anti-tumor small molecule compound targeting at human phosphatidylethanolamine-bindingprotein-4 Download PDFInfo
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Abstract
The invention relates to an anti-tumor small molecule compound targeting at human phosphatidylethanolamine-bindingprotein-4, which is synchronized by a medicine virtual screening platform based on the combination of bioinformatics and a computer technology. The small molecule compound has the advantages of good permeability, small toxin and side effect, simple structure, easy synchronization and the like. In addition, the compound can be used together with a tumor necrosis factor (TNF-Alpha) to enhance the anti-tumor effect of the latter, so as to play the role of curing tumor. Therefore, the compound is expected to become a new anti-tumor medicine. The invention also relates to a medicine compound of the small molecule compound and purposes thereof.
Description
Technical field
The invention belongs to biotechnology and medical domain.Particularly, the present invention relates to a kind of based on bioinformatics and computer technology, the specificity that obtains through virtual screening suppresses the proteic micromolecular compound of hPEBP4, this micromolecular compound has targeting antitumor cell hPEBP4 protein function, suppress growth of tumour cell and cause the function of apoptosis of tumor cells, thereby plays the effect of treatment tumor.The invention still further relates to the pharmaceutical composition that contains this micromolecular compound, and disclose the method that this compound medicine is used for disease treatment, particularly the purposes in the treatment of malignant tumor.
Background technology
Tumor is the second largest killer of face of mankind nowadays.Along with the development of oncomolecularbiology and the decoding of gene information, scientist has disclosed the molecule that works in a large number in tumor takes place.On this basis, neoplasm targeted therapy arises at the historic moment.Targeted therapy moves towards the clinical service for patients that is by the gene data of magnanimity from laboratory, becomes one of the most breathtaking field in the oncology studies.We can say that the most significant progress that recent two decades comes the oncotherapy field to obtain just is coming into operation of a plurality of targeted drugs.The area of computer aided drug screening by software on protein three-dimensional structure figure directly and chemical compound achieve a butt joint and screen, not only shortened the cycle of conventional medicament research and development greatly, and it is pointed strong, biological tolerance is good, onset is rapid, the advantage that cell permeability is strong is fresh combatants of neoplasm targeted therapy.
Human phosphotidylethanolabinding binding protein 4 (hPEBP4) is a new gene of finding recently.It is general high expressed in ovary, mammary gland, prostate and B lymphatic system tumor, does not reach and see Table in normal structure.Wang Xiaojian etc. report that in 2004 the expression excessively of this gene is relevant with the apoptosis that the anti-TNF-α of breast cancer cell causes for the first time, it suppresses mechanism of apoptosis and hPEBP4 block downstream signal with MEK in conjunction with Raf-1 relevant (the Wang X etc. of activation, J Biol Chem, 2004,279:45855-45864).
Other has experiment to show that hPEBP4 may also participate in suppressing the apoptosis of the carcinoma of prostate that TRAIL causes.Tumor invasion mechanism is not thoroughly illustrated so far as yet through the exploration in more than 100 years, but the viewpoint that the escape (" evasion of apoptosis ") of apoptotic signal has participated in cell carcinogenesis is widely accepted (Hanahan, D.﹠amp; Weinberg, R.A.Cell, 2000,100:57-70).
Since hPEBP4 is just specifically at the tumor cell high expressed, and participated in the opposing of tumor to apoptotic signal, therefore may can cancel its apoptosis inhibit feature at the micromolecular compound of this molecule, and might with drug combination such as TNF-α, open up a new road for the treatment of tumor.
At present, though developed the chemical compound that some suppress tumor growths, people still need to develop and new have the growth of tumour cell of inhibition or inducing tumor cell is transferred the active chemical compound of dying.
Summary of the invention
Purpose of the present invention just provide a kind of have suppress growth of tumour cell or inducing tumor cell is transferred the active chemical compound of dying.Another object of the present invention just provides the purposes of described chemical compound.
In a first aspect of the present invention, the purposes of acceptable salt on chemical compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone [3-(2-(2-hydroxy-5-nitrophenyl)-5-phenyl-1H-imidazol-4-yl) phenyl) is methanone (phenyl)], its pharmacy, health care conduct and learning or the bromatology or ester or their mixture is provided, and it is used to prepare the treatment tumor, suppress growth of tumour cell and/or inducing tumor cell is transferred the material of dying.
In an embodiment of the invention, described material is pharmaceutical composition, Halth-care composition or food additive.
In yet another embodiment of the present invention, described chemical compound, its pharmaceutically or on the health care conduct and learning acceptable salt or ester or their mixture account for the 0.001-100wt% of described material gross weight.
In a preference, described chemical compound, its pharmaceutically or on the health care conduct and learning acceptable salt or ester or their mixture account for the 1-95wt% of described material gross weight, preferred 5-90wt%, more preferably 10-80wt%.
In another preference, described material only contains acceptable salt or ester or their mixture on chemical compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone, its pharmacy, health care conduct and learning or the bromatology.
In another preference, described compositions contains acceptable carrier or excipient on pharmacy, health care conduct and learning or the bromatology.
In another preferred embodiment of the present invention, described compositions is unit dosage forms or multi-pharmaceutics, and wherein said chemical compound, its pharmaceutically or on the health care conduct and learning content of acceptable salt or ester or their mixture be the 0.05-50000mg/ agent, preferred 0.1-10000mg/ agent, more preferably 0.5-5000mg/ agent.
In yet another embodiment of the present invention, described compositions also contains other medicine that suppresses tumor.
In a preference, the described medicine that other suppresses tumor is selected from: cause apoptosis medicine, tumor vessel inhibition medicine or immunoregulation medicament, preferably cause the apoptosis medicine.
In a preference, the described apoptosis medicine that causes is selected from: tumor necrosis factor or TRAIL, preferably tumor necrosis factor, more preferably humanTNF-.
In yet another embodiment of the present invention, the dosage form of described compositions is tablet, capsule, powder agent, granule, suspensoid or injection.
In yet another embodiment of the present invention, described tumor or tumor cell are the tumor or the tumor cells of expressing human phosphotidylethanolabinding binding protein 4.
In a preference, described tumor or tumor cell are selected from: breast carcinoma, pulmonary carcinoma, gastric cancer, carcinoma of prostate, ovarian cancer, colon cancer, carcinoma of prostate, hepatocarcinoma or B lymphatic system tumor, preferred breast carcinoma, pulmonary carcinoma, gastric cancer, colon cancer, carcinoma of prostate or hepatocarcinoma, more preferably breast carcinoma.
In another preference, human phosphotidylethanolabinding binding protein 4 expressions of described tumor or tumor cell are higher than normal cell, preferably exceed 30%, more preferably exceed 50%.
In a second aspect of the present invention, a kind of compositions is provided, described compositions contains:
(1) acceptable salt or ester or their mixture on chemical compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone, its pharmacy, health care conduct and learning or the bromatology;
(2) cause the apoptosis medicine; And
(3) acceptable carrier or excipient on pharmacy, health care conduct and learning or the bromatology.
In a preference, the weight ratio of described component (1) and component (2) is 1: 1000 to 1000: 1, preferred 1: 500-500: 1, more preferably 1: 100-100: 1, preferred again 1: 50-50: 1.
In another preference, described component (1) accounts for the 0.001-99.9wt% of composition total weight, preferred 1-95wt%, more preferably 5-90wt%, preferred again 10-80wt%.
In yet another embodiment of the present invention, the described apoptosis medicine that causes is a tumor necrosis factor.
In a preference, described compositions also contains the therapeutic agent that is selected from down group: chemotherapeutic, as Fructus Bruceae breast, amycin, tamoxifen, 5-fluorouracil, Tegadifur, harringtonine, cytosine arabinoside, NSC-241240, paclitaxel, flutamide, ifosfamide, doxifluridine, Glass platinum, bend azoles or teniposide etc.; Tumor vessel suppresses medicine, as angiostatin, endostatin etc.; Or immunoregulation medicament such as Coriolous Dersicolor (Fr.) Quel glycopeptide, lentinan etc.
In a third aspect of the present invention, the purposes of acceptable salt on chemical compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone, its pharmacy, health care conduct and learning or the bromatology or ester or their mixture is provided, and it is used to prepare the inhibitor of human phosphotidylethanolabinding binding protein 4.
In a fourth aspect of the present invention, a kind of purposes of the mixture that is made of acceptable salt or ester or their mixture on chemical compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone, its pharmacy, health care conduct and learning or the bromatology and tumor necrosis factor is provided, and it is used to prepare the treatment tumor, suppress the compositions that growth of tumour cell and/or inducing tumor cell accent are died.
In another aspect of this invention, a kind of purposes of the mixture that is made of (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone and tumor necrosis factor is provided, it is characterized in that, be used to prepare treatment tumor, inhibition growth of tumour cell and/or inducing tumor cell and transfer the compositions of dying.
In another preference, described compositions is a pharmaceutical composition.
In another preference, described compositions also contains and causes the apoptosis medicine, more preferably is the humanTNF-.
In another preference, described medicine composition dosage form is tablet, capsule, powder agent, granule, suspensoid or injection.
In another preference, described tumor or tumor cell are to express proteic tumor of hPEBP4 or tumor cell.Preferably, described tumor is selected from down group: breast carcinoma, pulmonary carcinoma, gastric cancer, colon cancer, carcinoma of prostate, hepatocarcinoma etc.; More preferably, described tumor is selected from down group: breast carcinoma.
This aspect on the other hand in, a kind of compositions is provided, described compositions contains pharmaceutically acceptable carrier and (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone and causes the apoptosis medicine.
In another preference, the described apoptosis medicine that causes is a tumor necrosis factor.
In another preference, described compositions also contains the therapeutic agent that is selected from down group: Fructus Bruceae breast, amycin, tamoxifen, 5-fluorouracil, Tegadifur, harringtonine, cytosine arabinoside, NSC-241240, paclitaxel, flutamide, ifosfamide, doxifluridine, Glass platinum, bend azoles or teniposide, angiostatin, endostatin, polysaccharide-peptide, lentinan.
In another preference, described (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone and causing is transferred and to be died that weight ratio is 1: 1000 to 1000: 1 between the medicine.
This aspect on the other hand in, the purposes of a kind of (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone is provided, be used to prepare the inhibitor of human phosphotidylethanolabinding binding protein 4.
This aspect on the other hand in, a kind of purposes of the mixture that is made of (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone and tumor necrosis factor is provided, has been used to prepare the treatment tumor, suppresses growth of tumour cell and/or inducing tumor cell is transferred the compositions of dying.
In another preference, the present invention at tumor be the tumor of hPEBP4 abnormal expression in the growth course, as breast carcinoma.
This aspect on the other hand in, a kind of method for the treatment of tumor is provided, it comprises step: the mammalian object for the treatment of for needs is used micromolecular compound of the present invention.
In another preference, this method also is included in and uses before the micromolecular compound of the present invention, among or tumour medicine, the especially tumor necrosis factor etc. of using other afterwards cause and transfer the medicine of dying.
Others of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Description of drawings
Below in conjunction with accompanying drawing the present invention is further set forth.
Fig. 1 has shown DC240016 and the external bonded surface plasmon resonance result of hPEBP4;
Fig. 2 has shown the cell growth inhibited that DC240016 enhance TNF-α causes, wherein compound used therefor concentration is 5 μ M, and TNF-α concentration is 20ng/ml;
Fig. 3 has shown the inductive apoptosis of DC240016 enhance TNF-α, and wherein compound used therefor concentration is 5 μ M, and TNF-α concentration is 20ng/ml.
The specific embodiment
The inventor finds that through extensive and deep research the expression of hPEBP4 in the part tumor cell often raises, and the expression and the function that suppress hPEBP4 can suppress the propagation of tumor cell and the oncogenic activity of inside and outside.For this reason, the inventor use software from tens thousand of candidate compounds, sifted out some may with the protein bound micromolecular compound of hPEBP4; Use external method that these chemical compounds have been carried out second subsequently and take turns screening in conjunction with experiment and MTT, obtain first one strongly enhance TNF-α to the Compound D C240016 of breast cancer cell line MCF-7 inhibited proliferation, i.e. micromolecular compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone.Finished the present invention on this basis.
Particularly, the inventor studies show that, the selectivity high expressed of hPEBP4 in the breast cancer tumour tissue do not reach and see Table in normal galactophore tissue, and prompting hPEBP4 may take place with tumor and grow closely related.
In L929 cell line, the inductive apoptosis of TNF-α can be obviously resisted in expressing excessively of hPEBP4, promotes the cell growth, and pointing out it may be a molecule with anti-apoptotic effect.
The inventor's research finds that also in the breast cancer tumour cell of high expressed hPEBP4, the expression that suppresses hPEBP4 can strengthen the breast cancer tumour cell sensitivity apoptosis-induced to TNF-α, suppresses the clonality of tumor cell.Prompting hPEBP4 is likely the action target spot of treatment breast carcinoma.
The inventor studies show that, anti-apoptotic effect molecule hPEBP4 in processes such as cell adjusting and controlling growth, apoptosis, tumor generation, play an important role.Therefore, hPEBP4 probably in the diagnosis of clinical tumor and treatment as potential candidate's target.
On this basis, the inventor has screened a large amount of chemical compounds, thereby obtained a kind of micromolecular compound that can effectively suppress tumor, described micromolecular compound is specifically at the anti-apoptosis molecule of protein level targeting---hPEBP4 albumen, biological behaviour to the tumor cell of expressing hPEBP4 is intervened, thereby effectively suppress the function of hPEBP4, reach antitumous effect.
Active component
As used herein, term " micromolecular compound of the present invention ", " Compound D C240016 " or " The compounds of this invention ", " (phenyl) of the present invention ketone derivatives " are used interchangeably, and all point out micromolecular compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone and pharmaceutically acceptable salt and reactive derivative.
(3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone is the lead compound of a kind of targeting in human phosphotidylethanolabinding binding protein (hPEBP4), and its structural formula is as follows:
(3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone is a kind of known compound, can buy (as can be available from from Dutch Specs company) from commercial channels, also can prepare by conventional methodology of organic synthesis.
In the present invention, preferably " active component " refers to such micromolecular compound: described chemical compound and human hPEBP 4 albumen can mutually combine, and described chemical compound and TNF-α associating can make the growth of breast carcinoma MCF-7 cell be reduced to (i.e. reduction at least 60%) below 40%, preferably be reduced to below 38%, more preferably be reduced to below 35%, or to be reduced to above numerical value be between the scope of end points.
As used herein, among the present invention used (phenyl) ketone derivatives can with by pharmaceutically or the acceptable acid of physiology or the deutero-salt form of alkali use.These salt include, but is not limited to: the salt that forms with following mineral acid: example hydrochloric acid, sulphuric acid, nitric acid or phosphoric acid; With the salt of following organic acid formation, as acetic acid, oxalic acid, succinic acid or maleic acid; And other salt, include but not limited to: with the salt of alkali metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium) formation.The particularly preferred salt of one class is sodium salt or potassium salt.
The present invention also comprises the The compounds of this invention that exists with the form of " prodrug " of ester (for example carbamate) or other routine (when with this form administration, can change into active part in vivo).
Micromolecular compound of the present invention can effectively suppress the proteic function of human hPEBP 4, thereby suppresses the propagation of tumor cell, promotes the apoptosis of tumor cell.Particularly, micromolecular compound of the present invention, reverses the biological behaviour of the proteic tumor cell of positive expression human hPEBP 4 at human hPEBP 4 albumen at molecular level.Experiment proves: (1) suppresses the expression of hPEBP4 and the propagation that function can suppress tumor cell, promotes apoptosis of tumor cells; (2) suppress the expression of hPEBP4 and the external oncogenicity that function can suppress tumor cell in the body; (3) expression and the function that suppresses hPEBP4 can suppress the intravital growth of tumor cell.
Pharmaceutical composition
The present invention also comprises the pharmaceutical composition that contains (phenyl) ketone derivatives and pharmaceutically acceptable salt or ester.(phenyl) ketone derivatives of the present invention and pharmaceutical composition thereof can be used for treating cancer, promptly give (phenyl) ketone derivatives of the safe and effective amount of administration.
The compounds of this invention can with other therapeutic agent coupling, as cause apoptosis medicine TNF-a, TRAIL, Fructus Bruceae breast, amycin, tamoxifen, 5-fluorouracil, Tegadifur, harringtonine, cytosine arabinoside, NSC-241240, paclitaxel, flutamide, ifosfamide, doxifluridine, Glass platinum, bend azoles or teniposide etc.; Tumor vessel suppresses medicine angiostatin, endostatin etc.; Immunoregulation medicament polysaccharide-peptide, lentinan etc. can be by suppressing the treatment of diseases that hPEBP controls, alleviates or cures, for example cancer such as breast carcinoma.In addition, chemical compound of the present invention also can share with antineoplastic Chinese medicine (or its preparation).
A kind of preferred pharmaceutical composition also contains to cause transfers die medicine, especially tumor necrosis factor, as huamn tumor necrosis factory alpha etc.
When (phenyl) ketone derivatives or its pharmaceutically acceptable salt or ester are used for the treatment of tumor, it can with one or more pharmaceutically acceptable carrier or mixed with excipients, as solvent, diluent etc., thereby form pharmaceutical composition.
Liquid carrier comprises: sterilized water, Polyethylene Glycol, nonionic surfactant and edible oil (as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami).Solid-state carrier comprises: starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose and kaolin, as long as be fit to the characteristic of active component and required specific administration mode.Normally used adjuvant also can advantageously be comprised in pharmaceutical compositions, for example flavoring agent, pigment, antiseptic and antioxidant such as vitamin E, vitamin C, 2,6 ditertiary butyl p cresol (BHT) and butylhydroxy anisole (BHA).
Usually, pharmaceutical composition of the present invention comprises following dosage form: oral administered dosage form: as tablet, capsule, dispersible powder, granule or suspension (suspensoid) (containing 0.05-5% suspending agent (cosolvent) according to appointment), syrup (containing 10-50% sugar according to appointment) and elixir (containing the 20-50% ethanol of having an appointment); Perhaps carry out the parenteral canal drug administration with sterile injectable solution or suspensoid form (containing the 0.05-5% cosolvent of having an appointment in the medium waiting to ooze).These pharmaceutical preparatioies can contain and the blended about 0.001-99.9wt% of carrier usually, preferred 0.5-99.5wt%, 2.5-90wt% preferably, the active component of 5%-60wt% (weight) ((phenyl) ketone derivatives or its pharmaceutically acceptable salt or ester) more preferably is by the gross weight of compositions.
When pharmaceutical compositions, usually, these chemical compounds of the present invention can be formulated in nontoxic, the inert and pharmaceutically acceptable aqueous carrier medium, its pH is about 5-8 usually, preferably pH is about 6-8, although pH value can change to some extent with being prepared Substance Properties and disease to be treated.
The pharmaceutical composition for preparing can carry out administration by conventional route, comprising (but being not limited to): in the tumor, intramuscular, intraperitoneal, intravenous, subcutaneous, Intradermal, oral or topical.Preferred intravenously administrable mode.
(phenyl) that the present invention is used but ketone derivatives also parenteral or intraperitoneal administration.The solution or the suspension that also can in the water that suitably is mixed with surfactant (as hydroxypropyl cellulose), prepare these reactive compounds (as free alkali or pharmaceutically acceptable salt).Also can in glycerol, liquid, Polyethylene Glycol and the mixture in oil thereof, prepare dispersion liquid.Under routine storage and service condition, contain antiseptic in these preparations to prevent growth of microorganism.
The medicament forms that is adapted to inject comprises: aseptic aqueous solution or dispersion liquid and aseptic powder (being used for preparing aseptic injectable solution or dispersion liquid) temporarily.In all situations, these forms must be aseptic and must be that fluid is discharged fluid to be easy to syringe.Under manufacturing and condition of storage must be stable, and must be able to prevent the pollution effect of microorganism (as antibacterial and fungus).Carrier can be solvent or disperse medium, wherein contains just like water, alcohol (as glycerol, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetable oil.
When using (phenyl) of the present invention ketone derivatives, also can with other oncotherapy means (as radiotherapy) or other therapeutic agent (as TNF-α etc.) coupling.
The effective dose of used active component can change with the order of severity of the pattern of administration and disease to be treated.Yet, usually when The compounds of this invention every day with about 0.01-100mg/kg the weight of animals (0.02-20mg/kg body weight preferably, when dosage more preferably 0.1-10mg/kg body weight administration) gives, can obtain gratifying effect, preferably give with 1-4 time dosage every day, or with the slow release form administration.For most of large mammal, the accumulated dose of every day is about 5-5000mg or higher, preferably 10-1000mg.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 dosage of scalable is replied so that optimal treatment to be provided.For example, by an urgent demand of treatment situation, but give the dosage that several times separate every day, or dosage is reduced pari passu.
From being easy to prepare the position with administration, preferred pharmaceutical composition is a fluid composition.The intravenously administrable of (phenyl) ketone derivatives is preferred.
Halth-care composition
Except pharmaceutical compositions is used for the treatment of tumor, in the present invention, also acceptable salt or ester or extract on (phenyl) ketone derivatives or its health care conduct and learning can be used to prepare Halth-care composition, thereby be used for adjuvant therapy of tumors.
In the present invention, Halth-care composition contains on (phenyl) ketone derivatives of safe and effective amount (as 0.01-99wt%) or its health care conduct and learning acceptable carrier on acceptable salt or ester or extract and the health care conduct and learning.
Halth-care composition of the present invention can equally with pharmaceutical composition contain acceptable salt or ester or extract on (phenyl) ketone derivatives of same amount or its health care conduct and learning.Usually, the content of (phenyl) ketone derivatives can be more lower slightly in the Halth-care composition, for example contains acceptable salt or ester on 0.01-50wt% (phenyl) ketone derivatives or its health care conduct and learning.
Halth-care composition of the present invention can be made the dosage form of any routine by conventional method, preferably tablet, oral liquid, granule and capsule preparations.
Food additive
Except pharmaceutical compositions is used for the treatment of tumor and as Halth-care composition, be used for beyond the adjuvant therapy of tumors, in the present invention, also acceptable salt or ester or extract on (phenyl) ketone derivatives or its bromatology can be used to prepare food additive, thereby be used for adding food, improve the anti-tumor capacity and the adjuvant therapy of tumors of object.
In the present invention, food additive can contain (phenyl) ketone derivatives of safe and effective amount (as 0.01-99wt%) or its bromatology goes up acceptable carrier on acceptable salt or ester or extract and the bromatology.
Food additive of the present invention can equally with pharmaceutical composition or Halth-care composition contain acceptable salt or ester or extract on (phenyl) ketone derivatives of same amount or its bromatology.Usually, the content of (phenyl) ketone derivatives can be lower than the content in the health product in the food additive, for example contains acceptable salt or ester on 0.01-50wt% (phenyl) ketone derivatives or its bromatology.
In addition, in appropriate circumstances, it also is feasible that acceptable salt or ester or extract on (phenyl) ketone derivatives of the present invention or its bromatology are directly used as food additive, as long as they can not influence the taste and/or the outward appearance of food.
Food additive of the present invention can be made the form of any routine by conventional method, for example solution, powder, syrup etc.
Major advantage of the present invention is:
(a) the present invention is directed to the designed micromolecular compound of the proteic structure of human hPEBP 4, but efficient targeting suppresses anti-apoptosis molecule---hPEBP4 albumen, thereby be used for treatment of cancer;
(b) micromolecular compound of the present invention can also be united with other medicines and treatment means, is used for the treatment of malignant tumor.
(c) micromolecular compound of the present invention has good penetrability, and toxic and side effects is little, and is simple in structure, advantage such as is easy to synthesize.
Embodiment
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, usually according to normal condition, people such as Sambrook for example, " molecular cloning: laboratory manual " (New York, publishing house of cold spring harbor laboratory, New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or the condition of advising according to manufacturer.
Unless otherwise indicated, otherwise percentage ratio and umber calculate 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 among the present invention.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Cell line
MCF-7 cell line: ATCC:HTB-22 (available from ATCC), this is the breast cancer tumour cell line of a kind of positive expression hPEBP4.
The cultural method of MCF-7 cell line is as follows: in the RPMI1640 that contains 10% calf serum (Invitrogen company) culture fluid, placing 37 degrees centigrade, volume fraction is 5% CO with cell inoculation
2The conventional cultivation in the incubator, no medicine cultivated for two weeks before the experiment.
The screening of embodiment 1. micromolecular compounds (DC240016)
Adopt computer assisted virtual screening method to carry out.
At first, with the method for bioinformatics, utilize computer software (described software is Modeller8.0) to set up the 3 d structure model of hPEBP4.Then, the compound library (about 280,000 chemical compounds) available from Dutch Specs company is screened, choose best 8700 according to marking with DOCK 4.0 softwares (U.S. Kuntz laboratory).
1. continue to use Flex X software (available from BioSolveIT company) to dock, marking is got preceding 600 according to Flex X.Then, using commercially available autodock 3.05 softwares (U.S. Scripps university Mancur Olson laboratory) is that initial conformation is docked with the conformation of Flex X butt joint.The property of medicine of association class as a result (druglikeness) of butt joint is analyzed and unnecessary analogue compounds and obviously irrational are removed in perusal, chooses 100 chemical compounds at last.
Wherein, DC240016 micromolecular compound structural formula is suc as formula shown in the I, i.e. (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone:
(formula I)
For the DC240016 that selects (available from Dutch Specs company), by based on surface plasmon resonance (Surface Plasmon Resonance, SPR) Biacore 3000 instruments (Amersham company) of technology, the interaction between the real-time tracking biomolecule.
The result confirms that DC240016 combines external with hPEBP4, Figure 1 shows that the external binding curve of hPEBP4 of DC240016.
Calculate by analysis software and to obtain its dissociation constant R=10e-6.
Embodiment 3. micromolecular compounds (DC240016) are to the growth inhibited of tumor cell
Present embodiment has adopted conventional mtt assay.Concrete grammar is as follows:
The MCF-7 cell is spread 96 orifice plate overnight incubation with the density of 3000 cells/well.Then, micromolecular compound DC240016 is united separately or with the humanTNF-of 20ng/ml final concentration with variable concentrations (1.25,2.5,5,10,25,50 μ M) add in the hand-hole.After 44 hours, in every hole, add MTT (5mg/ml) 10 μ l, hatch to inhale after 4 hours for 37 degrees centigrade and abandon supernatant.Behind 150 μ l dmso solution purple crystals, place microplate reader (Model of Bio-Rad company 680), detect the absorbance at 570nm place.
The result shows that DC240016 can be in the inhibition of the 5 remarkable enhance TNF-α of μ M final concentration (20ng/ml) on cell proliferation, and pair cell causes significant toxic action (Fig. 2) and it uses not separately.
Embodiment 4.DC240016 chemical compound is to the detection of the enhancement effect of TNF-α killing tumor cell
The density of breast cancer cell line MCF-7 cell with 30000/hole is taped against in 24 orifice plates, hatch 16-24 hour after, add DC240016 to final concentration 5 μ M.After 4 hours, add TNF-α again to final concentration 20ng/ml or 50ng/ml.Act on after 48 hours, with detecting with flow cytometer (the Beckton Dickinson FACSCalibur of company) behind fluorescent dye rhodamine 123 (R-123) and iodate third ingot (PI, Invitrogen company) the labelling apoptotic cell.The cell of R-123/PI jack to jack adapter has been represented the cell of early apoptosis, and R-123 feminine gender and PI positive cells are represented apoptosis and dead cell in late period.
The result is as shown in Figure 3: coupling apoptosis rate (about 45%) significance of TNF-α (20ng/ml) and DC240016 (5 μ M) be higher than independent cell (about 14%) with TNF-α.In addition, consistent with MTT result: as to use the apoptosis (6%) that chemical compound does not cause significant cell separately.
But chemical compound specificity of the present invention suppresses human phosphotidylethanolabinding binding protein 4 (hPEBP4), therefore can be used for treating this proteic tumor of high expressed, as breast carcinoma.The result of the above embodiments of the present invention shows that The compounds of this invention can stably suppress hPEBP4, collaborative TNF-α killing tumor cell.
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 purposes of acceptable salt or ester or their mixture on chemical compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone, its pharmacy, health care conduct and learning or the bromatology, it is characterized in that, be used to prepare treatment tumor, inhibition growth of tumour cell and/or inducing tumor cell and transfer the material of dying.
2. purposes as claimed in claim 1 is characterized in that, described material is pharmaceutical composition, Halth-care composition or food additive.
3. purposes as claimed in claim 1 is characterized in that, described chemical compound, its pharmaceutically or on the health care conduct and learning acceptable salt or ester or their mixture account for the 0.001-100wt% of described material gross weight.
4. purposes as claimed in claim 1 is characterized in that, described compositions also contains other medicine that suppresses tumor.
5. purposes as claimed in claim 1 is characterized in that, the dosage form of described compositions is tablet, capsule, powder agent, granule, suspensoid or injection.
6. purposes as claimed in claim 1 is characterized in that, described tumor or tumor cell are the tumor or the tumor cells of expressing human phosphotidylethanolabinding binding protein 4.
7. a compositions is characterized in that, described compositions contains:
(1) acceptable salt or ester or their mixture on chemical compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone, its pharmacy, health care conduct and learning or the bromatology;
(2) cause the apoptosis medicine; And
(3) acceptable carrier or excipient on pharmacy, health care conduct and learning or the bromatology.
8. compositions as claimed in claim 7 is characterized in that, the described apoptosis medicine that causes is a tumor necrosis factor.
9. the purposes of acceptable salt or ester or their mixture on chemical compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone, its pharmacy, health care conduct and learning or the bromatology, it is characterized in that, be used to prepare the inhibitor of human phosphotidylethanolabinding binding protein 4.
10. one kind by the purposes with the mixture of tumor necrosis factor formation of acceptable salt or ester or their mixture on chemical compound (3-(2-(2-hydroxyl-5-Nitrobenzol)-5-phenyl-1 hydrogen-imidazol-4 yl) phenyl) (phenyl) ketone, its pharmacy, health care conduct and learning or the bromatology, it is characterized in that, be used to prepare treatment tumor, inhibition growth of tumour cell and/or inducing tumor cell and transfer the compositions of dying.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998027065A1 (en) * | 1996-12-16 | 1998-06-25 | Ontogen Corporation | Modulators of proteins with phosphotyrosine recognition units |
| CN101234113A (en) * | 2007-02-01 | 2008-08-06 | 中国人民解放军第二军医大学 | Anti-tumor small molecular compound targeting to phosphatidylethanolamine conjugated protein 4 of human |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998027065A1 (en) * | 1996-12-16 | 1998-06-25 | Ontogen Corporation | Modulators of proteins with phosphotyrosine recognition units |
| CN101234113A (en) * | 2007-02-01 | 2008-08-06 | 中国人民解放军第二军医大学 | Anti-tumor small molecular compound targeting to phosphatidylethanolamine conjugated protein 4 of human |
Non-Patent Citations (1)
| Title |
|---|
| 裘建明: "hPEBP4促进肿瘤细胞ERa介导的转录活化的研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
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