CN109796505B - Preparation method and application of amide compound with antitumor activity - Google Patents
Preparation method and application of amide compound with antitumor activity Download PDFInfo
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- CN109796505B CN109796505B CN201910165222.1A CN201910165222A CN109796505B CN 109796505 B CN109796505 B CN 109796505B CN 201910165222 A CN201910165222 A CN 201910165222A CN 109796505 B CN109796505 B CN 109796505B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 10
- -1 amide compound Chemical class 0.000 title claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000003446 ligand Substances 0.000 claims abstract description 15
- 239000010949 copper Substances 0.000 claims abstract description 14
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052802 copper Inorganic materials 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 10
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000013078 crystal Substances 0.000 claims abstract description 9
- 239000000706 filtrate Substances 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 150000002815 nickel Chemical class 0.000 claims abstract description 5
- 238000010992 reflux Methods 0.000 claims abstract description 5
- 206010029260 Neuroblastoma Diseases 0.000 claims description 8
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 41
- 230000000694 effects Effects 0.000 abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
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- 229910021586 Nickel(II) chloride Inorganic materials 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 abstract description 3
- ZLQBNKOPBDZKDP-UHFFFAOYSA-L nickel(2+);diperchlorate Chemical compound [Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O ZLQBNKOPBDZKDP-UHFFFAOYSA-L 0.000 abstract description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract 2
- 239000008280 blood Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 150000001879 copper Chemical class 0.000 abstract 1
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 abstract 1
- 229910052697 platinum Inorganic materials 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 19
- 102000002072 Non-Receptor Type 1 Protein Tyrosine Phosphatase Human genes 0.000 description 8
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 238000002835 absorbance Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- INVGWHRKADIJHF-UHFFFAOYSA-N Sanguinarin Chemical compound C1=C2OCOC2=CC2=C3[N+](C)=CC4=C(OCO5)C5=CC=C4C3=CC=C21 INVGWHRKADIJHF-UHFFFAOYSA-N 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 239000003472 antidiabetic agent Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- FCEXWTOTHXCQCQ-UHFFFAOYSA-N Ethoxydihydrosanguinarine Natural products C12=CC=C3OCOC3=C2C(OCC)N(C)C(C2=C3)=C1C=CC2=CC1=C3OCO1 FCEXWTOTHXCQCQ-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229940084560 sanguinarine Drugs 0.000 description 2
- YZRQUTZNTDAYPJ-UHFFFAOYSA-N sanguinarine pseudobase Natural products C1=C2OCOC2=CC2=C3N(C)C(O)C4=C(OCO5)C5=CC=C4C3=CC=C21 YZRQUTZNTDAYPJ-UHFFFAOYSA-N 0.000 description 2
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 239000000872 buffer Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
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- 208000016097 disease of metabolism Diseases 0.000 description 1
- KAKKHKRHCKCAGH-UHFFFAOYSA-L disodium;(4-nitrophenyl) phosphate;hexahydrate Chemical compound O.O.O.O.O.O.[Na+].[Na+].[O-][N+](=O)C1=CC=C(OP([O-])([O-])=O)C=C1 KAKKHKRHCKCAGH-UHFFFAOYSA-L 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
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- 229940055695 pancreatin Drugs 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
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- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a preparation method and application of an amide compound with antitumor activity, the structural formula is as follows,
Description
Technical Field
The invention relates to a preparation method of an amide compound with antitumor activity, and application of the compound in preparing an anticancer medicament and an antidiabetic medicament.
Background
Since the discovery of cisplatin, the application of transition metal compounds with targeting functions of proteins and DNA in the field of anticancer drugs has attracted much attention, and among the numerous bridged ligands, oxamide bridged ligand has been regarded as a multifunctional ligand, and has been paid attention to by scientists due to its unique bridged structure and its complex, however, the research on oxamide coordination compounds has been mostly focused on the fields of catalysis and molecular magnetism, and in recent years, more and more researchers have been applying oxamide coordination compounds to anticancer drugs.
Type II diabetes, an endocrine-disturbance metabolic disease, has become a third chronic disease seriously threatening human health after tumor and cardiovascular diseases. In the existing research on hypoglycemic drugs, many reports are made on Protein Tyrosine Phosphatase 1B (PTP1B) inhibitors, but no report is found on the research on the PTP1B inhibitory activity of the compounds.
Disclosure of Invention
In view of the above prior art, the present invention provides a novel active three-dimensional structure compound, and provides a preparation method and applications thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
the active three-dimensional structure compound has the following structural formula:
the invention also provides a preparation method of the active three-dimensional structure compound, which comprises the following preparation steps:
dissolving 2.0-4.0mmol of oxamide mononuclear copper ligand in 10-20ml of methanol, dissolving 1.0-2.0mmol of nickel salt in 5-10ml of methanol, adding into the methanol solution of the mononuclear copper ligand, reacting at 60-100 ℃ for 1-3 hours, cooling, filtering, and slowly volatilizing the filtrate for 1 week to obtain blue blocky crystals, namely the active three-dimensional structure compound.
Preferably, the nickel salt includes: any one or a mixture of more of nickel perchlorate, nickel chloride and nickel bromide.
The reaction equation is as follows:
the invention also provides application of the active three-dimensional structure compound in preparation of a medicine for treating human neuroblastoma cells SK-N-BE.
The invention has the beneficial effects that: the molecular formula of the active three-dimensional structure compound is C56H68Cu4Ni2N12O20F4(ii) a The molecular weight of 1676.77 has high anticancer activity, and can BE used as a raw material for preparing potential drugs for treating human neuroblastoma cells SK-N-BE.
In addition, the inventor for the first time finds that the compound has hypoglycemic activity. Compared with the currently commonly used similar hypoglycemic drugs, the active three-dimensional structure compound has the characteristics of high activity, low cost, simple preparation method and the like, and provides a new way for developing related drugs.
Detailed Description
The present invention will be further illustrated by the following examples, which are intended to be merely illustrative and not limitative.
Example 1:
dissolving 2mmol of oxamide mononuclear copper ligand in 10ml of methanol, dissolving 1mmol of nickel perchlorate in 5ml of methanol, adding the solution into the methanol solution of the mononuclear copper ligand, refluxing for 5 hours at 60 ℃, filtering, and slowly volatilizing the filtrate for 1 week to obtain blue blocky crystals. Namely the active three-dimensional structure compound. The molecular structure of the active three-dimensional structure compound is as follows:
the active three-dimensional structure compound of example 1 was tested using infrared, elemental analysis and X-ray single crystal diffraction and the results were as follows:
infrared spectrum (KBr, cm-1): vos (C ═ O)1616, 1583, 1541.
Elemental analysis (C)56H68Cu4Ni2N12O20F4)：Calculated:C,40.11；H,4.09；N,10.02％.Found:C,40.13；H,4.08；N,10.04％。
X-ray single crystal diffraction results:
crystallographic data and structural analysis parameters of compounds
Example 2:
dissolving 2mmol of oxamide mononuclear copper ligand in 20ml of methanol, dissolving 1mmol of nickel chloride in 10ml of methanol, adding into the methanol solution of the mononuclear copper ligand, refluxing at 60 ℃ for 5 hours, filtering, and slowly volatilizing the filtrate for 1 week to obtain blue blocky crystals. Namely the active three-dimensional structure compound.
Example 3:
dissolving 2mmol of oxamide mononuclear copper ligand in 10ml of methanol, dissolving 1mmol of nickel bromide in 5ml of methanol, adding into the methanol solution of the mononuclear copper ligand, refluxing at 60 ℃ for 5 hours, filtering, and slowly volatilizing the filtrate for 1 week to obtain blue blocky crystals. Namely the active three-dimensional structure compound.
Test example 1:
the determination of the in vitro anticancer activity of the active three-dimensional structure compound is realized by an MTT experimental method, and the principle is as follows: based on the metabolic reduction of exogenous MTT (3- (4, 5-dimethylthiozol-2-yl) -2, 5-diphenylterazolium bromide), NADP-related dehydrogenase was present in mitochondria of living cells, yellow MTT was reduced to insoluble blue-violet crystalline Formazan (Formazan), dead cells were not treated with this enzyme, MTT was not reduced, Formazan was dissolved in dimethyl sulfoxide DMSO, and then the optical density at a characteristic wavelength (570nm wavelength) was measured with a microplate reader to determine the data. The method can indirectly reflect the number of living cells. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number. The method is widely used for activity detection of some bioactive factors, large-scale screening of anti-tumor drugs, cytotoxicity test, tumor radiosensitivity determination and the like.
The results of analyzing human neuroblastoma cells SK-N-BE by MTT analysis and determining the IC50 value are shown in Table 1, and the data in Table 1 show that the compound of the invention has high in vitro activity on human neuroblastoma cells SK-N-BE and can BE used as a candidate compound of potential anticancer drugs.
Determination of antitumor activity of compound by MTT method
The activity screening was performed using sanguinarine hydrate as a positive control, using human neuroblastoma cell SK-N-BE tumor cells, at two concentrations, 5. mu. mol/L and 1. mu. mol/L.
(1) And after the superclean bench is subjected to ultraviolet irradiation for 30min, the ultraviolet lamp is turned off, and the illuminating lamp and the fan are turned on.
(2) Discarding the old culture medium, adding PBS to wash for 2-3 times, adding pancreatin, digesting the adherent cells, adding culture medium containing 10% fetal calf serum to stop digestion, collecting the cells, centrifuging at 900rmp/min for 5min, and adding new culture medium to the culture medium before discarding for resuspension.
(3) Cells were counted and adjusted to 5000 cells/well.
(4) Cells were transferred to 96-well plates at 100. mu.l per well and then placed in CO2A constant temperature incubator.
(5) After cell attachment, 100. mu.l of compounds at different concentrations were added, 3 wells each, and 100. mu.l of medium was added to each well as a blank.
(6) After 48h incubation, 20. mu.l MTT was added to each well.
(7) After culturing for 4h, directly throwing the plate, adding 200 mul of dimethyl sulfoxide into each hole, fully dissolving, and measuring the absorbance at 490nm by using an enzyme-labeling instrument, wherein 630nm is used as a reference wavelength. Wherein,
absorbance value of compound 490nm absorbance value-630 nm absorbance value,
inhibition (%) × (1-mean absorbance value of compound/mean absorbance value of blank) × 100%.
(8) Compound IC50Detecting and screening out compounds with better activity for IC50And (4) measuring. The IC of sanguinarine is known from the literature50Approximately 1. mu. mol/L, so the concentration gradient of the compound was set to 20, 5, 1.25, 0.31, 0.078. mu. mol/L (4-fold dilution) and was used as-is. Human neuroblastoma cells SK-N-BE were used for the experiments.
TABLE 1 in vitro Activity test data of the three-dimensional Structure Compound anticancer drug
| Human neuroblastoma cell | |
| Sample IC50 | 3.4μM/mL |
| Cell line | SK-N-BE |
Test example 2:
the use of the active three-dimensional structure compound anticancer agents of examples 1-3 above in the preparation of a medicament for the treatment of diabetes.
The compounds synthesized in examples 1-3 above were tested for their inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) as test compounds, according to the following specific test methods:
200. mu.L of the reaction system contained PTP1B (recombinant expression), buffer (25mM HEPES,50mM sodium chloride, 2.5mM EDTA, 0.1% BSA, pH 7.2) and the above compounds, while blank control (not containing enzyme and the above compounds) and negative control (not containing the above compounds) were set up, reacted at 37 ℃ for 10min, protein tyrosine phosphatase substrate PNPP was added, reacted at 37 ℃ for 30min, 2M Na2CO3 was added to terminate the reaction, and OD was measured at 405 nm. The inhibition rate was calculated from the OD value, and ═ 1- (OD sample-OD blank)/(OD negative-OD blank) ] × 100%. During primary screening, double holes are arranged at single concentration of each sample, the IC50 value of the sample with the inhibition rate of more than 70 percent is determined, six concentrations are diluted by each sample in a gradient manner, and double holes are arranged at each concentration. IC50 was calculated from the inhibition using a 4Parameter Logistic Model in Xlfit software. The test results are shown in Table 2.
TABLE 2 data for the in vitro inhibitory Activity of the Compound PTP1B
| Sample IC50 | 5.32±0.77(μM) |
| Sodium orthovanadate | 6.85±0.74(μM) |
As can be seen from the activity results in Table 2, the compound of the present invention shows good inhibitory activity against protein tyrosine phosphatase 1B, and the effect is significantly superior to that of positive control sodium orthovanadate, so that the compound can be used for preparing a medicament for treating diabetes.
Although the present invention has been described with reference to the specific embodiments, it is not intended to limit the scope of the present invention, and various modifications and variations can be made by those skilled in the art without inventive changes based on the technical solution of the present invention.
Claims (3)
1. An amide compound with anti-tumor activity is characterized in that the structural formula is as follows:
2. the preparation method of the amide compound with the antitumor activity according to claim 1, which is characterized by comprising the following preparation steps:
dissolving 2.0-4.0mmol of oxamide mononuclear copper ligand in 10-20ml of methanol, dissolving 1.0-2.0mmol of nickel salt in 5-10ml of methanol, adding into the methanol solution of the mononuclear copper ligand, refluxing at 60-100 ℃ for 5-10 hours, filtering, and slowly volatilizing the filtrate for 1 week to obtain the amide compound with the antitumor activity, wherein the amide compound with the antitumor activity is a blue blocky crystal.
3. The application of the amide compound with the antitumor activity according to claim 1 in preparing a medicament for treating human neuroblastoma cells SK-N-BE and an application in a medicament with the hypoglycemic activity.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286057A (en) * | 2011-07-07 | 2011-12-21 | 北华大学 | Oleanane-type triterpenoid compounds and preparation method and medicinal use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286057A (en) * | 2011-07-07 | 2011-12-21 | 北华大学 | Oleanane-type triterpenoid compounds and preparation method and medicinal use thereof |
Non-Patent Citations (3)
| Title |
|---|
| A novel Mn-Cu bimetallic complex for enhanced chemodynamic therapy with simultaneous glutathione depletion;Shuhua Cao等;《Chem. Commun.》;20191002;第55卷;第12956-12959页 * |
| 两类功能性化合物的合成、结构及生物活性研究;李法辉;《中国博士学位论文全文数据库工程科技Ⅰ辑》;20110715;B014-12页，特别是第100页第1段，第105页第1段，图4-4，表4-5，第103页第1段 * |
| 新型不对称草酰胺桥联多核配合物的合成、结构、抗癌活性及与DNA相互作用研究;韩雅婷;《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》;20090215;B014-54页，特别是第43页第3段，第45页第2段 * |
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