CN108440577A - A kind of copper-based complex of mixture and its preparation method and application - Google Patents
A kind of copper-based complex of mixture and its preparation method and application Download PDFInfo
- Publication number
- CN108440577A CN108440577A CN201810253423.2A CN201810253423A CN108440577A CN 108440577 A CN108440577 A CN 108440577A CN 201810253423 A CN201810253423 A CN 201810253423A CN 108440577 A CN108440577 A CN 108440577A
- Authority
- CN
- China
- Prior art keywords
- copper
- sbr
- mixture
- preparation
- based complex
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000010949 copper Substances 0.000 title claims abstract description 87
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229910052802 copper Inorganic materials 0.000 title claims abstract description 47
- 239000000203 mixture Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 60
- 239000003446 ligand Substances 0.000 claims abstract description 16
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims abstract description 16
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 9
- 239000001103 potassium chloride Substances 0.000 claims abstract description 9
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 9
- 239000004037 angiogenesis inhibitor Substances 0.000 claims abstract description 8
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims abstract description 8
- 229960003080 taurine Drugs 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 claims abstract description 6
- 239000012046 mixed solvent Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000002262 Schiff base Substances 0.000 claims abstract description 3
- -1 schiff bases anion Chemical class 0.000 claims abstract description 3
- 230000007935 neutral effect Effects 0.000 claims abstract 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 238000002156 mixing Methods 0.000 abstract description 2
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 abstract 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 34
- 230000006907 apoptotic process Effects 0.000 description 18
- 206010028980 Neoplasm Diseases 0.000 description 17
- 210000004881 tumor cell Anatomy 0.000 description 17
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 14
- 241000287828 Gallus gallus Species 0.000 description 12
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 12
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 229910052697 platinum Inorganic materials 0.000 description 11
- 230000003013 cytotoxicity Effects 0.000 description 8
- 231100000135 cytotoxicity Toxicity 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- 102220002645 rs104894309 Human genes 0.000 description 8
- 238000011534 incubation Methods 0.000 description 7
- 210000001161 mammalian embryo Anatomy 0.000 description 7
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 7
- 229960005314 suramin Drugs 0.000 description 7
- 210000003556 vascular endothelial cell Anatomy 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000005779 cell damage Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- WEUFQISIJPSTBM-UHFFFAOYSA-N 2-bromo-6-methoxyphenol Chemical class COC1=CC=CC(Br)=C1O WEUFQISIJPSTBM-UHFFFAOYSA-N 0.000 description 2
- 102000004121 Annexin A5 Human genes 0.000 description 2
- 108090000672 Annexin A5 Proteins 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 230000001772 anti-angiogenic effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012148 binding buffer Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000005747 tumor angiogenesis Effects 0.000 description 2
- 210000003606 umbilical vein Anatomy 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035572 chemosensitivity Effects 0.000 description 1
- 210000003711 chorioallantoic membrane Anatomy 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000004699 copper complex Chemical class 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- UGWKCNDTYUOTQZ-UHFFFAOYSA-N copper;sulfuric acid Chemical compound [Cu].OS(O)(=O)=O UGWKCNDTYUOTQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000008236 heating water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/08—Copper compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a kind of the copper-based with object and its preparation method and application of mixture.Its structural formula of the copper-based complex of the mixture is [Cu (C10H10NO5SBr)(C12H8N2)]·CH3OH, wherein [Cu (C10H10NO5SBr)(C12H8N2)] it is list of coordination units, C10H10NO5SBr is schiff bases anion ligand, C12H8N2It is neutral ligand 1,10' phenanthrolenes.Preparation method first mixes taurine and highly basic, and organic solvent stirring and dissolving is added, and 5 bromine, 2 hydroxyl, 3 methoxybenzaldehyde is then added, and constant temperature stirs 2 ~ 4h, stops reaction, obtains the sylvite K of ligand2C10H10NO5SBr；Again by the sylvite K of ligand2C10H10NO5SBr and mantoquita mixing, are dissolved in the mixed solvent of methanol/water, add 1,10' phenanthrolenes, and 8 ~ 20h of isothermal reaction obtains the copper-based complex of mixture after reaction.The copper-based of the mixture matches object, is both the candidate of antitumor drug and good angiogenesis inhibitor, is a kind of candidate of novel difunctional antitumor drug.
Description
Technical field
The present invention relates to mixture Metal Substrate complex, copper-based complex of specifically a kind of mixture and preparation method thereof and answer
With.
Background technology
Oncotherapy is faced with always stern challenge.Growth, deterioration, infiltration and the transfer of tumour are close with new vascular generation
Cut phase is closed.Malignant tumour can derive the vascular system of itself and obtain nutrition, after tumour cell obtains nutrition, and promote tumour
The generation of blood vessel, it means that tumor vessel and tumour cell play the role of one in the growth of tumour and mutually promote.This
Outside, inhibiting Tumor Angiongesis, inducing apoptosis of tumour cell can reach significantly antitumous effect simultaneously, find existing tumour
The effect of Agiogenesis inhibition has the antitumor drug for killing tumour cell dual function significant again.
Copper is a vital trace element in all organisms, and copper complex is effective cytotoxic drug.
Copper activity compound is different from currently used platinum medicine, and it in terms of mechanism of action, bio distribution and cytotoxicity
Fight those chemosensitivities difference or traditional platinum medicine to produce the cancer of drug resistance be effective, be at least substantially effective
's.In addition, copper rather than other metals, have close relationship, it is special that vascular endothelial cell has copper to angiogenesis
Sensibility makes copper level reduction be effectively reduced tumor vascular density because of chelation, and copper chelate itself is to swollen
The influence of tumor angiogenesis is not almost studied.Ours the study found that an active copper base complex can be used as tumor vessel
Formation inhibitor, but also be the derivant of the apoptosis and damage of the tumour cell of tumour cell and resistance to cis-platinum, and pair with it is swollen
Tumor angiogenesis is studied with tumor cell proliferation, existence with closely related signal of interest molecule is shifted, and elaborates to live
Property copper-based complex inhibit Tumor Angiongesis and kill the molecule mechanism of the tumour cell of tumour cell and resistance to cis-platinum.
Invention content
The technical problem to be solved by the invention is to provide one kind itself can not only be used for antitumor drug but also as tumour
The mixture copper-based active complex of angiogenesis inhibitors.
The technical problems to be solved by the invention are achieved by the following technical programs：
A kind of copper-based complex of mixture, structural formula are [Cu (C10H10NO5SBr)(C12H8N2)]·CH3OH, wherein [Cu
(C10H10NO5SBr)(C12H8N2)] it is list of coordination units, C10H10NO5SBr is schiff bases anion ligand, C12H8N2It is that neutrality is matched
Body 1,10'- phenanthrolenes.
The preparation method of the copper-based complex of the mixture, comprises the following steps：
S1. taurine and highly basic are mixed, organic solvent stirring and dissolving is added, the bromo- 2- hydroxy-3-methoxies of 5- are then added
Benzaldehyde, constant temperature stir 2 ~ 4h, stop reaction, obtain the sylvite K of ligand2C10H10NO5SBr；
S2. by the sylvite K of ligand2C10H10NO5SBr and soluble copper salt mixing, are dissolved in the mixed solvent of methanol/water, add
1,10'- phenanthrolene, 8 ~ 20h of isothermal reaction obtain the copper-based complex [Cu (C of mixture after reaction10H10NO5SBr)
(C12H8N2)]·CH3OH。
Above-mentioned preparation method, mole of the bromo- 2- hydroxy 3-methoxybenzenes formaldehyde of taurine, highly basic and 5- described in S1
Than being 1 ~ 2：2~3：1 ~ 2, the highly basic is potassium hydroxide.
Preferably, the molar ratio of the taurine described in S1, highly basic and the bromo- 2- hydroxy 3-methoxybenzenes formaldehyde of 5- is 1：
2：1.
Organic solvent described in S1 is absolute alcohol, and thermostat temperature is 45 ~ 55 DEG C.
Preferably, the organic solvent described in S1 is absolute methanol, and thermostat temperature is 50 DEG C, constant temperature time 3.0h.
The sylvite K of ligand described in S22C10H10NO5The molar ratio of SBr, mantoquita and 1,10'- phenanthrolenes are 1 ~ 3:
2~4:1~2。
Preferably, the sylvite K of the ligand described in S22C10H10NO5SBr, soluble copper salt and 1,10'- phenanthrolenes
Molar ratio be 2:3:2.
Mantoquita described in S2 is copper sulphate, copper nitrate, copper chloride；Preferably sulfuric acid copper.
Methanol/water mixed solvent volume ratio described in S2 is VMethanol: VWater = 24:1。
Thermostat temperature described in S2 is 50 DEG C, reaction time 12h.
The copper-based complex application in preparation of anti-tumor drugs of the mixture.
Application of the copper-based complex of the mixture as angiogenesis inhibitor.
Application of the copper-based complex of the mixture as antitumor drug and angiogenesis inhibitor.
Preferably, the copper-based complex of the mixture is as antitumor and angiogenesis inhibitor application.
Beneficial effects of the present invention：（1）The copper-based complex of mixture of the present invention, which has, significantly inhibits tumour cell
The even tumor cell proliferation of resistance to cis-platinum, inducing cell apoptosis and the ability of damage, and inhibit vascular endothelial cell proliferation, move
The effect that shifting and pipe are formed；（2）The copper-based complex of mixture of the present invention has significant cytotoxicity to tumour cell, and to non-
The cytotoxicity of tumour normal cell is small；（3）The copper-based complex of the mixture has cytotoxicity more significant than cis-platinum, and
It is in vivo and external all with significantly apoptosis-induced effect to the tumour cell of resistance to cis-platinum, inhibit Tumor Angiongesis in addition
Effect is better than positive control suramin effect.Therefore, of the present invention with copper-based complex is to inhibit tumour growth and suppression
The candidate of the antitumor drug of the dual function of Tumor Angiongesis processed.
Description of the drawings
Fig. 1 is the crystal structure figure of the copper-based complex of mixture of the present invention.
Fig. 2（A）Cervical cancer cell C33A apoptosis and injury experiment result figure are induced for the copper-based complex of mixture of the present invention,
In（a）For the experimental result of the copper-based complex of mixture and 20 h of C33A cell incubations,（b）For the copper-based complex of mixture and C33A
The experimental result of 40 h of cell incubation；
（B）For A549/DDP cell incubations inducing cell apoptosis and the damage for 24 hours of the copper-based complex of mixture of the present invention and resistance to cis-platinum
Hinder experimental result picture, DDP in figure：Cis-platinum；
（C）Human umbilical vein endothelial cells HUVECs apoptosis and injury experiment result figure are induced for the copper-based complex of mixture of the present invention,
Wherein（a）The experimental result of 24 h is incubated for the copper-based complex of mixture and HUVECs,（b）For the copper-based complex of mixture with
HUVECs is incubated the experimental result of 48 h；
Cu-1 refers to the copper-based complex of mixture in figure.
Fig. 3 (a) is the copper-based complex of mixture of the present invention and positive control suramin in the case where growth factor VEGF stimulates,
The inhibiting effect result figure that Human umbilical vein endothelial cells HUVECs micro-pipes are formed；
(b) be the copper-based complex of mixture of the present invention growth factor VEGF stimulation under, to chicken embryo allantoic sac vascularization inhibition
Exercising result figure.
Specific implementation mode
The content of present invention is further described below in conjunction with specific embodiment, but is not limitation of the invention.
The copper-based complex of 1 mixture of embodiment [Cu (C10H10NO5SBr)(C12H8N2)]·CH3The preparation of OH
（1）By taurine（1.2514g 10 mmol）And KOH（1.1220 g, 20 mmol）It is dissolved in 35 mL absolute methanols, then by
It is added dropwise to the bromo- 3- methoxyl groups-salicylides of 5- of 15ml（2.3104g 10 mmol）Absolute methanol solution, stirred in 50 DEG C of water-baths
It mixes 3 hours, obtains yellow clarified solution；Most of solvent is removed by vacuum distillation, is filtered, washing obtains yellow powder, vacuum
After 2 days dry, i.e. the sylvite K of ligand2C10H10NO5SBr；
(2) K is weighed2C10H10NO5SBr（0.0829 g, 0.2mmol）And anhydrous cupric sulfate（0.0527g, 0.3 mmol）It is added
The mixed solvent of 25ml first alcohol and waters（VMethanol: VWater= 24:1）, it is placed in 50 DEG C of heating water baths and is stirred at reflux, obtains yellow green clarification
Liquid；After twenty minutes, 1,10'- phenanthrolenes are added in reflux（0.0399 g, 0.2 mmol), it is small that continuation constant temperature is stirred at reflux 12
Shi Hou, stops reaction, and cooled and filtered obtains bright green clarified solution；Filtrate stands at room temperature, volatilizees naturally, behind several days
Blocky green crystals, as [Cu (C is precipitated10H10NO5SBr)(C12H8N2)] · CH3OH。
[Cu (the C of embodiment 210H10NO5SBr)(C12H8N2)]·CH3OH vitro cytotoxicities are tested
Mtt assay：It is 8 × 10 to take the tumour cell in exponential phase, adjustment viable cell concentrations4/ ml is added on 96 well culture plates,
Per 100 μ l of hole, 12 h are cultivated in the incubator after adherent, then be separately added into tested with the diluted various concentration of free serum culture
100 μ l of sample, each concentration of sample-adding group sets 6 multiple holes, while doing negative control, is placed in 37 DEG C, 5%CO248 h are cultivated, then
MTT is added（5 mg/ml）The stillness of night is gently sucked out with micro syringe after 4 h in 20 holes μ l/, and dimethyl sulfoxide (DMSO) is added（DMSO）
150 holes μ l/, 10 min of oscillation or so, OD values are measured with microplate reader under 490 nm wavelength.Cell survival inhibiting rate is calculated, is led to
It crosses software and calculates its half-inhibition concentration IC50。
Inhibiting rate=(ODNegative cell mean -ODTest cell mean ) / (ODNegative cell mean- ODCulture medium compares) × 100 %
With MTT technique studies [Cu (C10H10NO5SBr)(C12H8N2)] ·CH3OH inhibits the ability of different cell Proliferations.It is selected
Cell have human cervical carcinoma cell lines（C33A and HeLa）, people's lung cancer cell line of resistance to cis-platinum（), A549/DDP human umblilical vein endothelial
Cell strain（HUVECs）.The IC from table 150Value is as can be seen that [Cu (C10H10NO5SBr)(C12H8N2)]·CH3OH is thin to non-cancer
Born of the same parents' vascular endothelial cell has certain cytotoxicity, the IC having50For（5.25 ± 0.034）μM, illustrate [Cu
(C10H10NO5SBr)(C12H8N2)] · CH3OH has apparent inhibition to vascular endothelial cell proliferation, shows to tumour blood
The generation of pipe has significant inhibiting effect, this also with vascular endothelial cell to metallic copper rather than other metals have it is special partially
Like it is related, especially when vascularization.[Cu(C10H10NO5SBr)(C12H8N2)]·CH3OH to cervical cancer cell C33A and
The toxicity of HeLa is than reading, IC much larger to the toxicity of non-cancerous cells50Respectively（2.99 ± 0.28）With（1.96 ±
0.01）μM, under equal conditions, [Cu (C10H10NO5SBr)(C12H8N2)]·CH3OH has surpassed cis-platinum to cytotoxicity,
Significant cytotoxicity, IC are still even shown to the lung cell A549 of resistance to cis-platinum50For（8.28 ± 0.88）µM.Cause
This, [Cu (C of the present invention10H10NO5SBr)(C12H8N2)]·CH3OH, which has, significantly inhibits surveyed tumor cell proliferation
Ability, and to vascular endothelial cell also have very strong Inhibit proliferaton effect.
[Cu (the C of table 1.10H10NO5SBr)(C12H8N2)] ·CH3OH is incubated the IC of 48 h with subject cell50Value
3 stream type cell analyzer of embodiment measures [Cu (C10H10NO5SBr)(C12H8N2)]·CH3The external evoked cells of OH wither
It dies and injury experiment
Apoptosis assay kit Annexin V/PI purchases are in BD companies of the U.S. (BD Bioscience), according to kit
Operation instruction carries out apoptosis detection.Cell (2 × 105/ hole) it is planted in 12- orifice plates（It is healthy and free from worry）12 h are cultivated, are then used different dense
[Cu (the C of degree10H10NO5SBr)(C12H8N2)]·CH3OH and cell incubation regular hour（C33A cells are incubated 20 respectively
H and 40 h；A549/DDP is incubated for 24 hours;HUVECs is incubated for 24 hours and 48h）.To detect early and late apoptosis, suspension
It is all collected with adherent cell, is washed twice, centrifuged 5 minutes with 1000 r/min rotating speeds, in removing with 1 × PBS
The stillness of night.Cell is resuspended with 100 μ l Binding Buffer.Then, cell first is contaminated with 5 μ L Annexin-V, gently
After cell is resuspended, then with 5 μ L PI dye cells.Cell is gently resuspended, incubation 15 minutes is protected from light at 37 DEG C.Then plus
Binding Buffer are resuspended cell and adjust cell density, after membrane filtration, use stream type cell analyzer（FACS
Calibur, BD Bioscience) detection.
Experimental result as shown in Fig. 2,（A）Figure the result shows that, [Cu (C10H10NO5SBr)(C12H8N2)]·CH3OH energy
With the increase of concentration and being incremented by for time, significantly induces Hela Cell Apoptosis and damage to a certain degree.5 µM
[Cu(C10H10NO5SBr)(C12H8N2)]·CH3OH and C33A cell incubation 40h, inducing cell damage are 10.9%, carefully
The total apoptosis of born of the same parents is up to 57.1%, wherein early wither is 29.8%, it is 27.3% that evening, which withers,.Concentration increases to 6.5 μM of [Cu
(C10H10NO5SBr) (C12H8N2)] CH3OH when, induce total apoptosis up to 65.7%.[Cu(C10H10NO5SBr)
(C12H8N2)]·CH3OH also play the role of to A549/DDP it is significantly apoptosis-induced, incubation time be for 24 hours, 4.0,8.0
With 12.0 μM of [Cu (C10H10NO5SBr)(C12H8N2)]·CH3OH induction A549/DDP total apoptosis rate be respectively
19.6%, 24.5% and 49.1%.And [Cu (C10H10NO5SBr)(C12H8N2)]·CH3OH is to the apoptosis-induced of HUVECs
Although effect and cellular damage slightly increase also with increase and the growth of time of concentration, more than to tumour cell
The effect of apoptosis-induced and cellular damage is weak.To sum up the result shows that, 5.0 μM of [Cu (C10H10NO5SBr)(C12H8N2)] • CH3OH
Tumour cell C33A apoptosis and damage can be significantly induced in vitro, but very weak to the damage and apoptosis of vascular endothelial cell.
[Cu (the C of embodiment 410H10NO5SBr)(C12H8N2)]•CH3OH inhibits HUVECs tube formation assay in vitro
Matrigel is taped against to 96-orifice plates of precooling, per 60 μ of hole by matrigel in 4 DEG C of dissolvings overnight according to operation instruction
L is incubated 30 minutes in cell incubator and cures.The first given the test agent with various concentration of cell（[Cu(C10H10NO5SBr)
(C12H8N2)]·CH3OH and suramin）And VEGF (20 ng/mL) is incubated 12 h, then collects resuspension and has been inoculated into base
In the hole of matter glue, per 200 μ L 4.0 × 10 of hole4A cell.Be then placed into cell incubator and cultivate, at the same do blank with
VEGF (20 ng/mL) is compareed, and after 12h, the integrality and number of tubular structure are formed with inverted microscope observation HUVECs
Amount, takes pictures.
Experimental result such as Fig. 3（a）Shown, compared with Control, VEGF (20 ng/mL) can be stimulated significantly
HUVECs forms tubular structure, and the quantity of pipe is mostly good with integrality, however with the [Cu (C of low concentration10H10NO5SBr)
(C12H8N2)] • CH3After OH and VEGF (20 ng/mL) are incubated HUVECs cells, the quantity and integrality of pipe it is good with
[Cu(C10H10NO5SBr)(C12H8N2)]·CH3The concentration of OH increases and substantially reduces, 5.0 μM of [Cu (C10H10NO5SBr)
(C12H8N2)]·CH3OH almost inhibits the pipe of HUVECs to be formed, the positive control suramin phase with same concentrations
Than [Cu (C10H10NO5SBr)(C12H8N2)]·CH3OH is better than the inhibition of suramin.The experimental results showed that [Cu
(C10H10NO5SBr)(C12H8N2)]·CH3OH can significantly inhibit the migration of HUVECs and pipe is formed.
[Cu (the C of embodiment 510H10NO5SBr)(C12H8N2)]•CH3OH inhibits the experiment of chicken chorioallantois angiogenesis
Chicken embryo villus allantoic sac, which is commonly used for building anti-angiogenic model, to be carried out analytical chemistry induction of vascular and inhibits tumor vessel.By
Smart egg hatches about 6 days at 37 DEG C in the sterile constant-temperature incubator that humidity is 80%, then by egg from allantoic sac region
Shell on open about 1 aperture cm aperture, observe the growing state of the blood vessel in chicken embryo.By angiogenic growth compared with
Good chicken embryo grouping：Control、VEGF（100 ng/egg）、[Cu(C10H10NO5SBr)(C12H8N2)]·CH3OH + VEGF
（100 ng/egg）And positive controls suramin+VEGF（100 ng/egg）.Each group test sample is respectively acting on chicken embryo
In angiosomes, it is each detect sample and various concentration set 4 chicken embryo parallel tests.Aseptically sample-adding finishes, and uses
Adhesive tape seals open hole, is put into sterile constant-temperature incubator and continues to be incubated 4 days.It then takes out, opens original
Hole observes the arterial bifurcation situation of chicken embryo villus allantoic sac in each test group, takes pictures.Anti-angiogenic effect is opposite with artery branch pipe
Quantity is evaluated.
Experimental result such as Fig. 3（b）Shown, compared with Control, VEGF (100 ng/egg) can significantly stimulate chicken
Allantoic sac vascularization, artery branch pipe quantity ratio Control groups increase significantly, show that VEGF can stimulate chicken allantoic sac blood vessel
It is formed, however [Cu (the C of 7.5 nmol/egg10H10NO5SBr)(C12H8N2)]·CH3OH is at VEGF (100 ng/egg)
Chicken allantoic sac vascularization is significantly inhibited under stimulation, and effect is better than the suramin inhibition of the amount of same substance, with
[Cu(C10H10NO5SBr)(C12H8N2)]·CH3The amount of OH substances increases, inhibition enhancing.The experimental results showed that [Cu
(C10H10NO5SBr)(C12H8N2)]·CH3OH can significantly inhibit chicken allantoic sac vascularization.The knot of embodiment 4 and embodiment 5
Fruit shows [Cu (C10H10NO5SBr)(C12H8N2)]·CH3OH may be angiogenesis inhibitors.
Claims (10)
1. a kind of copper-based complex of mixture, which is characterized in that its structural formula is [Cu (C10H10NO5SBr)(C12H8N2)]·
CH3OH, wherein [Cu (C10H10NO5SBr)(C12H8N2)] it is list of coordination units, C10H10NO5SBr is schiff bases anion ligand,
C12H8N2It is neutral ligand 1,10'- phenanthrolenes.
2. the preparation method of the copper-based complex of mixture described in claim 1, which is characterized in that comprise the following steps：
S1. taurine and highly basic are mixed, anhydrous organic solvent stirring and dissolving is added, the bromo- 2- hydroxyls -3- first of 5- is then added
Oxygroup benzaldehyde, constant temperature stir 2 ~ 4h, stop reaction, obtain the sylvite K of ligand2(C10H10NO5SBr)；
S2. by the sylvite K of ligand2(C10H10NO5SBr it) is mixed with mantoquita, is dissolved in the mixed solvent of methanol/water, adds 1,
10'- phenanthrolenes, 8 ~ 20h of isothermal reaction obtain the copper-based complex [Cu (C of mixture after reaction10H10NO5SBr)
(C12H8N2)] ·CH3OH。
3. preparation method according to claim 2, which is characterized in that the bromo- 2- hydroxyls of taurine, highly basic and 5- described in S1
The molar ratio of base-m-methoxybenzaldehyde is 1 ~ 2：2~3：1 ~ 2, the highly basic is potassium hydroxide.
4. preparation method according to claim 3, which is characterized in that the bromo- 2- hydroxyls of taurine, highly basic and 5- described in S1
The molar ratio of base-m-methoxybenzaldehyde is 1：2：1.
5. preparation method according to claim 2, which is characterized in that the ligand described in S2 is K2(C10H10NO5SBr in)
Anion, mantoquita and 1,10'- phenanthrolenes molar ratio be 1 ~ 3：1~5：1 ~ 3, the methanol/water mixed solvent volume
Than for VMethanol: VWater = 24:1。
6. preparation method according to claim 2, which is characterized in that the ligand described in S2 is K2(C10H10NO5SBr in)
Anion, mantoquita and 1,10'- phenanthrolenes molar ratio be 2:3:2.
7. preparation method according to claim 2, which is characterized in that the mantoquita described in S2 is copper sulphate, copper nitrate, chlorine
Change copper.
8. the copper-based complex application in preparation of anti-tumor drugs of mixture described in claim 1.
9. application of the copper-based complex of mixture described in claim 1 as angiogenesis inhibitor.
10. application of the copper-based complex described in claim 1 as antitumor drug and angiogenesis inhibitor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810253423.2A CN108440577B (en) | 2018-03-26 | 2018-03-26 | Mixed copper-based complex and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810253423.2A CN108440577B (en) | 2018-03-26 | 2018-03-26 | Mixed copper-based complex and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108440577A true CN108440577A (en) | 2018-08-24 |
| CN108440577B CN108440577B (en) | 2020-05-12 |
Family
ID=63197222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810253423.2A Active CN108440577B (en) | 2018-03-26 | 2018-03-26 | Mixed copper-based complex and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108440577B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018893A (en) * | 2019-11-25 | 2020-04-17 | 桂林医学院 | Sulfur-containing amino alcohol Schiff base copper complex and preparation and application thereof |
-
2018
- 2018-03-26 CN CN201810253423.2A patent/CN108440577B/en active Active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018893A (en) * | 2019-11-25 | 2020-04-17 | 桂林医学院 | Sulfur-containing amino alcohol Schiff base copper complex and preparation and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108440577B (en) | 2020-05-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Liu et al. | Inhibitory effect of modified citrus pectin on liver metastases in a mouse colon cancer model | |
| CN113444085B (en) | Antitumor compound capable of overcoming cisplatin resistance and preparation and application thereof | |
| CN107955042A (en) | Platinum complexes, preparation method and application with active anticancer | |
| CN107353313B (en) | New chemical entities calcium mangafodipir and other mixed metal complex, preparation method, composition and treatment methods | |
| CN108440577A (en) | A kind of copper-based complex of mixture and its preparation method and application | |
| CN107501331B (en) | A kind of platinum complex and its synthetic method inhibiting SKOV3 cell | |
| Schreiber et al. | Lack of secretion of serum protein by transplanted rat hepatomas | |
| CN106279002B (en) | Dithiocarbonic acid derivative and its preparation method and application | |
| CN104910196B (en) | A kind of chiral copper-based organic metal framework of four core and its preparation method and application | |
| CN109908364A (en) | Using human serum albumins as the synthetic method and application of gold (III) metal composite of carrier | |
| JP2016515585A5 (en) | ||
| CN109810128A (en) | It is a kind of using 2- pyridine carboxaldehyde thiosemicarbazones as the indium complex of ligand and its synthetic method and application | |
| CN108553455B (en) | Application of trialdehyde phloroglucinol thiosemicarbazone heterozygote compound in antitumor drugs | |
| CN103110621A (en) | Applications of tea double-chlorine carboxamide and tea double-bromine carboxamide or like in preparation of products for prevention and treatment of diseases such as cancer | |
| CN107488198B (en) | A kind of couroupitine A platinum complex and its synthetic method and application | |
| CN108017608A (en) | Flavone derivatives and its preparation method and application | |
| CN108498500B (en) | Application of Aiphanol in resisting tumors | |
| CN112079853A (en) | Zinc complex with 2-pyridylaldehyde thiosemicarbazone as ligand and synthetic method and application thereof | |
| CN105294834A (en) | Imidazo-pyridine-6-formyl-AA-OBzl, as well as synthesis, activities and application thereof | |
| CN109705158A (en) | A kind of independence pair center Ag complexs and preparation method thereof and anticancer activity evaluation | |
| CN107456457B (en) | Application of 2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxyphenyl-8- (1,4 oxaziridin-4-methylene) -4H-chromen-4-one compound in preparation of medicine for treating cancer | |
| CN104725431A (en) | Cobalt (II) complex of quinolinone derivative, and synthesis method and application thereof | |
| CN112592292B (en) | Fluorescent compound, preparation method thereof and application thereof in interactive evidence positioning of liver tumor focus tissues | |
| CN103830265B (en) | A kind of Chinese medicine extract combination treating the malignant tumor such as the esophageal carcinoma, gastric cancer and preparation method thereof | |
| CN103202837B (en) | Applications of artemisine derivatives and pharmaceutically acceptable salts thereof in preparing drugs for treating leukemia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP02 | Change in the address of a patent holder |
Address after: No.1 Zhiyuan Road, Lingui District, Guilin City, Guangxi Zhuang Autonomous Region Patentee after: GUILIN MEDICAL University Address before: 541004 No.109, Huancheng North 2nd Road, Qixing District, Guilin City, Guangxi Zhuang Autonomous Region Patentee before: GUILIN MEDICAL University |
|
| CP02 | Change in the address of a patent holder |