CN102432612A - 4,7-dihydrotetrazole[1,5-a]pyrimidine derivative and application thereof to preparation of antitumor medicine - Google Patents
4,7-dihydrotetrazole[1,5-a]pyrimidine derivative and application thereof to preparation of antitumor medicine Download PDFInfo
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- CN102432612A CN102432612A CN2011102639533A CN201110263953A CN102432612A CN 102432612 A CN102432612 A CN 102432612A CN 2011102639533 A CN2011102639533 A CN 2011102639533A CN 201110263953 A CN201110263953 A CN 201110263953A CN 102432612 A CN102432612 A CN 102432612A
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Abstract
The invention discloses one kind 4,7- dihydro tetrazolium [1,5-a] pyrimidine derivatives, which is characterized in that the chemical structural formula of 4,7- dihydro tetrazolium [1, the 5-a] pyrimidine derivatives is as shown in following general formula:
In formula, X is methylene CH2, imino group NH or 0; R1 is the alkyl of C1~C3, the phenyl containing a substituent group of C6~C8, benzyl, the 5- or 6-membered fragrant heterocyclic radical containing N; R2 are as follows: the phenyl containing 1~3 substituent group, 5- or 6-membered fragrant heterocyclic radical or benzheterocycle group containing N; Wherein, the substituent group is selected from: hydrogen, methyl, methoxyl group, ethyoxyl, benzyloxy, nitro. Present invention firstly discovers that kind 4,7- dihydro tetrazolium [1,5-a] pyrimidine derivatives or its pharmaceutical salt has the function of ROCK inhibitor, and the proliferation of lung carcinoma cell, breast cancer cell is significantly inhibited, may be used as the drug of preparation anti-lung cancer, anti-breast cancer.
Description
Technical field
The present invention relates to a kind of 4,7-dihydro tetrazolium [1,5-a] pyrimidine derivatives and the application in the preparation antitumor drug thereof.
Background technology
Cancer is that malignant tumour is the No.1 killer of present human health.The statistic data of Ministry of Health's announcement in 2010 shows that malignant tumour has become the Chinese primary cause of the death.Therefore, treatment for cancer is very urgent.Cancer is a process that multistep is rapid, relates generally to the variation of a plurality of genes; When the gene of regulating cell growth is undergone mutation or is damaged; The programmed death of cell is suppressed; Make cell out of hand, growth that continues and division and produce tumour can be quickened the formation of tumor neogenetic capillary vessel simultaneously in the infiltration of these cancer cells and the transfer process.In the most general genovariation, what cause these defectives is the abnormal activation of GTP enzyme Ras family.The proteic sudden change of Ras comes to light and occurs in 30% the human tumor, and the Rho family protein is the member of the super family of Ras of small G-protein, has the GTP enzymic activity.
Rho kinases (ROCKs) belongs to the serine/threonine protein kitase of AGC family, and it is first found Rho downstream effect factor, through the influence of phosphorylation light chain having been regulated the variation of RhoA inductive myosin cytoskeleton.Research shows that all respects of Rho family protein and tumor development all are related, and comprises growth of tumor and propagation, invasion and attack and transfer, apoptosis, tumor neovasculature formation etc.What Rho protein continued in human tumor is activated, uncontrolled propagation, invasion and attack body and vicious transformation.Because the effect of Rho/ROCK signal in tumor cell proliferation, differentiation and motion makes that treating some tumour that has Rho signal excessive activation through blocking-up ROCK signal becomes the focus that people pay close attention to.ROCK is divided into two kinds of ROCK I and ROCK II.The over-expresses of ROCK is or/and highly activate the generation all can cause disease, and relevant with it disease mainly comprises cardiovascular disorder, nervous system disorders, fibrotic disease and tumour etc.At anti-tumor aspect, find that all the ROCK suppressor factor can suppress invasion by tumor cells and transfer in the research of people on liver cancer cell, ovarian cancer cell, liver cancer cell, lung cancer cell line, breast carcinoma cell strain, bladder cell strain etc.
Aspect antitumor drug research, external many pharmaceuticals and scientific research institution are developing the new ROCK suppressor factor with antitumous effect.At present, though there are some ROCK suppressor factor to get into I phase or II phase clinical study stage (like BA-210), the ROCK suppressor factor that success is gone on the market only has one, promptly method Soviet Union ground you (Fasudil), and only limit to the Japanese market.Therefore, actively seek and design new ROCK suppressor factor, and explore its anticancer effect, have important clinical meaning and wide application prospect.
Summary of the invention
It is a kind of 4 that goal of the invention of the present invention provides, 7-dihydro tetrazolium [1,5-a] pyrimidine derivatives and the application in the preparation antitumor drug thereof.
For reaching the foregoing invention purpose, the technical scheme that the present invention adopts is: a kind of 4, and 7-dihydro tetrazolium [1,5-a] pyrimidine derivatives, its chemical structural formula is shown in following general formula:
In the formula, X is methylene radical CH
2, imino-NH or O;
R
1Containing a substituent phenyl, phenmethyl, contain 5 yuan or the 6 membered aromatic heterocycle bases of N for the alkyl of C1～C3, C6～C8;
R
2For: contain 1～3 substituent phenyl, contain 5 yuan or 6 membered aromatic heterocycle bases or the benzheterocycle group of N;
Wherein, said substituting group is selected from: hydrogen, methyl, methoxyl group, oxyethyl group, benzyloxy, nitro.
In the optimized technical scheme, said 4,7-dihydro tetrazolium [1; 5-a] pyrimidine derivatives is selected from: 7-(4-hydroxy 3-methoxybenzene base)-5-methyl-6-carboxylic acid benzene methyl-4,7-dihydro tetrazolium (1,5-α) pyrimidine, 7-(3; 4-diethoxy phenyl)-and 6-[N-(2-p-methoxy-phenyl) formamido-]-5-methyl-4,7-dihydro tetrazolium (1,5-α) pyrimidine, 7-(4-benzyloxy-3-p-methoxy-phenyl)-6-(N-phenyl formamide base)-5-methyl-4; 7-dihydro tetrazolium (1,5-α) pyrimidine, 7-(2-N-pyrimidine)-5-fluoro-6-carboxylic acid benzene methyl-4,7-dihydro tetrazolium (1; 5-α) pyrimidine, 7-phenyl-6-(N-phenmethyl) formamido--5-methyl-4,7-dihydro tetrazolium (1,5-α) pyrimidine, 7-(1; 3-benzo dioxole)-6-[N-(2-p-methoxy-phenyl) formamido-]-5-methyl-4,7-dihydro tetrazolium (1,5-α) pyrimidine, 7-(3-methoxyl group-3 '-nitro-4-hydroxy phenyl)-6-[N-(2-p-methoxy-phenyl) formamido-]-5-methyl-4; 7-dihydro tetrazolium (1; 5-α) pyrimidine, 7-(4-benzyloxy phenyl)-6-[N-(2-pyridine) formamido-]-4,7-dihydro tetrazolium (1,5-α) pyrimidine, 7-(4-p-methoxy-phenyl)-6-carboxylic acid isopropyl esters-4; 7-dihydro tetrazolium (1,5-α) pyrimidine; Its chemical structural formula is as follows successively:
The present invention is to above-mentioned 4, and 7-dihydro tetrazolium [1,5-a] pyrimidine derivatives has further carried out Determination of biological activity, finds that they all have obvious inhibiting activity to ROCK1, for mammary cancer and lung carcinoma cell fragmentation effect is in various degree arranged all at cell levels
Therefore; The present invention requires to protect above-mentioned 4 simultaneously; 7-dihydro tetrazolium [1; 5-a] pyrimidine derivatives or its pharmaceutically useful salt are in the application of preparation ROCK suppressor factor, and said pharmaceutically useful salt comprises hydrochloride, phosphoric acid salt, vitriol, acetate, PHENRAMINE MALEATE, citrate, benzene sulfonate, toluenesulfonate, fumarate, tartrate.
It is above-mentioned 4 that the present invention requires to protect simultaneously, the application in the anti-lung cancer of preparation, breast cancer medicines of 7-dihydro tetrazolium [1,5-a] pyrimidine derivatives or its pharmaceutically useful salt.
Because the technique scheme utilization, the present invention compared with prior art has advantage:
1. the present invention has found 4 first; 7-dihydro tetrazolium [1; 5-a] pyrimidine derivatives or its pharmaceutically useful salt possesses the function of ROCK suppressor factor, and the propagation of lung carcinoma cell, breast cancer cell is had the obvious suppression effect, and can be as the medicine of the anti-lung cancer of preparation, anti-breast cancer.
Description of drawings
Prepare 7-(4-hydroxy 3-methoxybenzene base)-5-methyl-6-carboxylic acid benzene methyl-4 among Fig. 1 embodiment one, the synthetic route chart of 7-dihydro tetrazolium (1,5-α) pyrimidine;
Fig. 2 be among the embodiment two suppressor factor to the inhibition curve of ROCK1;
Fig. 3. (a). the combination conformation (suppressor factor adopt rod shape models show) of suppressor factor in the ROCK1 active pocket; (b). the interaction pattern between suppressor factor and the ROCK1 active pocket residue;
Suppressor factor is to the fragmentation effect of HeLa cell among Fig. 4 embodiment two;
Suppressor factor is to the fragmentation effect of H460 lung carcinoma cell among Fig. 5 embodiment two;
Suppressor factor is to the fragmentation effect of MDA-231 breast cancer cell among Fig. 6 embodiment two;
The mouse body weight is schemed over time among Fig. 7 embodiment two.
Embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is further described:
Embodiment one: preparation 7-(4-hydroxy 3-methoxybenzene base)-5-methyl-6-carboxylic acid benzene methyl-4,7-dihydro tetrazolium (1,5-α) pyrimidine.
Referring to (Yao, C.Heterocyl.Chem.2008,45,1609; Gein, V.L.Russ.J.Org.Chem.2010,46,699; Zeng; L.Y.J.Comb.Chem.2010,12,35); Synthetic route according to Fig. 1: with these three commercial reagent of Vanillin (5), 5-amino tetrazole (2) and benzyl acetoacetate (6) is raw material, and the method for treating different things alike through three components just can a step obtain compound 7.This reaction can be carried out during to 130-170 ℃ at direct heating under the solvent-free condition; Adding after thionamic acid is catalyzer, solvent-free or ethanol is that temperature of reaction drops to 85 ℃ and just can finely carry out under the condition of solvent; As catalyzer, Virahol is a solvent, also can obtain good productive rate under the condition of reflux with the iodine of 10mol%.Behind the recrystallization, the purity of compound can arrive more than 95%.Product is analyzed, and analytical results shows that products therefrom is 7-(4-hydroxy 3-methoxybenzene base)-5-methyl-6-carboxylic acid benzene methyl-4,7-dihydro tetrazolium (1,5-α) pyrimidine, and its chemical structural formula is:
Embodiment two:
(1) embodiment one gained compound is carried out the enzyme inhibition activity experiment of ROCK 1
Experimental principle: compound R OCK1 suppresses active measurement and has adopted the Z ' of Invitrogen company-LYTE technology; This technology is basis with phosphorylation and non-phosphorylating polypeptide to the sensitivity differences that proteolyze cuts based on FRET (FRET) principle.
Experimental technique: the preparation of (1) reagent.Kinase buffer liquid: the 5X kinase buffer liquid of 2ml is diluted with water to 10ml; Compound: with the compound that will test be diluted with water to a concentration gradient; The mixing solutions of ROCK kinases/substrate: the mixing solutions of preparing 2250 μ L ROCK/ substrates; The concentration of enzyme is 10ng/ml, and the concentration of substrate is 4 μ M, and solvent is a kinase buffer liquid; Phosphorylation polypeptide solution: serine/threonine phosphorylation 7 peptides of 2 μ L are added in the kinase buffer liquid of 498 μ L, fully mixing; ATP solution: the ATP solution of preparing 1110 μ L.Concentration is 50 μ M, and solvent is a kinase buffer liquid; Developer: by 1: 32768 dilution proportion developer A.(2) experimental procedure: 1. the compound solution that 2.5 μ L is prepared is added to black 384 orifice plates; 2. the mixing solutions that adds 5 μ LROCK kinases/substrates; 3. add 2.5 μ LATP solution; 4. 384 orifice plates are at room temperature shaken and cultivated 1 hour; 5. 5 μ L developers are joined in the orifice plate, continue reaction 1 hour; 6. orifice plate is placed the ELIASA reading.
Experimental result: the 7-of different concns (4-hydroxy 3-methoxybenzene base)-5-methyl-6-carboxylic acid benzene methyl-4; 7-dihydro tetrazolium (1; 5-α) pyrimidine carries out the enzyme inhibition activity experiment of ROCK 1, finds that this compound has good restraining active, and its 503nhibiting concentration IC50 is 13.7 μ M/L (Fig. 2).
(2) evaluation of interaction pattern between suppressor factor and the ROCK1
Experimental principle: based on molecular docking and molecular dynamics simulation, from the interaction pattern between atomic scale prediction suppressor factor and the ROCK1.
Experimental procedure: the result based on the molecular docking prediction obtains, to the molecular dynamics simulation that suppressor factor/ROCK1 carries out 5ns, simulate and adopted AMBER9.0.
Experimental result: suppressor factor and the interaction between the ROCK1 through molecular docking prediction and molecular dynamics simulation obtain are as shown in Figure 3.Predict shows that the molecular recognition between suppressor factor and the ROCK1 is mainly through Van der Waals and interaction of hydrogen bond.Hydroxyl on the suppressor factor and amino meeting and Gly88 and two stable hydrogen bonds of Asn203 formation; Two phenyl ring can produce strong Van der Waals and interact with a plurality of hydrophobic residue on every side, comprise Leu 107, Ile82, Val90 and Leu205; Meeting of the positive ion of Lys and phenyl ring form the interaction of π positively charged ion in addition.
(3) cellular sensitivity experiment
Experimental principle: the MTT analytical method is the basis with viable cell metabolite reductive agent MTT tetrazolium bromide, utilizes ELIASA to be determined at the absorbancy at 490nm place, reflecting the viable cell number, thereby measures the fragmentation effect of compound to tumour cell.
Experimental procedure: 1. collect the logarithmic phase cell, the adjustment concentration of cell suspension, every hole adds 100 μ L, bed board make cell density to be measured be 1000-10000/hole (marginal pore is filled with aseptic PBS); 2. 96 orifice plates are placed on 5%CO2, hatch in 37 ℃ of incubators, be paved with the hole to cell monolayer at the bottom of, add the medicine of concentration gradient.In principle, get final product dosing behind the cell attachment, or two hours, or time half a day, but we are everlasting evening before that day bed board, dosing in morning next day.General 5-7 gradient, every hole 5 μ L establish 3-5 parallel hole; 3.5%CO2 was hatched 16-48 hour for 37 ℃, and inverted microscope is observed down; 4. every hole adds 20 μ L MTT solution (5mg/ml, i.e. 0.5%MTT), continues to cultivate 4h.If medicine and MTT can react, discard nutrient solution after can be earlier centrifugal, carefully use PB S after 2-3 time, adding contains the nutrient solution of MTT again; 5. stop cultivating, the careful suction removed nutrient solution in the hole; 6. every hole adds 150 μ L DMSO 99.8MIN.s, puts low-speed oscillation 10min on the shaking table, and crystallisate is fully dissolved.Measure light absorption value at the 490nm place through enzyme-linked immunosorbent assay instrument.And ROCK 1 crosses high expression level in multiple cancer cells; So the anticancer cytoactive that we attempt this compound with multiple cancer cells, the cancer cells of use have H460, HepG-2, A549,7721, K562, KB, MCF-7, MDA-231, Lp1 and OPM-2.Confirm the toxicity size of this kind compound through the HeLa cell experiment.
Experimental result: experimental result shows; The HeLa cytotoxicity of compound lower (Fig. 4); But compound has good anticancer cytoactive (Fig. 5 and 6) to MDA-231 mammary cancer especially A549 lung carcinoma cell, and the median lethal concentration of A549 lung carcinoma cell is ED50=7.5 μ M/L.So compound 7-(4-hydroxy 3-methoxybenzene base)-5-methyl-6-carboxylic acid benzene methyl-4; 7-dihydro tetrazolium (1; 5-α) it is active that pyrimidine not only has good ROCK 1 inhibition; Also have good lung carcinoma cell and tangible breast cancer cell fragmentation effect, might become a kind new medicine of treatment tumour.
(4) chmice acute toxicity test
Experimental principle: acute toxicity test is mainly studied the interior single or multiple of certain hour and is given toxic reaction and the death condition that animal produced after the chemical substance.This experiment can obtain mld (LD
50), can cause the agent amount of being tried that laboratory animal 50% is dead.According to OECD chemical substance toxicity grading standard in 1998, with 5,50,300,2000,5000mg/kg is dividing point, and material toxicity is divided into 5 grades.Work as LD
50During＞2000mg/kg, this kind compound can be considered to nontoxic basically.
Experimental procedure: 10 of balb/c mouse are adopted in experiment, about body weight 20g.Adopt the mode of oral administration, dosage is 2000mg/kg, observes 14 days after the administration.
Experimental result: experimental result shows that mouse does not have any unusual condition, does not have dead.As shown in Figure 7, after administration, the body weight of mouse is steadily increasing, explains that this compound is very safe, can assert nontoxicly basically, can be used as a kind of potential medicine and carries out follow-up research and development.
Claims (3)
1. one kind 4,7-dihydro tetrazolium [1,5-a] pyrimidine derivatives is characterized in that, and is said 4, and the chemical structural formula of 7-dihydro tetrazolium [1,5-a] pyrimidine derivatives is shown in following general formula:
In the formula, X is methylene radical CH
2, imino-NH or O;
R
1Containing a substituent phenyl, phenmethyl, contain 5 yuan or the 6 membered aromatic heterocycle bases of N for the alkyl of C1～C3, C6～C8;
R
2For: contain 1～3 substituent phenyl, contain 5 yuan or 6 membered aromatic heterocycle bases or the benzheterocycle group of N;
Wherein, said substituting group is selected from: hydrogen, methyl, methoxyl group, oxyethyl group, benzyloxy, nitro.
2. claim 1 is said 4, and 7-dihydro tetrazolium [1,5-a] pyrimidine derivatives or its pharmaceutically useful salt are in the application of preparation ROCK suppressor factor.
3. claim 1 is said 4, the application in the anti-lung cancer of preparation, breast cancer medicines of 7-dihydro tetrazolium [1,5-a] pyrimidine derivatives or its pharmaceutically useful salt.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103193780A (en) * | 2012-04-24 | 2013-07-10 | 广州融新生物科技有限公司 | Use of 4,7-dihydrotetrazyl[1,5-alpha]pyrimidine compound and its derivatives in preparation of drug for prevention or treatment on cerebral hemorrhage |
| CN106817899A (en) * | 2014-07-15 | 2017-06-09 | 百时美施贵宝公司 | As the volution heptane of ROCK inhibitor |
| CN110229161A (en) * | 2019-07-12 | 2019-09-13 | 江苏建筑职业技术学院 | The solvent-thermal process method of tetrazole simultaneously [1,5-a] pyrimidine derivatives |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103193780A (en) * | 2012-04-24 | 2013-07-10 | 广州融新生物科技有限公司 | Use of 4,7-dihydrotetrazyl[1,5-alpha]pyrimidine compound and its derivatives in preparation of drug for prevention or treatment on cerebral hemorrhage |
| CN103193780B (en) * | 2012-04-24 | 2015-07-08 | 广州融新生物科技有限公司 | Use of 4,7-dihydrotetrazyl[1,5-alpha]pyrimidine compound and its derivatives in preparation of drug for prevention or treatment on cerebral hemorrhage |
| CN106817899A (en) * | 2014-07-15 | 2017-06-09 | 百时美施贵宝公司 | As the volution heptane of ROCK inhibitor |
| CN106817899B (en) * | 2014-07-15 | 2021-03-09 | 百时美施贵宝公司 | Spiroheptane as ROCK inhibitor |
| CN110229161A (en) * | 2019-07-12 | 2019-09-13 | 江苏建筑职业技术学院 | The solvent-thermal process method of tetrazole simultaneously [1,5-a] pyrimidine derivatives |
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