CN104109163A - IKK-beta-targeted 2-acetamido-8-substituted guanine derivative, and application and preparation method thereof - Google Patents
IKK-beta-targeted 2-acetamido-8-substituted guanine derivative, and application and preparation method thereof Download PDFInfo
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- CN104109163A CN104109163A CN201410033587.6A CN201410033587A CN104109163A CN 104109163 A CN104109163 A CN 104109163A CN 201410033587 A CN201410033587 A CN 201410033587A CN 104109163 A CN104109163 A CN 104109163A
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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Abstract
The invention discloses an IKK-beta-targeted 2-acetamido-8-substituted guanine derivative, and an application and a preparation method thereof. The A549 cell inhibition activity of the above compound increases if the administration concentration increases, and the compound basically has no inhibition effect on b16-f10, H460 and U251 cell strains, so the selective inhibition effect is of special significance for being used as a specific antitumor medicine.
Description
Technical field
The invention belongs to antitumor drug and organic synthesis field, in particular to a kind of 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative taking IKK-β as target spot, application and preparation method thereof.
Background technology
Protein tyrosine kinase (proteintyrosinekinases, PTKs) be that the upper γ-phosphoric acid of a class catalysis ATP is transferred to the kinases on protein-tyrosine residue, the multiple substrate protein white matter of energy catalysis tyrosine residues phosphorylation has vital role in Growth of Cells, propagation, differentiation.Therefore in the treatment research that comprises cancer and other numerous diseases, Tyrosylprotein kinase is all target and the object of research.Block or regulate and control a promising strategy that has been become antitumor research by the abnormal disease producing of these signal paths by developing tyrosine kinase inhibitor (tyrosinekinaseinhibitor, TKI) optionally.
Fibroblast growth factor acceptor (FibroblastGrowthFactorReceptor, FGFRs) is the tyrosine kinase receptor that a class is worn film, and research shows, the gene of FGFRs change and the variation of expression amount relevant with the generation of various diseases.For example: normal mammary epithelial cell and breast cancer cell expression FGFR-1 are detected, find that breast cancer cell expression FGFR-1 is high more than normal breast cell; RitaS etc. find that the cause of disease of achondroplastic dwarf's disease (A-ehondroplasia, ACH) is relevant with the point mutation of FGFR-3 gene; There is report, on the inoblast, neurogliocyte and the retinal pigment epithelium that form Proliferative vetreoretinopathy, all have the expression of FGFR; In addition, in the kinds of tumor cells such as bladder cancer, cancer of the stomach, colorectal carcinoma, carcinoma of endometrium, prostate cancer, fibroma, rhabdosarcoma, neurospongioma and melanoma, all find sudden change or the high level expression of FGF/FGFR.Therefore, FGFR is regarded as one for the treatment of target of the diseases such as tumour and receives much concern.
And FGFR and fibroblast growth factor (FibroblastGrowthFactor, FGFs) can mediate many barss Signal Transduction Pathways in conjunction with the FGF/FGFR signal transmission forming, propagation to normal cell and tumour cell, differentiation, and important regulating effect is all brought into play in the aspect such as the growth of tumour and transfer, vasculogenesis, neural formation.In FGF/FGFR signal transduction pathway, main signal pathway is ras → MAPK and PI3K/AKT approach.When after part FGF and receptors bind, trigger receptor dimer, make acceptor generation autophosphorylation, thereby be combined with the SH2 structural domain of the adaptor protein Grb2 in downstream, then be combined with SOS, ras successively, thereby ras is activated, then activate successively Raf, MEK, MAPK etc., the activation of this approach is mainly relevant with differentiation with cell proliferation.After receptor phosphorylation, can also be combined with PLC γ, activate the signal pathways such as PI3K and AKT, or activate PI3K/AKT approach by ras coupling, the activation of this approach is mainly to promote cells survival, opposing apoptosis.
If therefore can research and develop the fibroblast growth factor Tyrosylprotein kinase micromolecular inhibitor (FGFRTKI) of highly selective, can suppress the transmission of FGFR signal, the injury repairing of inhibition tumor cell, make cell fission be arrested in the G1 phase, induce and maintain apoptosis, anti-angiogenesis etc., thereby reach antineoplastic effect.Therefore, research and development highly selective, high efficiency FGFR inhibitor are pursuing a goal of current medical worker and urgent task.
Summary of the invention
The object of this invention is to provide a kind of 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative, application and preparation method thereof, in order to realize object of the present invention, intend adopting following technical scheme.
One aspect of the present invention relates to a kind of 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative taking IKK-β as target spot, it is characterized in that described 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative has the structure being shown below:
In a preferred embodiment of the present invention, described R is selected from: phenyl, 2', 4'-3,5-dimethylphenyl, 2'-p-methoxy-phenyl, indoles-3'-base, 2', 3'-Dimethoxyphenyl, 4'-bromo indole-3'-base.
The present invention also relates to the preparation method of above-mentioned 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative on the other hand, it is characterized in that being undertaken by reaction as follows:
The present invention also relates to the application of above-mentioned 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative on the other hand, and the described selectivity in vitro that is applied as suppresses the application in human lung adenocarcinoma cell growth.
In another aspect of this invention, also relate to the application of above-mentioned 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative, described be applied as the application in the medicine of preparing selective therapy adenocarcinoma of lung.
In another aspect of this invention, also relate to the application of above-mentioned 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative, the described application being applied as in the medicine of preparation and FGFR-1 receptor associated diseases.
Compound of the present invention is the increase along with administration concentration to the inhibition activity of A549 cell, its inhibiting rate also can increase, but this compounds is to b16-f10, the basic unrestraint effect of H460 and U251 cell strain, this optionally restraining effect has special meaning for it as specific antitumor drug.
Embodiment
Embodiment 1:
Synthetic route
G1:R=phenyl G4:R=2', 4'-3,5-dimethylphenyl
G2:R=2'-p-methoxy-phenyl G5:R=indoles-3'-base
G3:R=2', 3'-Dimethoxyphenyl G6:R=4'-bromo indole-3'-base
Experimental implementation
(1) TAHMS concrete operations referring to document (Shao Weiqing, the grand .2 of hair, 4,5-triamino-6-hydroxy pyrimidine vitriol synthetic. Chinese Journal of Pharmaceuticals 2002,33 (12): 579.).
(2) 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative synthesizing process: to synthesize M2 as example: take 2,4,5-triamino-6-hydroxy pyrimidine vitriol 0.239g(1.0mmol), Benzaldehyde,2-methoxy 0.136g (1.0mmol), in 100ml round-bottomed flask, adds 40ml dimethyl sulfoxide (DMSO).Be placed in 80 DEG C of oil baths, add reflux, temperature constant magnetic stirring reaction.Follow the tracks of reaction with tlc silica gel plate, after question response finishes, reaction solution is cooled to room temperature, add water to Precipitation, suction filtration (solvent DMSO is collected in waste liquid cylinder), with hot ethanol washing, is placed in moisture eliminator and is dried to obtain thick product M2.With NaOH solution dissolving gained desciccate, then adjust PH to 7 with hydrochloric acid, can obtain the product after recrystallization, product colour is light yellow.Therefore this experiment is selected 80 DEG C for reaction conditions, and after 5 hours, reaction completes substantially.Reaction solution is cooling to add water, and can make product separate out with precipitation forms.After product is dissolved with NaOH, hydrochloric acid adjusts PH to neutral, can make it again to separate out by purified product, all has higher yields.
(3) the 8-9 substituted guanine analog derivative M1-6 of 10.0mmol, uses 45ml diacetyl oxide, and under 120 DEG C of reaction conditionss, productive rate can reach 84% left and right, and the reaction times is about 2.5 hours.
The productive rate of G1-G6 and relevant sign are referring to table 1 and table 2
Table 1
Table 2
Compound G(1-6) be all faint yellow solid; Compound G(1-6) be dissolved in methyl alcohol, the ethanol of DMSO, heat, water insoluble, ether, acetone.
Pharmacodynamics activity experiment method
The cultivation of 1A549 cell strain, frozen, recovery
A549 cell is human lung adenocarcinoma cell, belongs to continuous cell line, the cultivation of can stably going down to posterity.
The cultivation of A549 cell strain: A549 cell takes out from liquid nitrogen container, rapidly as in 37 DEG C of thermostat(t)ed waters, in in 2-3min, inner substratum is melted completely, the centrifugal 3-5min of 800r/min, add containing 10%FBS, 1% dual anti-RPMIMEDIUM1640 and DMEM substratum, put 37 DEG C, 5%CO2 incubator and cultivate 24 in cultivating and make to change fresh culture after cell attachment, after 0.5% trysinization in 3 days, go down to posterity in 1:3 ratio.
A549 cell strain frozen: the cell culture of digestion method in logarithmic phase routinely, make single cell suspension, calculate total cellular score, viable cell quantity can not be less than 90%, by centrifugal cell suspension 800r/min 5min, abandoning supernatant, is divided in frozen tubule after adding refrigerating fulid, classification is freezing, finally drops into liquid nitrogen and preserves.
The recovery of A549 cell strain: take out the cryopreservation tube that has A549 cell from liquid nitrogen container, put into water-bath and melt.By centrifugal cell suspension 800r/min 5min.With 1ml rifle head, supernatant liquor is removed, added the cell culture fluid of 1ml preheating that cell is dispelled out, then add fresh medium Eddy diffusion cell to proceed to cultivation box, under inverted microscope, observe, 37 DEG C, 5%CO2 cultivation.After 24h, the nutrient solution more renewing.The routine cultivation of going down to posterity.
Aforesaid method can be used for b16-f10(mouse skin melanoma cell equally), H460(human lung carcinoma cell), U251(glioma cell) cultivation, freezing and thawing.
The cytotoxicity experiment (mtt assay) of 2 gained compounds
A549 cell covers with to 80%-90%, with being prepared into single cell suspension after 0.5% trysinization, collects logarithmic phase cell, adjusts concentration of cell suspension after cell counting.Divide in 96 orifice plates, 5 × 103/ holes, are placed in CO2 incubator (37 DEG C, 5%CO2) and cultivate after 24h, and cell attachment and well-grown, absorb whole nutrient solutions.Add the medicine of different concns, each concentration is established 6 multiple holes, every hole adds 20ulMTT solution (5mg/ml, be 0.5%MTT), in CO2 incubator, continue to cultivate after 4h, carefully suck nutrient solution in hole, every hole adds 150ul dimethyl sulfoxide (DMSO) (DMSO), put low-speed oscillation 10min on shaking table, crystallisate is fully dissolved.Measure the light absorption value (OD) in each hole at enzyme-linked immunosorbent assay instrument 490nm place, record result (DMSO is control group), obtain IC50 by GraphpadPrims processing data.Experimental data is all with mean ± standard deviation (x ± s) represent; Acquired results is in table 3.
The 3 inhibiting rate experiments of screening gained compound to FGFR-1
In this experiment, by CaliperMobilityShiftAssay method, in vitro 12 of gained compounds are carried out to the inhibition active testing to FGFR-1.Testing drug is divided into 0.1uM, 1uM, and tri-concentration of 10uM, Staurosporine is reference substance.
Experimental technique is as follows:
(1) compound concentration is finally diluted to 50uM, 5uM and 0.5uM, for subsequent use in 384 orifice plates, taking 100%DMSO as control group, 250mMEDTA is lowcontrol.
(2) FGFR1 enzyme is added in the damping fluid of 1.25x and prepare 2.5x enzyme solution.
(3) add and in 1.25x damping fluid, prepare 2.5x polypeptide solution by ATP with containing the polypeptide of FAM mark.
(4) in each hole, add the enzyme solution of the above-mentioned preparation of 10 μ l2.5x, incubated at room 10min.
(5) then add the 2.5x polypeptide solution of the above-mentioned preparation of 10 μ l2.5x in each hole, hatch after for some time at 28 DEG C, add 25 μ lstopbuffer stopped reaction.
(6) in the upper reading of data of Caliper, and transfer data to inhibiting rate.Per-cent inhibiting rate=(max-reading of data)/(max-min) * 100.Max represents DMSO control group, and min represents lowcontrol.Final acquired results is in table 4.
The inhibiting rate of table 3 compound to A549 Growth of Cells
Due to the b16-f10(mouse skin melanoma cell calculating), H460(human lung carcinoma cell), U251(glioma cell) MTT result be negative value, illustrate that such medicine does not have restraining effect to these three kinds of Growth of Cells, and can only produce growth-inhibiting effect to A549 cell.As can be seen from Table 3, with drug level increase, medicine is to A549(human lung adenocarcinoma cell) growth inhibitory effect also simultaneously increase.Be 12.82 μ mol/l according to the IC50 of the control drug calculating, the compound of contrast synthesized, its IC50 is all greater than contrast medicine, illustrates that this compounds is not so good as positive control drug 5-fluor-uracil to the growth-inhibiting effect of A549 cell.
The inhibition activity of table 4 compound to FGFR-1
As can be seen from Table 4, G1-6 shows the activity that suppresses relatively preferably FGFR-1; 8 G5 that replace for indoles show the relative activity that suppresses preferably FGFR-1 with G6.
The above is the preferred embodiments of the present invention; it should be pointed out that for those skilled in the art, do not departing under the prerequisite of principle of the present invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1. a 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative, is characterized in that described 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative has the structure being shown below:
2. 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative according to claim 1, described R is selected from: phenyl, 2', 4'-3,5-dimethylphenyl, 2'-p-methoxy-phenyl, indoles-3'-base, 2', 3'-Dimethoxyphenyl, 4'-bromo indole-3'-base.
3. the preparation method of the 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative described in claim 1 or 2, is characterized in that being undertaken by reaction as follows:
4. the application of the 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative described in claim 1 or 2, the described selectivity in vitro that is applied as suppresses the application in human lung adenocarcinoma cell growth.
5. the application of the 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative described in claim 1 or 2, described is applied as the application in the medicine of preparing selective therapy adenocarcinoma of lung.
6. the application of the 2-acetylaminohydroxyphenylarsonic acid 8-9 substituted guanine derivative described in claim 1 or 2, the described application being applied as in the medicine of preparation and FGFR-1 receptor associated diseases.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085411A (en) * | 2015-08-14 | 2015-11-25 | 江苏八巨药业有限公司 | Preparation method of 6-hydroxy-2,3,5-triamidopyrimidine sulfate |
| CN108794477A (en) * | 2018-08-06 | 2018-11-13 | 华东师范大学 | A kind of N2The preparation method of 9 substituted guanine class compound |
| CN109535083A (en) * | 2018-12-26 | 2019-03-29 | 浙江本立科技股份有限公司 | The preparation method of 2,4,5-triamino-6-hydroxypyrimidine sulfate and folic acid |
| CN113214166A (en) * | 2021-06-23 | 2021-08-06 | 田雨 | Synthesis process, intermediate and pharmaceutical process of 2,4, 5-triamino-6-hydroxypyrimidine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012035423A1 (en) * | 2010-09-15 | 2012-03-22 | Katholieke Universiteit Leuven, K.U. Leuven R&D | Anti-cancer activity of novel bicyclic heterocycles |
-
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012035423A1 (en) * | 2010-09-15 | 2012-03-22 | Katholieke Universiteit Leuven, K.U. Leuven R&D | Anti-cancer activity of novel bicyclic heterocycles |
Non-Patent Citations (3)
| Title |
|---|
| CHRISTOPHER K. MCLAUGHLIN, ET AL.: "Conformational Properties of a Phototautomerizable Nucleoside Biomarker for Phenolic Carcinogen Exposure", 《J.PHYS.CHEM.A》, vol. 110, no. 19, 25 April 2006 (2006-04-25), pages 6224 - 6230 * |
| KATHERINE M. SCHLITT, ET AL.: "Concerning the Hydrolytic Stability of 8-Aryl-2’-deoxyguanosine Nucleoside Adducts: Implications for Abasic Site Formation at Physiological pH", 《J.ORG.CHEM.》, vol. 74, 16 July 2009 (2009-07-16), pages 5793 - 5802 * |
| SANDRA SANTOS-SIERRA, ET AL.: "Novel pharmacological chaperones that correct phenylketonuria in mice", 《HUMAN MOLECULAR GENETICS》, vol. 21, no. 8, 13 January 2012 (2012-01-13), pages 1877 - 1887 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085411A (en) * | 2015-08-14 | 2015-11-25 | 江苏八巨药业有限公司 | Preparation method of 6-hydroxy-2,3,5-triamidopyrimidine sulfate |
| CN108794477A (en) * | 2018-08-06 | 2018-11-13 | 华东师范大学 | A kind of N2The preparation method of 9 substituted guanine class compound |
| CN109535083A (en) * | 2018-12-26 | 2019-03-29 | 浙江本立科技股份有限公司 | The preparation method of 2,4,5-triamino-6-hydroxypyrimidine sulfate and folic acid |
| CN113214166A (en) * | 2021-06-23 | 2021-08-06 | 田雨 | Synthesis process, intermediate and pharmaceutical process of 2,4, 5-triamino-6-hydroxypyrimidine |
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