CN104606186A - Application of fluoro-7-hydroxycoumarin compound in protein kinase inhibitor or/and antitumor drug - Google Patents
Application of fluoro-7-hydroxycoumarin compound in protein kinase inhibitor or/and antitumor drug Download PDFInfo
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- CN104606186A CN104606186A CN201510026735.6A CN201510026735A CN104606186A CN 104606186 A CN104606186 A CN 104606186A CN 201510026735 A CN201510026735 A CN 201510026735A CN 104606186 A CN104606186 A CN 104606186A
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Abstract
The invention discloses an application of a fluoro-7-hydroxycoumarin compound in a protein kinase inhibitor or/and an antitumor drug, and belongs to the technical field of pharmaceutical chemistry. According to the disclosed medical application of the fluoro-7-hydroxycoumarin compound, in-vitro protein kinase activity and antitumor cell proliferation activity detection proves that the compound can inhibit protein kinase CK2 activity, has a certain inhibition effect on proliferation of a lung cancer cell line A549 and a cervical carcinoma cell line Hela, and can be used as the protein kinase inhibitor and the antitumor drug.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to fluoro umbelliferone compound as kinases inhibitor or/and the application of anti-tumour cell proliferative field of medicaments.
Background technology
Protein kinase C K2 is a kind of multi-functional serine/threonine albuminoid kinases, pass through phosphorylates various substrates, participate in the physiological process such as the activity of oncogene and antioncogene in induced cell growth, inhibited apoptosis and conditioning signal path, there is short growth and the characteristic of anti-apoptotic and become important anticancer target.ATP competitive inhibitor plays inhibit feature by being attached to catalytic activity pocket.At present, only have Compound C X-4945 just to enter the phase II clinical trials stage, therefore, the antitumor inhibitor of novel protein kinase CK2 waits research and development.
Coumarin kind compound and derivant thereof are extremely extensive in occurring in nature distribution, have the biological activitys such as antibacterial, antiinflammatory, antitumor, anti-agglomeration, have potential medical value, be identified as important lead compound.Prior art shows, the 4-methyl 7-hydroxy kind coumarin compound do not replaced by fluorine, as the inhibitor of Protein kinase C K2, has lower inhibit activities.
The Protein kinase C K2 inhibitors 4 that prior art obtains-Methyl-7-hydroxy-coumarin compounds, only R
7electropositive district in OH and the CK2 catalytic activity pocket of position forms single polarity effect, there is lower inhibit activities, the present inventor is based on 7-hydroxy kind coumarin compound skeleton, modified with functional group optimization of different nature is carried out in different positions, finally determine 4-trifluoromethyl umbelliferone compounds, there is comparatively high protein kinase c K2 inhibit activities and anti-tumour cell proliferative activity.
Fluoro umbelliferone compound of the present invention is at kinases inhibitor or/and application in antitumor drug, and fluoro umbelliferone structural formula of compound is wherein as follows:
Wherein, R
6for any one of H, OH, Cl, R
8for any one of H, OH, Cl, but R
6and R
8be asynchronously OH or H.
The preferred structure of described fluoro umbelliferone compound is such as formula 2, shown in formula 3 and formula 4.
Formula 2, formula 3 and the fluoro umbelliferone compound shown in formula 4 are as the application of kinases inhibitor.
Further, the fluoro umbelliferone compounds shown in formula 1 as the application of Protein kinase C K2 inhibitor, the especially IC of formula 2, formula 3 and formula 4 correspondence
50value is respectively 107 μMs, 56.23 μMs and 0.4 μM, and activity is better than methyl substituted homologous series coumarin kind compound.
Fluoro umbelliferone compounds shown in formula 1 is as the application of anti-tumour cell proliferative medicine.
Further, formula 2, formula 3 and the fluoro umbelliferone compounds shown in formula 4 have the activity of certain anti-tumour cell proliferative.Tumor cell line comprises pulmonary carcinoma A549 and cervical cancer Hela cells, and activity is better than methyl substituted homologous series coumarin kind compound.
In the present invention, due to its R of compound described in formula 1
7oH and CK2 catalytic activity pocket in electropositive district form single polarity effect, there is certain inhibit activities, and work as R
4for CF
3time, at original R
7position OH and electropositive district formed on the basis of polarity effect, increased CF newly
3fluorine and the halogen bond effect that formed of CK2 catalytic activity pocket hinge region, thus the inhibit activities of compound is improved.
Summary of the invention
The present invention relates to fluoro umbelliferone compound as the application in kinases inhibitor and anti-tumour cell proliferative agent field of medicaments.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described, but the present invention is not limited to following examples.
The preparation method of compound shown in embodiment 1 structural formula 2
By compound Isosorbide-5-Nitrae-benzoquinone (0.500g, 4.63mmol)) be scattered in 3mL acetic anhydride, add 0.12mL concentrated sulphuric acid subsequently.Reactant liquor is heated to 50 DEG C, returns to room temperature after 1 hour, with saturated sodium bicarbonate and ethyl acetate separatory.Organic facies saturated common salt water washing, with anhydrous magnesium sulfate drying, column chromatography (normal hexane: ethyl acetate=5:1) obtains intermediate product 1,2,4-benzenetriol acetate (0.82g), and be yellow solid, productive rate is 70%.Compound 1,2,4-benzenetriol acetate (0.488g, 1.94mmol) is scattered in 2mL 70% perchloric acid, adds compound trifluoroacetic ethyl acetoacetate (0.34mL, 2.3mmol) subsequently.Reactant liquor is under agitation heated to 80 DEG C, returns to room temperature after 3 hours, with saturated sodium bicarbonate and ethyl acetate separatory.Organic facies is with after saturated common salt water washing, and with anhydrous magnesium sulfate drying, column chromatography (normal hexane: ethyl acetate=2:1), obtaining compound shown in structural formula 2 (0.32g), is light yellow solid, and productive rate is 68%.
1H NMR(400MHz,DMSO-d
6):10.59(brs,1H),9.76(brs,1H),7.03(d,1H,J＝1.4Hz),6.85(s,1H),6.69(s,1H).HRMS(ESI)m/z calculated for C
10H
5O
4F
3[M+H]
+:246.0067,found:246.0140。
The preparation method of compound shown in embodiment 2 structural formula 3
Compound Pyrogallol acid (0.500g, 3.97mmol) is scattered in the perchloric acid of 2mL70%, adds compound trifluoroacetic ethyl acetoacetate (0.70mL, 4.8mmol) subsequently.Reactant liquor is under agitation heated to 80 DEG C, returns to room temperature after 2 hours, with saturated sodium bicarbonate solution and ethyl acetate separatory.Organic facies uses saturated common salt water washing after being separated, and after anhydrous magnesium sulfate drying, with column chromatography for separation (normal hexane: ethyl acetate=5:1), obtaining compound shown in structural formula 3 (0.60g), is light yellow solid, and productive rate is 61%.
1H NMR(400MHz,DMSO-d
6):7.06(dd,1H,J＝2.1Hz,J＝8.8Hz),6.91(d,1H,J＝8.8Hz),6.72(s,1H).HRMS(ESI)m/z calculated for C
10H
5O
4F
3[M+H]
+:246.0067,found:246.0140。
The preparation method of compound shown in embodiment 3 structural formula 4
By chloro-for compound 2-Resorcinol (0.400g, 2.07mmol)) be scattered in the perchloric acid of 1.5mL 70%, add compound trifluoroacetic ethyl acetoacetate ((0.36mL, 2.48mmol) subsequently.)。This reactant liquor is under agitation heated to 80 DEG C, returns to room temperature after 2 hours, with saturated sodium bicarbonate and ethyl acetate separatory.Organic facies is with after saturated common salt water washing, and with anhydrous magnesium sulfate drying, column chromatography for separation (normal hexane: ethyl acetate=2:1), obtaining compound shown in structural formula 4 (0.39g), is light yellow solid, and productive rate is 72%.
1HNMR(400MHz,DMSO-d
6):11.74(br s,1H),7.52(dd,1H,J＝1.9Hz,J＝9.0Hz),7.10(d,1H,J＝9.0Hz),6.86(s,1H).HRMS(ESI)m/z calculated for C
10H
4O
3F
3Cl[M+H]
+:263.9801,found:263.9733。
Embodiment 4 coumarin compound Profilin kinase c K2 determination of activity
Chinese style 2 of the present invention, formula 3 and formula 4, and in table 1 compound 5,6 and 7 as test-compound.Enzyme reaction mixed liquor (is comprised 50mM Tris-HCl, 10mM MgCl2,10 μMs of γ
32p-ATP and dephosphorylation casein 2g/L) be set to negative control, in 96 hole microtest plates, add the test-compound of variable concentrations in the diluted table 1 of the present invention of enzyme reaction mixed liquor respectively, add CK2 and start reaction.Room temperature reaction 10min, gets the P of a certain amount of reactant liquor point to diameter 2cm
18cessation reaction on phosphocellulose filters, dries in the shade, and with orthophosphoric acid and the washing with acetone of 85mM, dries, adds scintillation solution for 80 DEG C, and liquid scintillation instrument counts.With the logarithm of concentration for abscissa, the probability unit of respective concentration suppression ratio is vertical coordinate curve plotting, tries to achieve IC
50value.The results are shown in Table 1.Embodiment 5 coumarin compound anti-tumour cell proliferative activity measures
Mtt assay is adopted to measure the inhibitory action of compound 5,6 and 7 pairs of lung cancer cell types and cervical cancer cell lines Hela in formula 2, formula 3 and the compound shown in formula 4 and table 1.The tumor cell being in cell log trophophase is made into certain density cell suspension, is inoculated in 96 orifice plates with 7500, every hole cell concentration.At 37 DEG C, 5%CO
2hatch under condition and cultivate 24h, hatch and cultivate 24h, arrange negative control 3 hole, every hole, other holes adds the test-compound of table 1 variable concentrations of the present invention, cultivates 48h.Every hole adds MTT, continues to cultivate 4h, stops cultivating.Add DMSO to every hole dissolving crystallized, in 490-570nm wave-length coverage, measure its absorbance value and curve plotting by microplate reader, indirect reaction cell survival quantity.
Table 1 coumarin compound Profilin kinase c K2 activity and anti-tumour cell proliferative activity (μM)
By the compound 2,3 and 4 in contrast table 1 respectively with 5,6 and 7 structural formula and inhibit activities data can find, R in the present invention
4for CF
3compound 2,3,4, the R obtained with prior art respectively
4for CH
3homologous series compound 5,6,7 compare, and all have stronger Protein kinase C K2 inhibit activities and anti-tumour cell proliferative activity.Its reasons in structure is mainly: R
4for CH
34-methyl class coumarin compound 5,6 and 7, only R
7the electropositive district of position OH and CK2 catalytic activity pocket forms single polarity effect, therefore has lower inhibit activities; And R
4for CF
34-fluoroform base class coumarin compound 2,3 and 4, at original R
7position OH and electropositive district formed on the basis of polarity effect, increased again CF newly
3fluorine and the halogen bond effect that formed of catalytic activity pocket hinge region, thus the inhibit activities of compound is improved.The present inventor proposes to be ensure that compound has the important feature basis of high inhibit activities with binding pocket each sublocus formation effect (especially can form polarity effect with hinge region and electropositive district) simultaneously.
Claims (5)
1. fluoro umbelliferone compound is at kinases inhibitor or/and application in antitumor drug, and fluoro umbelliferone structural formula of compound is wherein as follows:
R
6for any one of H, OH, Cl, R
8for any one of H, OH, Cl, but R
6and R
8be asynchronously OH or H.
2. according to the fluoro umbelliferone compound of claim 1 at kinases inhibitor or/and application in antitumor drug, it is characterized in that, fluoro umbelliferone compound is any one or a few in following structural formula 2-4:
3. according to the fluoro umbelliferone compound of claim 1 at kinases inhibitor or/and application in antitumor drug, it is characterized in that, as the application of Protein kinase C K2 inhibitor.
4. according to the fluoro umbelliferone compound of claim 1 at kinases inhibitor or/and application in antitumor drug, it is characterized in that, as the application of anti-tumour cell proliferative medicine.
5. according to the fluoro umbelliferone compound of claim 4 at kinases inhibitor or/and application in antitumor drug, it is characterized in that, tumor cell line comprises pulmonary carcinoma A549 and cervical cancer Hela cells.
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|---|---|---|---|
| CN201510026735.6A CN104606186B (en) | 2014-11-19 | 2015-01-20 | Application of the hydroxy coumarin compound of fluoro 7 in kinases inhibitor or/and antineoplastic |
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|---|---|---|---|
| CN201410664929 | 2014-11-19 | ||
| CN2014106649294 | 2014-11-19 | ||
| CN201510026735.6A CN104606186B (en) | 2014-11-19 | 2015-01-20 | Application of the hydroxy coumarin compound of fluoro 7 in kinases inhibitor or/and antineoplastic |
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| CN104606186B CN104606186B (en) | 2017-09-12 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105311016A (en) * | 2014-07-24 | 2016-02-10 | 中国科学院大连化学物理研究所 | Anti-apoptosis Mcl-1 protein inhibitor, and applications thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1701790A (en) * | 1996-02-16 | 2005-11-30 | 斯特里克斯有限公司 | Use of non-steroidal sulphamate compound in the preparation of medicine for treating tumor |
| CN104529972A (en) * | 2014-10-10 | 2015-04-22 | 北京工业大学 | Protein kinase inhibitor namely coumarin as well as preparation method and medical application thereof |
-
2015
- 2015-01-20 CN CN201510026735.6A patent/CN104606186B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1701790A (en) * | 1996-02-16 | 2005-11-30 | 斯特里克斯有限公司 | Use of non-steroidal sulphamate compound in the preparation of medicine for treating tumor |
| CN104529972A (en) * | 2014-10-10 | 2015-04-22 | 北京工业大学 | Protein kinase inhibitor namely coumarin as well as preparation method and medical application thereof |
Non-Patent Citations (1)
| Title |
|---|
| MOHD MUDASSIR HUSAIN等: "Natural Bond Orbital (NBO) Analysis and Binding Affinity towards Protein Kinase 2: DFT and Docking Studies of Coumarin Derivatives", 《CHEMICAL SCIENCE TRANSACTIONS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105311016A (en) * | 2014-07-24 | 2016-02-10 | 中国科学院大连化学物理研究所 | Anti-apoptosis Mcl-1 protein inhibitor, and applications thereof |
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