CN107827936B - Preparation and application of ferrocene selenide derivative - Google Patents
Preparation and application of ferrocene selenide derivative Download PDFInfo
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- -1 ferrocene selenide Chemical class 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 206010017758 gastric cancer Diseases 0.000 claims description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 150000001491 aromatic compounds Chemical class 0.000 claims description 4
- WJABCDIQFDQKQI-UHFFFAOYSA-N 4-(2,2-dibromoethylamino)benzoic acid Chemical compound BrC(CNC1=CC=C(C(=O)O)C=C1)Br WJABCDIQFDQKQI-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 claims description 2
- 238000006197 hydroboration reaction Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 1
- VPQBLCVGUWPDHV-UHFFFAOYSA-N sodium selenide Chemical compound [Na+].[Na+].[Se-2] VPQBLCVGUWPDHV-UHFFFAOYSA-N 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 9
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 8
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- 238000002474 experimental method Methods 0.000 abstract description 7
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
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- 108090000672 Annexin A5 Proteins 0.000 description 1
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- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
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- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- 230000001464 adherent effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 108010072788 angiogenin Proteins 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 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
- 229940127089 cytotoxic agent Drugs 0.000 description 1
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- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 229940088598 enzyme Drugs 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
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- 230000001939 inductive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- WALCGGIJOOWJIN-UHFFFAOYSA-N iron(ii) selenide Chemical class [Se]=[Fe] WALCGGIJOOWJIN-UHFFFAOYSA-N 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
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- 229910052711 selenium Inorganic materials 0.000 description 1
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- 210000002966 serum Anatomy 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel ferrocene selenide derivative and provides a preparation method thereof, which has the characteristics of low synthesis cost, mild reaction condition and convenient process operation. Meanwhile, the invention provides the application of the derivative in antitumor drugs, and biological experiments such as cell proliferation, cell apoptosis, cell cycle and the like prove that the ferrocene selenide derivative provided by the invention can effectively inhibit the proliferation of tumor cells, induce the apoptosis of the tumor cells, influence the cycle of the tumor cells, prove that the derivative has obvious influence on tumor apoptosis-related proteins and has obvious antitumor activity. Meanwhile, experiments prove that the derivative does not depend on ferrocene but changes the side chain structure of the ferrocene to enable molecules to be more hydrophobic. The invention has important reference value for the discovery of novel antitumor drugs.
Description
Technical field
The present invention relates to a kind of synthesis of anti-tumor drug and applications, and in particular to a kind of ferrocene selenide derivative and its
Preparation and application.
Background technique
Cancer seriously threatens human life and health due to lacking effective treatment means.Low toxicity novel in design is efficiently
Anticancer drug research, the research drug of molecular level and the interaction of tumour become it in the weight of anticancer drug research
Weight.
In traditional cytotoxic drug, cis-Platinum compound and its derivative are used as still in more cancer patient and resist
Cancer drug uses, although cisplatin medicine has huge success in the treatment of cancer, they have great harm to kidney, because
This, it is very necessary to seek less toxic efficient anticancer drug.Ferrocene is because having stability, hypotoxicity, armaticity, lipophilicity, richness
Electrical property, oxidation-reduction quality, the easily properties such as substitution and biocompatibility, and introduce after the group in organic molecule often to small point
Sub- compound brings excellent bioactivity, so Ferrocene and its derivative one of always is the hot spot of research.With
The progress and development of every technology, ferrocene selenide derivative is in multiple fields such as functional material, analytical chemistry, catalysis and medicine
All various aspects have a wide range of applications.Part ferrocene selenide derivative has certain activity in anti-tumor aspect, some
Ferrocene selenide derivative may be used as anti-tumor agent comprising salmosin, and moieties are practiced in clinic.But in face of existing
Modern numerous tumor diseases, existing anti-tumor drug are far from satisfying needs, and urgent need develops new type antineoplastic medicine.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the deficiencies of existing ferrocene selenide derivative, provide a new class of two
Luxuriant iron selenide derivative.
Another technical problem to be solved by the present invention is that providing, a kind of step is simple, the higher preparation method of yield, is based on
The preparation method can obtain the ferrocene selenide derivative.
The invention solves another technology be to provide the application of the ferrocene selenide derivative.
The purpose of the present invention is achieved by the following technical programs:
A kind of ferrocene selenide derivative is provided, shown in structural formula such as formula (I):
Wherein, n1It is 1,2,3 or 4；n2It is 1,2 or 3；R1For H, CH3Or CH2CH3。
The present invention also provides a kind of ferrocene selenide derivatives, shown in structural formula such as formula (II):
Wherein, n2For 1,2 or 3, R1For H, CH3Or CH2CH3, R2For CH, (CH2)2NCH2, (CH2)2NC6H4, (CH2)2NC6H4SCH2CH2。
The present invention also provides a kind of ferrocene selenide derivatives, shown in structural formula such as formula (III):
Wherein, n2For 1,2 or 3, R1For H, CH3Or CH2CH3, R2For CH, (CH2)2NCH2, (CH2)2NC6H4, (CH2)2NC6H4SCH2CH2。
Further, above-mentioned ferrocene selenide derivative is preparing the application in anti-tumor drug.
Further, the ferrocene selenide derivative is in preparation anti-liver cancer and anti-, lung cancer, gastric cancer, intestinal cancer or breast cancer drug
Application in object.
In structural formula shown in above-mentioned formula (II), work as n2It is 2, R1For H and R2For (CH2)2NC6H4When, the chemical combination that is characterized
Application of the object in preparation anti-gastric cancer medicament.
Further, the present invention also provides the preparation methods of above-mentioned ferrocene selenide derivative, specifically includes the following steps:
(1) under nitrogen protection, dehydrated alcohol and ferrocene selenide is added in the reaction vessel, hydroboration is added under ice bath
Sodium after being sufficiently stirred, then bromo-acid is added into reactor, controls 5~30 DEG C of reaction temperature, reacts 5~48h, obtains intermediate,
Wherein the molar ratio ferrocene Xi Mi ﹕ Peng Qingization Na ﹕ bromo-acid of reaction raw materials be 1 ﹕, 3~5 ﹕ 1~3, ferrocene selenide with it is anhydrous
The molar ratio of ethyl alcohol is 1 ﹕ 10~100；
(2) under nitrogen protection, in the reaction vessel be added solvent absolute ethyl alcohol, the intermediate in above-mentioned steps (1) and
Primary amine substituted aromatic shown in the structural formula of the aromatic compound such as formula (III), reacts 4~72h at 10~80 DEG C
Target product, wherein the molar ratio of intermediate and aromatic compound is 1 ﹕ 0.5~10, intermediate and solvent absolute ethyl alcohol
Molar ratio is 1 ﹕ 10~100；
Wherein, n2For 1,2 or 3, R1For H, CH3Or CH2CH3。
Further, the preparation method of above-mentioned ferrocene selenide derivative, bromo-acid described in step (1) are bromine second
Acid, 4- (dibromoethyl amino) benzoic acid, dibromoethyl amion acetic acid or 3- [4- (dibromoethyl amino) phenyl] sulphur propionic acid.
Compared with prior art, the beneficial effects of the present invention are: provide a kind of new ferrocene selenide derivative and
Its synthetic method, at low cost, reaction condition is mild, the convenient feature of technological operation.Meanwhile the present invention provides the derivatives
New application proves ferrocene selenium provided by the present invention by Bioexperiment such as cell Proliferation, Apoptosis and cell cycles
The proliferation of tumour cell, inducing apoptosis of tumour cell can be effectively suppressed in ether derivant, and influences tumour cell cycle, it was demonstrated that swollen
The related albumen of tumor apoptosis has a significant effect, and has significant anti-tumor activity.Meanwhile experiments have shown that the derivative induced cell withers
Dying is not to rely on ferrocene, but pass through and change ferrocene side-chain structure and property, keeps molecule more fat-soluble and targeting type.
The present invention is found to have important references value for new type antineoplastic medicine.
Detailed description of the invention
Fig. 1 is target compound in embodiment 11H-NMR figure；
Fig. 2 is target compound in embodiment 1 to stomach cancer cell MGC -803 inhibiting effect figure；
Fig. 3 is target compound in embodiment 2 to stomach cancer cell MGC -803 apoptotic effect figure；
Fig. 4 is target compound in embodiment 3 to stomach cancer cell MGC -803 cycle influences figure；
Fig. 5 is target compound in embodiment 4 to stomach cancer cell MGC -803 cell cycle protein dependent kinase CDK-2
Influence diagram.
Specific embodiment
For a better understanding of the present invention, the present invention is further illustrated below with reference to embodiment.
Embodiment 1
The synthesis of target compound: using ferrocene selenide as synthesis material, under nitrogen protection, ice bath is anti-with sodium borohydride
0.5h is answered, room temperature two hours, 4- (dibromoethyl amino) phenyl formic acid reaction 12 hours is added, wherein ferrocene Xi Mi ﹕ boron hydrogen
Hua Na ﹕ bromoacetic acid molar ratio is 1:4:2.Reaction solution is adjusted to acid with hydrochloric acid solution, is spin-dried for reaction solution.The extraction of methylene chloride water,
Lower layer's clear yellow solution is taken, anhydrous magnesium sulfate is dry, and a little silica gel is added into acquired solution, is spin-dried for.Cross pillar, irrigation
Methylene chloride: ethyl acetate=3:1. products therefrom and 4- (2- ethylamino-) benzene -1,2- diphenol under the action of catalyst, react
12h.It is spin-dried for, extracts, cross pillar.Obtain faint yellow solid compound, structural formula such as formula (II), wherein n2It is 2, R1For H and R2
For CH2)2NC6H4.Nuclear-magnetism characterization is shown in attached drawing 1, using DMSO hydrotropy, is configured to the storing liquid long-term preservation of 200 μM/L.
Cell strain: for gastric carcinoma cells (MGC-803) purchased from Central European biomedical innovation center, condition of culture is 10% tire
Cow's serum, RPMI1640 culture medium, 1% antibiotic are placed in 37 DEG C, 5%CO2 incubator.Routine culture, cell reach saturation shape
When state, 0.25% pancreatin had digestive transfer culture.
Cytoactive detection: logarithmic growth phase cell, the digestion of 0.25% pancreatin, 1000rpm are centrifuged 5min, abandon supernatant and match
Single cell suspension is made；Cell suspension, 100 μ L of every empty addition, so that is be added in every hole is thin are added in each hole in 96 orifice plates
Born of the same parents' number is 3000, and then 96 orifice plates are put into incubator and continue to cultivate 12h.Until the cell in 96 orifice plates is all adherent
After, supernatant is discarded, after the compound of various concentration is joined, every empty 100 μ L, each concentration repeats 3 holes.Again
The culture solution of the same volume is added in blank control wells, but cell is not added, repeats 3 holes.Then 96 holes that will be handled well
Plate is put into incubator, and routine culture 72h is continued, and then 10 μ L of CCK-8 (Japanese colleague) reagent is added in every hole, continues to be put into
CO2 incubator culture 2h.Finally 96 orifice plates are put into the microplate reader debugged, wavelength 450nm, are measured at this wavelength
The absorbance value in each hole.
The opposite proliferation activity of cell=(absorbance value-blank group absorbance value of processing group)/(control group absorbance
Value-blank group absorbance value) × 100%.
The results show that the present embodiment target compound has stronger inhibited proliferation, IC50 to MGC-803 cell
Value is cell inhibitory effect activity such as attached drawing 2.
Embodiment 2
Experimental cell: with embodiment 1；
Experimental drug: for target compound in embodiment 1；
Experimental method:
Logarithmic growth phase cell HepG2, the digestion of 0.25% pancreatin, 1000rpm are centrifuged 5min, and abandoning supernatant is configured to slender
Born of the same parents' suspension；MGC-803 cell suspension is added in each hole in 6 orifice plates, and the cell number being added in every hole is about 1 × 106It is a, then
6 orifice plates are put into incubator and continue culture for 24 hours.After for 24 hours, the compound (10 μM, 20 μM) of various concentration is added, is further continued for
Culture is for 24 hours.Cell is collected, is washed one time with PBS, 5 μ L Annexin V-FITC and 5 μ L PI are added, is mixed.Room temperature is protected from light
15min.The detection of apoptosis rate is carried out with flow cytometer.Every group repeats experiment 3 times.
The results show that target compound induces MGC-803 apoptosis, the apoptosis ratio of low dose group reaches
10.79%.The derivative, which has, promotes apoptotic effect, and at dose-dependant formula, inhibitory activity is shown in attached drawing 3.
Embodiment 3
Experimental cell: with embodiment 1；
Experimental drug: for the target compound in embodiment 1；
Experimental method: logarithmic growth phase cell MGC-803, the digestion of 0.25% pancreatin, 1000rpm are centrifuged 5min, take
It is configured to single cell suspension clearly；Each hole is added HepG2 cell suspension in 6 orifice plates, and the cell number being added in every hole is about 1 ×
106It is a, then 6 orifice plates are put into incubator and continue culture for 24 hours.After for 24 hours, be added various concentration compound (10 μM, 20
μM), it is cultivated for for 24 hours.It is rinsed cell 2 times with PBS, harvests cell using pancreas enzyme -EDTA.After washing one time with PBS again, quickly
The fixed cell of ethyl alcohol of suitable 75% pre-cooling is injected, 4 DEG C of refrigerators save overnight.Cell is washed one time with PBS, is added into filtrate
1U/mL RNase A and 5 μ g/mL PI dyestuffs mix, and room temperature places 30min, during which rocks uniformly mixed number under the conditions of being protected from light
It is secondary, the detection of period profile correlation circumstance is carried out with flow cytometer.
The results show that S phase cell block occurs for target compound induction MGC-803 cell, to MGC-803 Cycle Arrest
See attached drawing 4.
Embodiment 4
Experimental cell: with embodiment 1；
Experimental drug: for the target compound in embodiment 1；
Experimental method
Sample prepares: to 1 × 10620 μM of target compounds are added in a cell, collect culture 0h, 12h respectively, for 24 hours,
Cell after 36h, 48h after 500rpm is centrifuged 5min, is added dissolution into sediment and stops protease and phosphoric acid with containing 1%
P-MER the cell lysis buffer solution 1mL, ice bath 30min of enzyme inhibitor.After being centrifuged 10min, supernatant is collected, spectrophotometric is used
Meter is quantitative, at 95 DEG C, is denaturalized 10min with sample buffer, and be stored at 4 DEG C.
Loading electrophoresis: being added sample-loading buffer in sample protein extract and mix, and wherein buffer presses sample: loading is slow
Fliud flushing=4: then 1 volume ratio boils 5min at 95-100 DEG C.Sample is mixed, room temperature 12000rpm is centrifuged 2min, takes
Clear liquid is to be measured.Deposition condition: constant pressure 60min under constant pressure about 20min, separation gel 100V under concentration glue 80V.Transferring film closing.
Primary antibody (with the 1:1000 dilution in proportion of primary antibody dilution) is added, and shaking table sways incubation, controlled at 4 DEG C, the time
It is 24 hours.TBST is rinsed filter membrane 4 times.By secondary antibody (1:1000 dilutes in proportion with the secondary antibody diluent) room of film in conjunction with HRP
Warm shaking table, which sways, is incubated for 60-120min, then sufficiently washes film with TBST, rinses 4 times.Developing solution is added, is protected from light colour developing to appearance
It is put into distilled water when band and terminates reaction.
Development and image analysis result are shown, after compound stimulates MGC-803 cell, induction CDK-2 protein expression is lowered,
The results are shown in attached figure 5.
Above-described embodiment is only preferred embodiment, is not limited the embodiments.For the common of fields
For technical staff, other different forms of changes or modifications may be made based on the above description.It is all according to the present invention
Equivalent changes and modifications made by the content of claim all should be used as technology scope of the invention.
Claims (4)
1. a kind of ferrocene derivatives, which is characterized in that shown in its structural formula such as formula (II):
Wherein, n2It is 2, R1For H, R2For (CH2)2NC6H4。
2. application of the ferrocene derivatives described in claim 1 in preparation anti-gastric cancer medicament.
3. the preparation method of ferrocene derivatives described in claim 1, which comprises the following steps:
(1) under nitrogen protection, dehydrated alcohol 100ml is added in the reaction vessel, hydroboration is added under ice bath in ferrocene selenide
Sodium after being sufficiently stirred, then bromo-acid is added into reactor, controls 5~30 DEG C of reaction temperature, reacts 5~48h, obtains intermediate,
Wherein the molar ratio ferrocene Xi Mi ﹕ Peng Qingization Na ﹕ bromo-acid of reaction raw materials is 1 ﹕, 3~5 ﹕ 1~3；
(2) under nitrogen protection, dehydrated alcohol 100ml is added in the reaction vessel, the virtue that above-mentioned intermediate and primary amine replace is added
Aroma compounds, shown in the structural formula of the aromatic compound such as formula (III), 4~72h of reaction obtains target product, wherein intermediate
Molar ratio with aromatic compound is 1 ﹕ 0.5~10；
Wherein, n2It is 2, R1For H.
4. the preparation method of ferrocene derivatives as claimed in claim 3, which is characterized in that bromo described in step (1)
Acid is 4- (dibromoethyl amino) phenyl formic acid.
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