CN101112372A - Application of compound s1 in the preparation of anti-cancer medicine - Google Patents

Abstract

The invention relates to the field of cell biology and provides the application of a compound s1 in the preparation of anti-cancer drugs. Cancer becomes a first cause of death, and the substances which can kill the tumor and the growth of the cancer cells also become the hot spot in research in the current biomedical field. The s1 of the invention can kill or inhibit a variety of tumor cells and cancer cells; at the same time, the compound s1 of the invention also has the inhibition effect of phosphate kinase Aurora-B. All these probe that the compound s1 of the invention has the inhibition effect of malignant tumors. The compound s1 of the invention can be linked with the suitable pharmaceutical acceptable carriers to prepare the anti-cancer drugs, so as to inhibit the continuous growth of the tumors.

Description

The application of compound s 1 in the preparation cancer therapy drug

Technical field

The present invention relates to the cytobiology field, the application of compound s 1 in the preparation cancer therapy drug is provided.

Background technology

Tumor is the disease of serious harm human health.The sickness rate of tumor day by day increases in recent years, and the whole world has more than 600 ten thousand people to die from cancer every year at present, and new cases 8,000,000, this numeral are also increasing year by year.Have 1,000,000 New Development cancer patients every year in China's 1,300,000,000 populations, and patient to be treated about 2,000,000, dead about 1,300,000.Expect the end of the year in 2006, China will have 1,700,000 people to die from cancer, and cancer has become first cause of the death.

Malignant tumor is commonly called as cancer, is the lump unrestricted growth and diffusion that causes after the organ of human body and histiocyte morph.It can destroy the organ and the function of organization of human body, finite energy in the consumer, and people's vital movement is suffered damage, even cause death.

Mitosis is very important in a cell cycle process stage.Tumor and Normocellular difference are exactly unrestricted hypertrophy, and promptly mitosis loses normal regulation.Its occurrence cause of most tumor is the genomic unstability due to the mitosis, and genomic instability derives from chromosomal instability again, and chromosomal instability is the characteristic sign of cancer.Chromosomal separation, Centriolar duplicating with separating are taken place unusually, can cause the unusual of each cell chromosome number, both aneuploids, increase the chance of heterozygosity disappearance, the number increase of the disappearance of antioncogene or proto-oncogene all can make the conduction of metabolism of cell life and signal get muddled, and increases the chance of canceration.Kinases plays an important role in finishing mitosis and cell cycle regulating, thereby becomes present molecular biological research focus.

Summary of the invention

The purpose of this invention is to provide the application of compound s 1 in the preparation cancer therapy drug.

The invention provides structure as

The application of shown chemical compound in the preparation cancer therapy drug.The name of above-claimed cpd is called (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl) methylene]-1,3-dihydro-2H-indol-2-one abbreviates s1 as, and molecular weight is 238, can be by commercially available acquisition.The present invention comprises that also this chemical compound is carried out routine substitutes resulting chemical compound.

Among the present invention, compound s 1 can be used for preparing cancer therapy drug.

The present invention has detected the effect situation of compound s 1 for tumor cell and cancerous cell by standard MTS experiment, the result shows, SP1 of the present invention is to kinds of tumor cells and cancerous cell, and for example hepatoma carcinoma cell, colon cancer cell, stomach cancer cell and lung carcinoma cell etc. all kill and wound or suppress effect.

Studies show that further compound s 1 of the present invention has inhibitory action to phosphokinase Aurora-B.This has confirmed that further compound s 1 of the present invention has the inhibition effect of malignant tumors.

Malignant tumor is commonly called as cancer, is the lump unrestricted growth and diffusion that causes after the organ of human body and histiocyte morph.Kinases plays an important role in finishing mitosis and cell cycle regulating, thereby becomes present molecular biological research focus.AIK (Aurora/Ipl1 Kinase) is present one of known five big modulability kinases families.Up to the present, human Aiks family finds three member: Aik1, Aik2 (Aurora-B) and Aik3 altogether.Wherein, Aik2 mainly works in the cell mitogen phase.It follows albumen to participate in regulating the interaction of centromere and spindle microtubule as chromosome, this is instantaneous in mid-term to the later stage, Aurora-B migrates to cell mesozone band [Bischoff, J.R., Anderson by centromere, L., et al. (1998) EMBO J.17,3052-3065], be distributed in cell dish and back mitosis bridge latter stage, participate in back mitosis incident, thus with chromosomal separate with cytokinesis relevant.The sudden change of Aurora-B is suppressed the formation of branch dehiscence furrow, and causes forming apocyte.Aurora-B is positioned 17q13, and this zone occurs in the multiple cancerous cell of the mankind unusually, and in the colon cancer cell line of unusual ploidy the Aurora-B high expressed.Therefore, the scientific research personnel seeks the molecule with the Aurora-B effect one after another, and it is studied as antitumor drug.

The present invention has also set up the transplanted tumor mouse model, is used to detect the effect of s1 to in-vivo tumour and cancerous cell.The result shows that also s1 can suppress tumor growth in vivo.

Among the present invention, the pharmaceutical composition of forming by the compound s 1 that contains effective therapeutic dose (application quantity) and carrier pharmaceutically or excipient by the cancer therapy drug of compound s 1 preparation.

Among the present invention, described effective application quantity is mg/kg to 20 mg/kg body weight every day 0.1.

Among the present invention, prepared antitumor drug can be injection or tablet etc.

S1 of the present invention and analog thereof etc. when using (administration) in treatment, can provide different effects.Usually, can these materials are formulated in nontoxic, the inert and pharmaceutically acceptable aqueous carrier medium, wherein pH is about 5-8 usually, and preferably pH is about 6-8, although pH value can be with being changed to some extent by preparation 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): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.

With s1 of the present invention is example, can be with itself and suitable pharmaceutically acceptable carrier coupling.This class pharmaceutical composition contains protein and the pharmaceutically acceptable carrier or the excipient for the treatment of effective dose.This class carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.S1 of the present invention can be made into the injection form, for example is prepared by conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as tablet and capsule can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.The dosage of active component is the treatment effective dose, for example every day about 100 micrograms/kg body weight-Yue 20 mg/kg body weight.In addition, s1 of the present invention also can use with the other treatment agent.

When s1 of the present invention is used as medicine, can will treat this compound administration of effective dose in mammal, wherein should treat effective dose usually at least about 10 micrograms/kg body weight, and in most of the cases be no more than about 80 mg/kg body weight, preferably this dosage is about 500 micrograms/kg body weight-Yue 2 mg/kg body weight.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.

Cancer has become first cause of the death, and the material of killing tumor cells and growth of cancer cells also becomes the research focus of present biological medicine circle thus.S1 of the present invention kills and wounds kinds of tumor cells and cancerous cell or suppresses effect; Simultaneously, compound s 1 of the present invention has inhibitory action to phosphokinase Aurora-B.This has proved that all compound s 1 of the present invention has the inhibition effect of malignant tumors.Compound s 1 of the present invention be can be used for preparing cancer therapy drug with suitable pharmaceutically acceptable carrier coupling, to suppress the tumor continued growth.

Description of drawings

Fig. 1 is that s1 suppresses figure as a result to the HepG2 cell.As seen, s1 of the present invention is about 0.75 μ M to the IC50 (half causes death) of human liver cancer cell strain (HepG2).

The specific embodiment

Embodiment 1 vitro enzyme is lived and is suppressed experiment

Use escherichia expression system, clone, expression and purification have obtained people source Aurora-B protein kinase (the NCBI number of landing is NP_004208), are used for the high flux screening screening experiment.Adopt radio isotope technique, Aurora-B phosphorylated substrate MBP (UPSTATE company, CAT#13-110, lot#27845), with in the solution [γ- ³³P]-γ on the ATP- ³³P shifts and is covalently bound to substrate, makes its Ser phosphorylation, produces to have isotope-labeled substrate ³³P-MBP.Add scintillation solution at last and count by liquid scintillation counter and detect this enzymatic activity, can observe different chemical compounds to its active inhibition situation, with the activity of preliminary assessment chemical compound.

The parallel laboratory test result shows that compound s 1 of the present invention is 4.16nM to the IC50 that the Aurora-B protein kinase activity suppresses.

Embodiment 2 cancerous cell suppress experiment

Carry out according to standard MTS experiment, wherein concrete parameter is as follows:

Plant plate: 1000 cells/well

Chemical compound: s1

Incubation time: 96h

Add medicine post processing time: 3h

Compound concentration gradient: unit: uM

Repeated experiments: 6 groups

Data provide form: mean+SD

Cell strain: human liver cancer cell strain (HepG2)

The result shows that compound s 1 of the present invention is about 0.75 μ M to the IC50 that HepG2 suppresses.Specifically see the following form:

Drug level (uM)	25	12.5	6.25	3.125	1.5625	0.78125	0.390625	0.1953125	0
										s1- hepG2	0.0392± 0.0163	0.0767± 0.0174	0.111± 0.0156	0.124± 0.0128	0.131± 0.0158	0.134± 0.0267	0.165± 0.033	0.186± 0.045	0.286± 0.0148

Claims (5)

1. Structure as

   

   The application of shown chemical compound in the preparation cancer therapy drug.
2. 2. application as claimed in claim 1 is characterized in that, chemical compound shown in the claim 1 is used to prepare cancer therapy drug.
3. 3. use according to claim 1, it is characterized in that, the pharmaceutical composition that this cancer therapy drug is made up of the chemical compound shown in claim 1 that contains the effect consumption and carrier pharmaceutically or excipient.
4. 4. as application as described in the claim 3, it is characterized in that described effective application quantity is mg/kg to 20 mg/kg body weight every day 0.1.
5. 5. use according to claim 1, it is characterized in that this cancer therapy drug is injection or tablet.