CN101502508B - Application of 5-oxo-4-alkenylene-pyrazole derivative in preparing anti-tumor medicament - Google Patents
Application of 5-oxo-4-alkenylene-pyrazole derivative in preparing anti-tumor medicament Download PDFInfo
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Abstract
The invention belongs to the field of genetic engineering and chemistry and relates to the application of 5-oxo-4-alkenylene-pyrazole derivatives in the preparation of anti-tumor drugs. The biomedical field is focused on finding novel anti-tumor drugs with low side effects, therefore, the invention provides the application of 2-{2-bromo-6-methoxy-4-[(Z)-(5-oxo-1,3-diphenyl-1,5-dihydro-4H-pyrazol-4-ylidene)methyl]phenoxy}acetamide, a small-molecule compound, in preparing the anti-tumor drugs. The compound can obviously inhibit the proliferation of tumor cells and slow down the growth rate of mouse tumors, moreover, the compound, which is designed for the CYPJ protein structure of cellular targets, has particularly obvious effect on the tumor cells of highly-expressed CYPJ protein, therefore, by developing the small-molecule compound as a novel anti-tumor drug, the invention has obvious anti-tumor effect, reduces the damage on normal cells and ensures the good specificity.
Description
Technical field
The present invention relates to genetic engineering, chemical field and field of medicaments, relate to the application of a kind of 5-oxo-4-alkenylene-pyrazole derivatives in the preparation medicines resistant to liver cancer.
Background technology
Tumor is the disease that cell hyperproliferation produces, and malignant tumor has become one of human lethal most important reason, and cancer almost draws equal sign with death for a long time.Therefore, many cancer patients, when know oneself got cancer after, at first be to get a hard knock mentally, some people even cause nervous breakdown can't fall asleep, vim and vigour descend rapidly, the state of an illness worsens fast.
Tumor treatment has operation, chemotherapy, radiotherapy and biotherapy etc.The antitumor drug market of using in the tumor therapeutic procedure is all increasing always.The statistical data of the Frost&Sullivan of U.S. medical inquiry company shows that global antitumor drug market total sales volume was 24,000,000,000 dollars in 2004, and surge in 2008 will reach 55,000,000,000 dollars or higher in 2009 to 48,000,000,000 dollars.
The main effect of anti-malignant-tumor agent is to kill and wound cancerous cell, stops its schizogamy.Its concrete classification is following with drug effect:
One, to the effect and the classification of drug of biomacromolecule
(1) influences nucleic acid (DNA, RNA) biosynthetic medicine
Nucleic acid is all biological important living matters, and it is controlling proteinic synthetic.The fundamental structural unit of nucleic acid is a nucleotide, and synthetic miazines precursor and the purine precursor and the synthetic thereof of needing of nucleotide, so the medicine of this type action can be divided into the antimetabolite that 1. stops miazines nucleotide to form again, like 5-fluorouracil etc.2. the antimetabolite that stops purine class nucleotide to form is like the 6-mercaptopurine etc.3. the medicine that suppresses dihydrofolate reductase is like methotrexate etc.4. the medicine that suppresses the DNA polymerase is like cytosine arabinoside.5. the medicine that suppresses ribonucleotide reductase is like hydroxyurea.
(2) medicine that directly destroys DNA and stop it to duplicate
Alkylating agent, ametycin, bleomycin etc. are arranged.
(3) disturb transcription to stop the synthetic medicine of RNA
Multiple antitumor antibiotic is arranged, like the daunorubicin of actinomycin D and anthracene nucleus class, amycin etc.
(4) influence the medicine of protein synthesis
Can be divided into that 1. to influence the formation of spindle fiber spindle fiber be a kind of micro-tubular structure, be polymerized by the subunit of tubulin.Vinca and this type of podophyllotoxin generic medicine.2. disturb the medicine of ribosome function, like harringtonine.3. disturb the medicine of aminoacid supply, like the L-asparaginase.
(5) influence the medicine that hormonal balance is brought into play antitumaous effect
Adrenocortical hormone, androgen, estrogen etc. are arranged.
Two, on cell proliferation effect of kinetics
Tumor tissues is mainly by proliferating-cell population and non-proliferative cell (G
0) group becomes (seeing Figure 49-2) the former can constantly press the index division growth, this part cell the ratio of the whole cell masses of tumor be called growth ratio (growth fraction, GF).It is bigger to increase rapidly tumor (like acute leukemia etc.) GF value, and the most responsive to medicine near 1, curative effect of medication might as well; Increase slow tumor (like most solid tumors), the GF value is less, and 0.5～0.01, low to drug susceptibility, curative effect is relatively poor.The GF value early stage with a kind of tumor is bigger, and the curative effect of medicine is also better.
1. cell cycle nonspecific agent (CCNSA) (cellcycle non-specific drugs) is mainly killed each phase cell in the proliferating-cell population, like alkylating agent.They all are index to the amount effect curve of mouse marrow stem cell and lymph tumor cell, wherein chlormethine and mitomycin selectivity low (slope of curve of killing and wounding two types of cells is very approaching), and other alkylating agent selectivitys of great majority are higher.
2. cycle-specific agent (cell cycle specific drugs) only has stronger effect to certain first phase in proliferating cycle, as suppressing the synthetic medicine of nucleic acid the S phase is acted on significantly; Vinblastine etc. act on the M phase.This type medicine also increases with dosage the amount effect curve of bone marrow and oncocyte and descends, but when reaching doses to the horizontal direction turnover, become a level ground, promptly increase dosage again, no longer include more cell and be killed.
Recent decades; One of main purpose of development antineoplaston medicine is that a kind of method in common of development makes tumor cell pair cell cytotoxic drug responsive more; But and not obvious increase is sought the big focus that novel anti-tumor medicine with low side effects becomes biomedicine field to Normocellular toxicity.Clinical practice through for many years shows that the emphasis of following antitumor drug research and development is to use the compound mode of more rational targeting and cell toxicity medicament to reach better therapeutic effect.
Summary of the invention
The purpose of this invention is to provide a kind of new antitumor drug.
The invention provides the application of a kind of 5-oxo-4-alkenylene-pyrazole derivatives in the preparation antitumor cell; This 5-oxo-4-alkenylene-pyrazole derivatives be 2{2-bromo-6-methoxyl group-4-[(Z)-(5-oxo-1; 3-diphenyl-1; 5-dihydro-4H-pyrazoles-4-base alkene) methyl] benzene oxygen acetamide (be 2-{2-bromo-6-methoxy-4-[(Z)-(5-oxo-1; 3-diphenyl-1,5-dihydro-4H-pyrazol-4-ylidene) methyl] phenoxy}acetamide), abbreviate FD10 in the present invention as.
5-oxo of the present invention-4-alkenylene-pyrazole derivatives molecular weight is 506.35, structural formula as
Shown in, abbreviate FD10 in the present invention as.
The present invention finds that at first through the computer screening FD10 possibly be able to suppress the growth of tumor cell.Then, the present invention has measured the effect of FD10 to tumor cell.The result shows; FD10 is to tumor cell; For example HCC, lung carcinoma cell H1299, cervical cancer cell Hela, breast cancer cell MCF7 (all available from cell institute of Shanghai life sciences institute of the Chinese Academy of Sciences) etc. all have lethality to a certain degree, and can reduce the cloning efficiency of tumor cell.Research shows that HepG2 and 7721 cells can cause G after adding FD10
0-G
1The phase cytosis, S phase cell reduces, G
2/ M the phase does not have significant change, although degree has difference, trend is consistent.The S phase is the cellular material synthesis cycle, and the S phase reduces, and explains that FD10 can suppress the propagation of duplicating of cellular material.Thereby think that FD10 of the present invention has the effect that tumor cell increases that suppresses.
Further research shows, FD10 of the present invention suppresses better effects if for the high stable strain cell SK-CYPJ of CYPJ expressing quantity.
Cyclophilin Cycliphilins (CyPs) is the intracellular protein of widespread distribution, in plant, antibacterial and mammal, all exists, and has high conservative property, is found as the cell receptor of ciclosporin A at first.The mRNA of CYPJ gene is up-regulated expression in 71.42% liver cancer tissue.The CYPJ overexpression can promote the clone of L02 and SK-Hep1 cell to form, and the also contrast quickening of the speed of growth of CYPJ stable expression cell strain nude mice subcutaneous transplantation tumor.
In the zoopery level, with the right side oxter of SK-Hep1 injection cell nude mice.After the tumor body forms, FD10 and negative control group every other day tumor body inner injecting and administering once, successive administration 30 times (60 days).The weight of comparison of tumor after 60 days, result's injection has the tumor of FD10 to be significantly less than contrast, and statistical result has significant difference.And find that through after the statistical calculations chemical compound of the present invention does not influence the nude mice body weight in experimentation.Experimental result to the influence of mouse boosting cell propagation shows that also FD10 does not have tangible immunosuppressant reaction.Thereby think that this chemical compound has the function that suppresses growth of tumour cell.
Therefore, FD10 of the present invention can suppress growth of tumour cell, especially to active high tumor cell and the HCC of CYPJ.
Antitumor drug of the present invention can be a medicines resistant to liver cancer, and FD10 promptly of the present invention can be used for preparing medicines resistant to liver cancer.Antitumor drug of the present invention also can be pulmonary carcinoma, cervical cancer or breast carcinoma.
Micromolecular compound of the present invention can adopt the method for preparing preparation of various routines.For example, adopt the method for artificial chemosynthesis.
In the application of people FD10 of the present invention in the preparation antitumor drug, can be injection or tablet.
Under different environment, when using (administration), different effects can be provided.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 through conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.
With FD10 of the present invention is example, can be with itself and suitable pharmaceutically acceptable carrier coupling.This type pharmaceutical composition contains chemical compound and the pharmaceutically acceptable carrier or the excipient of treating effective dose.This type carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.FD10 of the present invention can be made into the injection form, for example prepares through conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as tablet and capsule can prepare through 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 1 microgram/kg body weight-Yue 5 mg/kg body weight.In addition, FD10 of the present invention also can use with the other treatment agent.
When FD10 of the present invention is used as medicine; Can this polypeptide of treatment effective dose be applied to 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 8 mg/kg body weight, preferably this dosage is about 10 micrograms/kg body weight-Yue 1 mg/kg body weight.Certainly, concrete dosage is factor such as considered route of administration, patient health situation also, and these all are within the skilled practitioners skill.
FD10 is carried out structural modification and optimization, but better application is in the preparation antitumor drug.Above-mentioned " structural modification and optimization " comprises makes it that half-life in better hydrophilic, stronger degradation resistant property, the longer body, the structure of modification of antitumor spectrum etc. widely arranged, and increases or reduce methyl, ethyl, propyl group, butyl, isopropyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclopenta, cyclohexyl, benzyl, phenyl, hydroxyl, carboxyl, amino, formoxyl, acetyl group, methoxyl group, halogen, furyl, pyrrole radicals or a pyridine radicals etc.Promptly FD10 is carried out structural modification or transformation, can change the dissolubility of this chemical compound, prolong the continuous action time in vivo, and prevent the drug metabolism inactivation, so that improve the action effect of this medicine.
The present invention also provides a kind of method that suppresses growth of tumour cell, is about in the culture fluid of FD10 adding tumor cell.Concrete method can adopt the method that is adopted among the embodiment 1, perhaps other conventional operation.
Among the present invention, described tumor cell can be HepG2 cell, SK-Hep1 cell or 7721 cells.The result shows that FD10 of the present invention is for tumor cell, and especially the hepatoma cell proliferation inhibition effect like HepG2 cell, SK-Hep1 cell or 7721 cells etc. is very obvious.
Seeking novel anti-tumor medicine with low side effects is a big focus of biomedicine field.The invention provides micromolecular compound 2-{2-bromo-6-methoxyl group-4-[(Z)-(5-oxo-1,3-diphenyl-1,5-dihydro-4H-pyrazoles-4-base alkene) methyl] benzene oxygen } application of acetamide (FD10) in the preparation antitumor drug.This chemical compound can obviously suppress the propagation of tumor cell, can slow down the mouse tumor speed of growth, and this chemical compound is to the design of cell target spot CYPJ protein structure, and is obvious especially for the proteic tumor cell effect of high expressed CYPJ.Therefore, micromolecular compound of the present invention is developed as new antitumor drug, and tumor killing effect is obvious, and normal cell injury is reduced, and specificity is good.
The specific embodiment
Embodiment 1MTS method is measured the growth inhibited effect of FD10 to the SK-Hep1 cell
Human hepatoma cell strain SK-Hep1 cell (ATCC company) 2～5 * 10
3/ hole is seeded to 96 orifice plates, cultivates to make it adherent back in 24 hours and add FD10 (Interchim company UZI/9516006), establishes 6 Concentraton gradient, and each concentration is established 3 multiple holes.Cell is at 37 ℃, 5%CO
2Cultivate after 72 hours under the condition; Outwell culture fluid; Measure cell survival rate with MTS test kit (Promega company); Method of testing is: cell is washed one time with serum-free medium, added the MTS chromophoric solution (adding 2ml solution 1 and 100 μ l solution 2 in the 10ml serum-free medium, abundant mixings) for preparing in advance according to the amount of 100 μ l/well.Do not have the hole of cell to be made as this bottom outlet with one, absorb in order to the bias light of calibration solution.Putting into cell culture incubator to cell continues to cultivate 2～4 hours; Read absorbance value (reference wavelength 630-700nm with ELIASA then; Measure wavelength 490nm), calculate cell survival rate, to measure the numerical value of hole absorbance value/control wells absorbance value as cell survival rate.
Result: 2-{2-bromo-6-methoxyl group-4-[(Z)-(5-oxo-1,3-diphenyl 1,5-dihydro-4H-pyrazoles-4-base alkene) methyl] benzene oxygen } acetamide is to the half-inhibition concentration IC of SK-Hep1 cell
50Value is 28.30 ± 7.28 (ug/ml).
Among the present invention, half-inhibition concentration IC
50Required drug level when value is meant cell growth inhibiting 50%.
The influence of embodiment 2FD10 cell cycle
Human hepatoma cell strain HepG2 cell (ATCC company), 7721 cells (ATCC company) and SK-CYPJ stable cell line (this chamber makes up and preserves) 3 * 10
5/ ware is inoculated in the 60mm Tissue Culture Dish, cultivates to make it adherent back adding FD10 in 24 hours.37 ℃ of CO
2Incubator is cultivated 48hr.Cell culture fluid and cell are collected in the cell centrifugation pipe together, and the centrifugal 10min of 1000rpm abandons supernatant.Cell is washed 1 time with 1 * PBS of 2ml pre-cooling, and the centrifugal 10min of 1000rpm abandons supernatant.With 4 ℃ of 70% precooled ethanol fixedly 2hr or longer (also can spend the night).The centrifugal 10min of 1000rpm carefully sops up supernatant.Resuspended with 500-1000 μ l PI dye liquor, dyeing 20min in room temperature dark place detects the cell cycle situation of change with flow cytometer behind the filter membrane.
The result shows that HepG2 and 7721 cells behind the adding FD10 can cause G0-G1 phase cytosis, and S phase cell reduces, and the G2-M phase does not have significant change.And it is more obvious for the high stable strain cell SK-CYPJ effect of CYPJ expressing quantity.
Table 1FD10 is to the influence of HepG2 cell cycle
Table 2FD10 is to the influence of 7721 cell cycles
Table 3FD10 is to the influence of SK-CYPJ cell cycle
Visible by above-mentioned three tables, FD10 is consistent to the trend of HCC cycle influence, and degree has difference.The FD10 that records is carried out statistical analysis to the cycle influence of HepG2 cell, use the t-method of inspection, the result shows that G0-G1 phase and S phase add FD10 and compare both with contrast there were significant differences, p＜0.01, and do not have significant difference in the G2-M phase, p＞0.05.With identical methods analyst FD10 to 7721 with the influence of SK-CYPJ cell, the result is with last similar, explain can cause behind the adding FD10 HepG2,7721 and the SK-CYPJ cell G0-G1 phase increase, the S phase reduces, and influences less to the G2-M phase.The S phase is the cellular material synthesis cycle, and the S phase reduces, and explains that FD10 can suppress the propagation of duplicating of cellular material.
Embodiment 3FD10 is to the influence of cloning efficiency
1000/ware of SK-Hep1 cell (ATCC company) is inoculated in the 60mm Tissue Culture Dish, and one group adds FD10, and another group adds DMSO as contrast.Continuous culture 15-20 days time, liquid is taken the circumstances into consideration to change in the centre.Wash once with room temperature 1 * PBS, 4 ℃ of methanol that add the 2ml pre-cooling are 10min fixedly.Discard the fixedly methanol of usefulness, wash once, add the GIMESA stain with 1 * PBS of pre-cooling, room temperature dyeing 10min, clear water is washed 3 times, and removal floating color is taken pictures, is counted.
Confirm clone's size according to cell number,, be called middle clone between 100-200 cell, be called little clone between 50-100 cell greater than big clone of being called of 200 cells.Difference between the big-and-middle clone repeats 2 each three wares and averages, and adds behind the FD10 the formed clone's digital display of SK-Hep1 cell work and is less than and adds formed clone's number behind the DMSO.These results suggest, FD10 can suppress cell clone and form.
Big-and-middle clone's number of table 4 host cell SK-Hep1
Embodiment 4FD10 is to the influence of nude mice subcutaneous transplantation tumor growth
The BALB/C-nu/nu nude mice was raised for 4 week-6 weeks under no-special pathogen (SPF) condition.The SK-Hep1 cell is got 3 * 10
6Be suspended among the PBS 200ul, with the injector to inject of No. 6 syringe needles oxter, right side nude mice.The subcutaneous transplantation tumor success rate of nude mice is 100%, and be 14 days incubation period, and the tumor surface is smooth or be nodositas.After the tumor body forms, FD10 and negative control group every other day tumor body inner injecting and administering once, successive administration 30 times (60 days), each dosage 25mg/kg.The weight of comparison of tumor after 60 days, result's injection has the tumor of FD10 to be significantly less than contrast, and statistical result has significant difference.Zoopery shows that chemical compound of the present invention does not influence the nude mice body weight in experimentation, and does not have the immunosuppressant reaction.Thereby think that this chemical compound has the function that suppresses growth of tumour cell.
Claims (5)
1.5-the application of oxo-4-alkenylene-pyrazole derivatives in the preparation medicines resistant to liver cancer; Wherein, This 5-oxo-4-alkenylene-pyrazole derivatives is 2-{2-bromo-6-methoxyl group-4-[(Z)-(5-oxo-1,3-diphenyl-1,5-dihydro-4H-pyrazoles-4-base alkene) methyl] benzene oxygen } acetamide.
2. application as claimed in claim 1 is characterized in that, the molecular weight of said 5-oxo-4-alkenylene-pyrazole derivatives is 506.35, its molecular structure as
Shown in.
3. application as claimed in claim 1 is characterized in that, this medicines resistant to liver cancer is injection or tablet.
4. a method that suppresses liver cancer cell growth is characterized in that, the described 5-oxo of claim 1-4-alkenylene-pyrazole derivatives is added in the culture fluid of HCC.
5. method as claimed in claim 4 is characterized in that, described HCC is HCC HepG2, SK-Hep1 or 7721.
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