CN102993193B - Use of nitrogen-3-isoxazolyl-3-4-thienyl-pyrimidyl sulfonyl propanamide derivative in preparing anti-tumor medicines - Google Patents
Use of nitrogen-3-isoxazolyl-3-4-thienyl-pyrimidyl sulfonyl propanamide derivative in preparing anti-tumor medicines Download PDFInfo
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- CN102993193B CN102993193B CN201210060809.4A CN201210060809A CN102993193B CN 102993193 B CN102993193 B CN 102993193B CN 201210060809 A CN201210060809 A CN 201210060809A CN 102993193 B CN102993193 B CN 102993193B
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- VSWAJUIKVAKHEO-UHFFFAOYSA-N CC(C1)ON=C1NC(CCS(c1nc(C(F)(F)F)cc(-c2ccc[s]2)n1)(=O)=O)=O Chemical compound CC(C1)ON=C1NC(CCS(c1nc(C(F)(F)F)cc(-c2ccc[s]2)n1)(=O)=O)=O VSWAJUIKVAKHEO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to the field of a medicine, in particular to the use of a nitrogen-(4,5-bihydroisoxazole-3-yl)-3-(4-(thiophene-2-yl)-pyrimidine-2-sulfonyl) propanamide derivative in preparing anti-tumor medicines. The invention solves the technical problem that a novel compound is provided for the medicine for inhibiting tumor metabolism. The technical scheme provided by the invention is to provide the use of a nitrogen-(4,5-bihydroisoxazole-3-yl)-3-(4-(thiophene-2-yl)-pyrimidine-2-sulfonyl) propanamide derivative in preparing anti-tumor medicines and the derivative is shown as formula I. According to the invention, the compound shown as formula I has a good anti-tumor effect creatively, and can be used to prepare an anti-tumor medicine composition. A novel selection for the field of preparing the anti-tumor medicines is provided, and the derivative has a good application prospect.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to nitrogen-(4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative preparing the purposes in antitumor drug.
Background technology
Malignant tumour has become the important killer that harm humans is healthy and survive, and its M & M exceedes cardiovascular disorder, and sickness rate has the trend obviously risen.Although update the discovery with novel drugs along with methods for the treatment of in recent years, make 5 of Partial tumors years survival rates increase to some extent, such as lung cancer, liver cancer, the prognosis of the cancers such as prostate cancer is still very poor, and mortality ratio is high.Tumour patient is attended by that energy expenditure is high, the metabolism disorder phenomenon such as lose weight more.The twenties in last century, German Nobel Laureate's Otto Wa Baige finds that the metabolism of tumor tissues obviously strengthens, and tumour cell mainly relies on glycolysis-and carries out metabolism, and it consumes sugared speed much larger than normal cell.In recent years, tumor metabolic unusual phenomenon causes the attention of people again, and this " watt berg's effect " starts again the focus becoming tumor research.The M2 type pyruvate kinase (PKM2) that Harvard University scientist finds mainly to be present in tumour cell can promote the generation of tumour cell " watt berg's effect ", and plays vital effect to the formation of tumour and growth.Experimental study finds, suppresses the activity of PKM2, can disturb the metabolism of tumour, the increment of Tumor suppression, increases the apoptosis of tumour cell, thus reaches the object of Tumor suppression growth.
Based on the important value of inhibitor in oncotherapy of PKM2, the target small-molecule drug that the present inventor has carried out for PKM2 designs and study on the synthesis work, some hypostazation compounds are designed and synthesized, entered cell in vitro screening, find that the increment of some of them compound on tumor cell has certain inhibit activities, they demonstrate good inhibit activities in various tumor cell strains, and also show good experiment effect in testing in vivo.
Summary of the invention
The medicine that the object of the invention is to for preparing treatment and prevention of tumour provides new effective selection.
Technical scheme of the present invention is to provide structure such as formula the nitrogen shown in I-(4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative preparing the purposes in treatment and prevention of tumour medicine:
Wherein, R
1, R
2, R
7, R
8be independently H, halogen, NH
2, CF
3, halo C1 ~ C8 alkyl, C1 ~ C8 alkoxyl group or C1 ~ C8 alkyl;
R
3~ R
6it is independently H or C1 ~ C8 alkyl;
R
9~ R
11be independently H, furans cyclic group, cyclopropyl, pyrazolyl or C1 ~ C8 alkyl.
Preferably, R
1~ R
6be independently H or C1 ~ C8 alkyl, and R
1and R
2in at least one is C1 ~ C8 alkyl;
R
7, R
8be independently H, C1 ~ C8 alkyl or CF
3, and R
7and R
8in at least one is CF
3;
R
9~ R
11it is independently H or C1 ~ C8 alkyl.
Preferred further, R
1~ R
6be independently H or C1 ~ C4 alkyl, and R
1and R
2in at least one is C1 ~ C4 alkyl;
R
7, R
8be independently H, C1 ~ C4 alkyl or CF
3, and R
7and R
8in at least one is CF
3;
R
9~ R
11it is independently H or C1 ~ C4 alkyl.
Further preferred, R
1, R
2be independently H or C1 ~ C8 alkyl, and R
1and R
2in at least one is C1 ~ C8 alkyl;
R
7, R
8be independently H or CF
3, and R
7and R
8in at least one is CF
3;
R
3~ R
6, R
9~ R
11for H.
Most preferred, R
1, R
2be independently H or methyl, and R
1and R
2in at least one is methyl;
R
7, R
8be independently H or CF
3, and R
7and R
8in at least one is CF
3;
R
3~ R
6, R
9~ R
11for H.
The present invention still further provides structure such as formula the nitrogen shown in II-(4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative preparing the purposes in treatment and prevention of tumour medicine:
Formula II
Wherein, described R
1' be independently H, halogen, NH
2, CF
3, halo C1 ~ C8 alkyl, C
1~ C
8alkoxyl group or C1 ~ C8 alkyl; Described R
2' be independently H, furan nucleus, cyclopropyl or pyrazoles.
Further, described R
1' be independently C1 ~ C4 alkyl, halo C1 ~ C4 alkyl or C
1~ C
4alkoxyl group.
Further, its chemistry of described compound is by name:
N-(5-methyl-4,5-dihydroisoxazol-3-yl)-3-(4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-ylsulfonyl)propanamide
Further, described compound has the structure shown in formula III
Beneficial effect of the present invention is; the creatively nitrogen shown in discoverable type I-(4; 5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) antitumor action that had of propanamide derivative; for the preparation of antineoplastic pharmaceutical compositions, and can show that it plays antitumor action possibly via the metabolism of reduction tumour cell by experiment.For antitumor drug preparation field provides a kind of selection newly, there is good application prospect.
Accompanying drawing explanation
Figure mono-is nitrogen in the present invention-(4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative is to the increment Inhibition test result of human lung carcinoma cell line A549.
Figure bis-is nitrogen in the present invention-(4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative is to the increment Inhibition test result of HepG2 cell lines.
Figure tri-is that Zhong isoxazole thiophene pyrimidine of the present invention is to the Experiment on therapy result of people lung cancer A549 tumor model.
Figure tetra-is that Zhong isoxazole thiophene pyrimidine of the present invention is to the Experiment on therapy result of people liver cancer HepG2 tumor model.
Figure five is that Zhong isoxazole thiophene pyrimidine of the present invention is to the Experiment on therapy result of human breast carcinoma MCF-7 tumor model.
Figure six is that Zhong isoxazole thiophene pyrimidine of the present invention is to the Experiment on therapy result of human colon carcinoma SW480 tumor model.
Figure seven is that Zhong isoxazole thiophene pyrimidine of the present invention is to the Experiment on therapy result of human ovarian cancer SKOV-3 tumor model.
Below in conjunction with accompanying drawing by illustrating the description of embodiment but do not limit the present invention.
Embodiment
The experiment in vitro of the compound Tumor suppression shown in the embodiment same form III
One, the source of the compound shown in formula III and physico-chemical property
A kind of nitrogen-(4 used in the specific embodiment of the invention; 5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) and propanamide derivative structural formula such as formula shown in III, buy from Dutch Specs company (Specs, Holland); relative molecular mass is 448.05
Gai isoxazole thiophene pyrimidine is buff powder, at water, poorly soluble in ethanol equal solvent.
Its chemistry is by name: N-(5-methyl-4,5-dihydroisoxazol-3-yl)-3-(4-(thiophen-2-yl)-6-(trifluoromethyl) pyrimidin-2-ylsulfonyl) propanamide;
Chinese name: nitrogen-(5-methyl-4,5-isoxazole-3-base)-3-(4-(thiophene-2-base)-6-(trifluoromethyl)-2-third sulfanylpyrimidine.
Two experiment materials
1, main agents
RPMI-1640, DMEM, foetal calf serum, pancreatin etc. are purchased from Gibco BRL company (Invitrogen Corporation, USA), and thiazole bromide blue tetrazolium (MTT), propidium iodide (PI), methyl-sulphoxide (DMSO) is Sigma company (USA) product.Nitrogen shown in formula III-(5-methyl-4; 5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-6-(trifluoromethyl) pyrimidine-2-alkylsulfonyl) propionic acid amide is purchased from Dutch Specs company; for chemical standard product; 10mg/ml storage liquid is mixed with DMSO during experiment in vitro; putting 4 DEG C of refrigerators keeps in Dark Place for subsequent use, faces the used time to be diluted to desired concn with complete culture solution.
2, clone and cultivation
This tests human lung carcinoma cell line (A549) used, human hepatoma cell strain (HepG2), human prostate cancer cell line (PC-3), Breast cancer lines (MCF-7), human colon cancer cell strain (SW480), human renal carcinoma cell strain (OSC) and human oophoroma cell line (SKOV-3) are purchased from ATCC company of the U.S., routine preservation.HepG2 cell and DMEM perfect medium, the 5%CO of SW480 cell containing 10% foetal calf serum, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates
2, 37 DEG C cultivate.PC-3 cell, MCF-7 cell, OSC cell, SKOV-3 cell and A549 cell RPMI-1640 perfect medium, the 5%CO containing 10% foetal calf serum, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates
2, 37 DEG C cultivate.
Three experimental techniques and result
1 statistical method
Experimental data mean ± standard deviation represents, adopts the process of SPSS13.0 statistical software.Measurement data adopts t inspection, and P<0.05 is that difference has statistical significance.
2 cell growth inhibition assays
2.1 experimental techniques (mtt assay)
Adjusting cell concn with complete culture solution is 2 × 10
4/ ml, is inoculated in 96 orifice plates, every hole 200 μ l; overnight incubation, uses nitrogen-(5-methyl-4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base of various dose next day respectively)-6-(trifluoromethyl) pyrimidine-2-alkylsulfonyl) (final concentration is respectively 10 to propionic acid amide; 5; 2.5,1.25,0.625; 0.312; 0.16 μ g/ml) process cell, isopyknic solvent control group simultaneously, DMSO concentration is that the DMSO on cell proliferation of 0.1%(0.1% does not affect).Eachly establish 5 multiple holes, 37 DEG C, 5%CO
2cultivate.Respectively at cultivation after 48 hours, get 1 culture plate, every hole adds 5mg/ml MTT reagent 20 μ l, continue cultivation 2 to 4 hours, abandon supernatant, then add DMSO150 μ l, vibration mixing 15min, measure absorbancy (A) value (A value is directly proportional to viable count) by microplate reader (λ=570nm), get its mean value.Relative cell proliferation inhibiting rate (%)=(control group A
570-experimental group A
570)/control group A
570× 100%.Experiment at least repeats 3 times (because of the acellular cell inhibitory effect effect of solvent control group, therefore control group here refers to solvent control group).In order to observe nitrogen-(5-methyl-4; 5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-6-(trifluoromethyl) pyrimidine-2-alkylsulfonyl) the whether free dependency of propionic acid amide cell inhibitory effect effect; carry out nitrogen-(5-methyl-4 further; 5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-6-(trifluoromethyl) pyrimidine-2-alkylsulfonyl) propionic acid amide effect A549 cell and HepG2 cell 72 hour cell Proliferation Ability test, test treatment process the same.
2.2 nitrogen-(4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative on cell proliferation Inhibition test result
Different concns nitrogen-(4; 5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) after the different cell of propanamide derivative effect; increase with drug level; cell inhibitory effect is more obvious; each dosage group is compared with control group, and cell proliferation inhibition rate difference all has statistical significance (P<0.05) (the results are shown in Table 1).Nitrogen-(5-methyl-4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-6-(trifluoromethyl) pyrimidine-2-alkylsulfonyl) half-inhibition concentration (IC of propionic acid amide process A549, HepG2, MCF-7, PC-3, SW480, OSC, SKOV-3 cell 48h
50) be respectively 1.58 μ g/ml, 3.01 μ g/ml, 4.57 μ g/ml, 5.69 μ g/ml, 3.58 μ g/ml, 4.74 μ g/ml, 10.2 μ g/ml.
Different concns nitrogen-(4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative effect A549 and HepG2 cell different time, cell inhibitory rate is with raising gradually action time (the results are shown in Figure 1 and Fig. 2).Each dosage group is compared with control group, and Relative cell proliferation inhibiting rate difference all has statistical significance (P<0.05).Cell growth inhibition assay result display nitrogen-(5-methyl-4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-6-(trifluoromethyl) pyrimidine-2-alkylsulfonyl) propionic acid amide energy significance suppress various different tissue sources ground tumour cell increment.
Table 1 nitrogen-(4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative is to the relative proliferation inhibition rate (%) of different tumor cell line
3 flow cytometry analysis detect apoptosis
3.1 experimental technique
The HepG2 cell of taking the logarithm vegetative period and PC-3 cell, according to every hole 1 × 10
5individual cell is inoculated in 6 orifice plates; cultivate after 24 hours, add nitrogen-(4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative; its final concentration is made to be respectively 10; 5,2.5,1.25; 0.625g/ml; each dosage group establishes 3 multiple holes, 37 DEG C, 5%CO
2cultivate.Cultivate after 72 hours, collect the cell of different treatment group and control group, wash 3 times with the PBS of 4 DEG C of precoolings, add 70% cold ethanol fixed cell.Add the PI dyestuff containing RNase after centrifugal, after half an hour, flow cytometer detects.
3.2 experimental result
HepG2 and PC-3 cell through-effect after through flow cytomery time find, a hypodiploid is there is before G0/G1 phase peak, use apoptosis program software to remove cell debris post analysis and confirm as apoptotic peak, this peak increases with drug level and rising presents obvious dose-dependently.Treatment group has been compared with control group significant difference (P<0.05) (the results are shown in Table 2); prompting nitrogen-(5-methyl-4,5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-6-(trifluoromethyl) pyrimidine-2-alkylsulfonyl) the increment restraining effect of propionic acid amide to A549 and HepG2 cell may be realized by cell death inducing.
Table 2 is to the apoptosis-induced ratio (%) of different cell strain
| Concentration (μ g/ml) | 10 | 5 | 2.5 | 1.25 | 0.625 |
| A549 | 61.5 | 62.1 | 56.9 | 31.4 | 13.3 |
| HepG2 | 66.2 | 53.5 | 36.7 | 28.6 | 11.8 |
The experiment of embodiment Er isoxazole thiophene pyrimidine Tumor suppression
One, the source of isoxazole thiophene pyrimidine and physico-chemical property
A kind of isoxazole thiophene pyrimidine structure formula used in the specific embodiment of the invention is such as formula shown in III, and buy from Dutch Specs company (Specs, Holland), relative molecular mass is 448.05,
Gai isoxazole thiophene pyrimidine is buff powder, at water, poorly soluble in ethanol equal solvent.
Its chemistry is by name: N-(5-methyl-4,5-dihydroisoxazol-3-yl)-3-(4-(thiophen-2-yl)-6-(trifluoromethyl) pyrimidin-2-ylsulfonyl) propanamide
Chinese name: nitrogen-(5-methyl-4,5-isoxazole-3-base)-3-(4-(thiophene-2-base)-6-(trifluoromethyl)-2-third sulfanylpyrimidine.
Two experiment materials
1, main agents
RPMI-1640, DMEM, foetal calf serum, pancreatin etc. are purchased from Gibco BRL company (Invitrogen Corporation, USA), and thiazole bromide blue tetrazolium (MTT), propidium iodide (PI), methyl-sulphoxide (DMSO) is Sigma company (USA) product.Isoxazole thiophene pyrimidine shown in formula II, purchased from Dutch Specs company, is chemical standard product, is mixed with 10mg/ml storage liquid during experiment in vitro with DMSO, puts 4 DEG C of refrigerators and keeps in Dark Place for subsequent use, faces the used time to be diluted to desired concn with complete culture solution.
2, cell strain and cultivation
This tests human lung carcinoma cell line (A549) used, human hepatoma cell strain (HepG2), Breast cancer lines (MCF-7), and human colon cancer cell strain (SW480) and human oophoroma cell line (SKOV-3) are purchased from ATCC company of the U.S., routine preservation.HepG2 cell and DMEM perfect medium, the 5%CO of SW480 cell containing 10% foetal calf serum, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates
2, 37 DEG C cultivate.MCF-7 cell, SKOV-3 cell and A549 cell RPMI-1640 perfect medium, the 5%CO containing 10% foetal calf serum, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates
2, 37 DEG C cultivate.
3, animal rearing
This tests SPF level nude mice used purchased from Beijing Fukang company of China, is for 6 to 8 weeks, raises the laminar flow animal room in constant temperature, constant humidity.
Three experimental techniques and result
1 statistical method
Experimental data mean ± standard deviation represents, adopts the process of SPSS13.0 statistical software.Measurement data adopts t inspection, and P<0.05 is that difference has statistical significance.
2 tumor model Experiment on therapy
2.1 experimental technique
Collecting cultured tumor cells, twoly wash twice without substratum, is 5 × 10 with pair adjusting cell concn without nutrient solution
7/ ml, is inoculated in back on the right side of nude mice, and after tumor growth to 50-100 cubic millimeter, abdominal injection treatment once a day, drug level is 1mg/kg, simultaneously isopyknic solvent control group, often organizes 10 mouse.Within every three days, measure a gross tumor volume, method of calculation are: volume=0.52 × length × wide × wide.Experiment at least repeats 3 times (because of the acellular cell inhibitory effect effect of solvent control group, therefore control group here refers to solvent control group).
2.2 isoxazole thiophene pyrimidine on cell proliferation Inhibition test results
The different tumor model of isoxazole thiophene pyrimidine effect, extend with medicine administration time, tumor control rate is more obvious, and each administration group is compared with control group, and tumor control rate difference all has statistical significance (P<0.05).The result of concrete each animal model for tumour is: the tumour inhibiting rate of A549 tumor model (the results are shown in Figure three), HepG2 tumor model (the results are shown in Figure four), MCF-7 tumor model (the results are shown in Figure five), SW480 tumor model (the results are shown in Figure six), SKOV-3 tumor model (the results are shown in Figure seven) tumor model is respectively 62%, 59%, 73%, 34%, 45%.
Claims (1)
1. nitrogen-(4; 5-2 dihydrogen isoxazole-3-base)-3-(4-(thiophene-2-base)-pyrimidine-2-alkylsulfonyl) propanamide derivative preparing the purposes in antitumor drug; it is characterized in that, described compound has the structure shown in formula III:
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| CN201210060809.4A CN102993193B (en) | 2011-03-09 | 2012-03-09 | Use of nitrogen-3-isoxazolyl-3-4-thienyl-pyrimidyl sulfonyl propanamide derivative in preparing anti-tumor medicines |
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Citations (4)
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| WO2008157003A2 (en) * | 2007-06-14 | 2008-12-24 | The Burnham Institute | Chemical inhibitors of bfl-1 and related methods |
| WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
| CN101669931A (en) * | 2008-09-08 | 2010-03-17 | 北京鼎国昌盛生物技术有限责任公司 | Application of long effective curcumin derivative in preparing anti-tumor disease drug |
| CN101857617A (en) * | 2010-04-28 | 2010-10-13 | 中国海洋大学 | Quinazoline sugar derivative and preparation method and application thereof |
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2012
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008157003A2 (en) * | 2007-06-14 | 2008-12-24 | The Burnham Institute | Chemical inhibitors of bfl-1 and related methods |
| WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
| CN101669931A (en) * | 2008-09-08 | 2010-03-17 | 北京鼎国昌盛生物技术有限责任公司 | Application of long effective curcumin derivative in preparing anti-tumor disease drug |
| CN101857617A (en) * | 2010-04-28 | 2010-10-13 | 中国海洋大学 | Quinazoline sugar derivative and preparation method and application thereof |
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