CN108484645A - A kind of pyrazolone-shrinking salicylyl hydrazine closes preparation and the bioactivity of copper complex - Google Patents
A kind of pyrazolone-shrinking salicylyl hydrazine closes preparation and the bioactivity of copper complex Download PDFInfo
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- 150000004699 copper complex Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- XSXYESVZDBAKKT-UHFFFAOYSA-N 2-hydroxybenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1O XSXYESVZDBAKKT-UHFFFAOYSA-N 0.000 title abstract description 7
- 239000003446 ligand Substances 0.000 claims abstract description 23
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims abstract description 12
- 208000019065 cervical carcinoma Diseases 0.000 claims abstract description 12
- 201000004101 esophageal cancer Diseases 0.000 claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 8
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- 125000006332 fluoro benzoyl group Chemical group 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 7
- 125000004429 atom Chemical group 0.000 claims abstract description 6
- 229910001431 copper ion Inorganic materials 0.000 claims abstract description 6
- 230000000694 effects Effects 0.000 claims abstract description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 239000010949 copper Substances 0.000 claims description 11
- 239000013078 crystal Substances 0.000 claims description 7
- 150000002429 hydrazines Chemical class 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052802 copper Inorganic materials 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- 241000219000 Populus Species 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims 3
- 230000035755 proliferation Effects 0.000 claims 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 1
- 201000010881 cervical cancer Diseases 0.000 claims 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims 1
- 238000002050 diffraction method Methods 0.000 claims 1
- 238000013518 transcription Methods 0.000 claims 1
- 230000035897 transcription Effects 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 9
- 230000001093 anti-cancer Effects 0.000 abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 230000001472 cytotoxic effect Effects 0.000 abstract description 5
- 238000009830 intercalation Methods 0.000 abstract description 4
- 230000002687 intercalation Effects 0.000 abstract description 4
- 230000004568 DNA-binding Effects 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002262 Schiff base Substances 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 238000009739 binding Methods 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- -1 pyrazoline ketone schiff bases Chemical class 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 150000004753 Schiff bases Chemical class 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000011095 buffer preparation Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- JLODBVPKGYAHHZ-UHFFFAOYSA-L copper methanol diacetate Chemical compound CO.C(C)(=O)[O-].[Cu+2].C(C)(=O)[O-] JLODBVPKGYAHHZ-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 125000002587 enol group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 150000004715 keto acids Chemical class 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241000252203 Clupea harengus Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940051880 analgesics and antipyretics pyrazolones Drugs 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- VQLYBLABXAHUDN-UHFFFAOYSA-N bis(4-fluorophenyl)-methyl-(1,2,4-triazol-1-ylmethyl)silane;methyl n-(1h-benzimidazol-2-yl)carbamate Chemical compound C1=CC=C2NC(NC(=O)OC)=NC2=C1.C=1C=C(F)C=CC=1[Si](C=1C=CC(F)=CC=1)(C)CN1C=NC=N1 VQLYBLABXAHUDN-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 235000019514 herring Nutrition 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
Classifications
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- 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
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to preparation and bioactivity that a kind of pyrazolone-shrinking salicylyl hydrazine closes copper complex.The dicopper complex4-amino-3 is prepared by solwution method, structural formula is [Cu2(μ‑L)2(DMF)2]（H23 methyl 4 of the phenyl of L=1 is to 5 pyrazolone-shrinking salicylyl hydrazine of fluoro benzoyl, DMF=N, N dimethylformamides）, an oxygen atom of two oxygen atoms of central metal copper ion and ligand, a nitrogen-atoms and DMF is coordinated, and two adjacent metal copper ions of the O2 atom bridgings in two ligands form the coordination environment of CuNO5.It is intercalation model to confirm that the complex has good DNA binding performances, combination by spectroscopic methodology.Being tested by MTT cytotoxic activities confirms that the complex has good antitumor activity, human cervical carcinoma cell Hela and human esophagus cancer cell Eca 109 can be inhibited to be proliferated, its effect is better than business anticancer drug cis-platinum, it was demonstrated that the complex in anti-cancer field there are larger medicine and pharmacology to be worth.
Description
Technical field
The present invention relates to preparations and application that a kind of 4- acyl groups pyrazolone-shrinking salicylyl hydrazine closes copper complex.
Background technology
The main reason for cancer is whole world morbidity and is dead.Currently, chemotherapy is one of main means of oncotherapy.Metal
Complex drug because its unique mechanism of action becomes a kind of potential antitumor drug, antitumor action and metal ion
Selection, the oxidation state of metal ion and ligand have close relationship.
1969, Rosenberg et al. researchs found that cis-platinum has strong effective active anticancer, have to clinical cancer chemotherapy
Tremendous influence.However, the therapeutic effect of cis-platinum but by its drug resistance, toxic side effect the shortcomings of serious limitation.In order to overcome
Along these defects of platinum medicine, various new antitumoral metal complexs are synthesized in succession.
Schiff bases is a kind of complex with azomethine base (C=N) being condensed to yield by carbonyl and primary amine complex, system
Standby condition is relatively easy, has structure diversity.In schiff base ligand contain with lone pair electrons N, the atoms such as O, S,
With good coordination ability, easily it is coordinated to form metal complex with metal.The experimental results show schiff bases and its cooperation
Object is in antibacterial, antiviral, anti-inflammatory and antitumor etc. has excellent performance.And pyrazoline ketone schiff bases is huge seat
Important one of branch in Fu Jian families, 1883, pyrazolone derivative drug-antipyrine of first synthesis, as
Ntipyretic analgesic medicine is used for clinical treatment, and the research for thus opening pyrazoline ketone complex in chemistry and biology is hot
Tide.4- acyl groups pyrazoline ketone schiff bases and its complex containing N, O and miscellaneous coordination atom are even more to show the disease-resistant of wide spectrum
The bioactivity such as poison, antibacterial, antitumor are the potential new type antineoplastic medicines of tool.
The present invention is condensed salicylyl hydrazine, synthesis 4- acyl group pyrazolone schiff bases 1- on the basis of 4- acyl group pyrazolones
Phenyl -3- methyl -4- synthesize a kind of novel cooperation to fluoro benzoyl -5- pyrazolone-shrinking salicylyl hydrazines as ligand
Object 1- phenyl -3- methyl -4- close copper to fluoro benzoyl -5- pyrazolone-shrinking salicylyl hydrazines, and the complex is thin to human cervical carcinoma
Born of the same parents Hela and human esophagus cancer cell Eca-109 are significantly inhibited, therefore the dicopper complex4-amino-3 will become non-
Often with potential anticancer drug.
Invention content
The purpose of the present invention is to provide a kind of new complexes 1- phenyl -3- methyl -4- to fluoro benzoyl -5- pyrazoles
Quinoline ketone contracting salicylyl hydrazine closes the preparation method and bioactivity of copper.Dicopper complex4-amino-3 is obtained using conventional solution synthetic method.
It is intercalation model to confirm that the complex has good DNA binding performances, combination by spectroscopic methodology.Pass through MTT cells
Cytotoxic activity experiment confirms that the complex is better than quotient to the inhibiting effect of human cervical carcinoma cell Hela and human esophagus cancer cell Eca-109
Industry anti-cancer agent cisplatin can be used as potential anticancer drug.
By the dicopper complex4-amino-3 synthesized by the X-ray single crystal diffractometer analysis present invention, chemical constitution is [Cu2(μ-
L)2(DMF)2].Ligand H2L is 1- phenyl -3- methyl -4- to fluoro benzoyl -5- pyrazolone-shrinking salicylyl hydrazines.Institute of the present invention
Two ligands are changed into enol form by keto-acid in the copper complex stated, and then respectively lose two hydrogen atoms, are changed into L2−Afterwards with two
A copper（II）Ion coordination.Wherein Cu (II) and two oxygen atoms of a ligand, an oxygen original of a nitrogen-atoms and DMF
Son is coordinated, and two adjacent metal copper ions of the O2 atom bridgings in two ligands form the coordination environment of CuNO5.
The preparation method of dicopper complex4-amino-3 provided by the invention includes the following steps.
Step A：5 mmol salicylyl hydrazines are dissolved in 15 mL ethyl alcohol, the 1- phenyl-of equimolar amounts is slowly added dropwise under stiring
It is slow as temperature after catalyst that appropriate glacial acetic acid is added to the ethanol solution of fluoro benzoyl -5- pyrazolones in 3- methyl -4-
80 DEG C are risen to, 4 h are stirred at reflux.Cooled and filtered, drying, obtain ligand.
Step B：0.06 mmol ligands are dissolved in 15 mL methanol/DMF（4:1）In mixed solution, then 2 are added dropwise thereto
The copper acetate methanol solution of mL equimolar amounts.It is filtered after stirring 2 h at room temperature, filtrate is precipitated green crystal after slowly volatilizing and is
Target product.
Being tested through ultra-violet absorption spectrum confirms that strong ultraviolet suction occurs at 245 nm and 369 nm in the dicopper complex4-amino-3
Peak is received, with the increase of DNA concentration, the absorption maximum peak intensity of dicopper complex4-amino-3 continuously decreases, and shows hypochromic effect, subtracts
Color rate is respectively 27% and 24%, illustrates that combination has occurred with DNA in complex.
Fluorescent quenching through EB-DNA it is experimentally confirmed that with complex concentration increase, DNA-EB systems are in wavelength 598
Fluorescence intensity at nm significantly decreases, and illustrates that dicopper complex4-amino-3 can be combined instead of EB with DNA, it was confirmed that complex with
The combination of DNA is intercalation model.Dicopper complex4-amino-3 and the binding constant of HS-DNA are determined by stern-volmer equations
KqFor：2.6×105 M-1, illustrate that the binding ability of dicopper complex4-amino-3 and HS-DNA are stronger.
The experiment of MTT cytotoxic activities shows the dicopper complex4-amino-3 to human cervical carcinoma cell Hela and human esophagus cancer cell
Eca-109 has good inhibiting effect（To the IC of human cervical carcinoma cell Hela and human esophagus cancer cell Eca-10950Value difference
For 6.66 ± 0.22 μM and 5.82 ± 0.59 μM）, and it is substantially better than business anti-cancer agent cisplatin（To human cervical carcinoma cell
The IC of Hela and human esophagus cancer cell Eca-10950Value is respectively 28.88 ± 3.27 μM and 47.66 ± 3.49 μM）, can be used as
Potential anticancer drug.
The beneficial effects of the present invention are：Provide a kind of dicopper complex4-amino-3 with active anticancer preparation method and
Analysis on Biological Activity.Prove that the complex has good combination effect to DNA, to human cervical carcinoma cell Hela and human esophagus cancer
Cell Eca-109 has preferable active anticancer, in anti-cancer field there are larger medicine and pharmacology to be worth, for grinding for anticancer drug
Study carefully exploitation and provides an important evidence with application development.
Description of the drawings
Fig. 1 is copper complex crystal structure figure.
Fig. 2 is the ultraviolet-visible spectrum change schematic diagram of copper complex as HS-DNA concentration increases.
Fig. 3 is the fluorescence quenching spectrum figure of copper complex EB competitive bindings HS-DNA.
Fig. 4 is the cytotoxic activity of two kinds of cancer cells of copper complex pair.
Specific implementation mode
Illustrated embodiment below in conjunction with the accompanying drawings, the invention will be further described, to be better understood from the present invention.
Embodiment 1：The synthesis of ligand L.5 mmol salicylyl hydrazines are dissolved in 15 mL ethyl alcohol, are slowly added dropwise under stiring
Appropriate glacial acetic acid conduct is added to the ethanol solution of fluoro benzoyl -5- pyrazolones in the 1- phenyl -3- methyl -4- of mole
Temperature is slowly increased to 80 DEG C after catalyst, is stirred at reflux 4 h.Cooled and filtered, drying obtain yellow target product.
C24H19FN4O3（Molecular weight：430.43）.Elemental analysis experiment value（Theoretical value %）：C 66.96（66.73）；H 4.45（4.36）；
N 13.02（13.36）.As a result almost the same with theoretical value.
Embodiment 2：The synthesis of copper complex.0.06 mmol ligands are dissolved in 15 mL methanol/DMF（4:1）Mixed solution
In, then the copper acetate methanol solution of 2 mL equimolar amounts is added dropwise thereto.It is filtered after stirring 2 h at room temperature, filtrate is slowly volatilized
It is target product that green crystal is precipitated afterwards.C54H48Cu2F2N10O8（Molecular weight：1130.10）.Elemental analysis experiment value（It is theoretical
Value %）：C 57.39（57.51）；H 4.28（4.10）；N 13.39（14.61）.As a result almost the same with theoretical value.
It is analyzed by X-ray single crystal diffractometer（Fig. 1）Illustrate, the chemical constitution of the dicopper complex4-amino-3 synthesized by the present invention
Formula is [Cu2(μ-L)2(DMF)2].Wherein ligand H2L is that 1- phenyl -3- methyl -4- shrink to fluoro benzoyl -5- pyrazolones
Poplar hydrazides.Two ligands are changed into enol form by keto-acid in copper complex of the present invention, then respectively lose two hydrogen atoms,
It is changed into L2−It is coordinated afterwards with two copper ions.Two oxygen atoms, a nitrogen-atoms and the DMF of wherein Cu (II) and a ligand
An oxygen atom be coordinated, two adjacent metal copper ions of the O2 atom bridgings in two ligands form matching for CuNO5
Position environment.
Embodiment 3：The dependence test for the dicopper complex4-amino-3 that embodiment 2 obtains and experiment.
One, the research of dicopper complex4-amino-3 and DNA interactions.
Dicopper complex4-amino-3 of the present invention is with DNA interaction capability study application herring sperm dnas (HS-DNA) as research
Object.Measure HS-DNA（With the Tris-HCl buffer preparations of NaCl and pH=7.2）Suction at 260 nm and 280 nm
Luminosity (A), A260/ A280In the range of 1.8-1.9, illustrate that HS-DNA solution meets requirement of experiment.HS-DNA is measured 260
Absorbance at nm calculates the concentration (ε of DNA according to Lang Mu-Beer law260 = 6600 L·mol-1·cm-1)。
1. ultra-violet absorption spectrum titrates.Complex is with Tris-HCl buffer preparations at 10-3 The solution of M is then dilute
It releases to 20 μM.Using Tris-HCl buffer solutions as blank control, it is molten that HS-DNA is gradually added into complex and blank control
Liquid (0-18.5 μM) measures the ultraviolet spectra in 235-450 nm wave-length coverages.Experimental result：It is such as Fig. 2 it can be seen that double
There is strong ultraviolet absorption peak at 245 nm and 369 nm in core copper complex, with the increase of DNA concentration, dicopper complex4-amino-3
Absorption maximum peak intensity continuously decrease, show hypochromic effect, the rate of losing lustre is respectively 27 % and 24 %, illustrate complex with
Combination has occurred in DNA.
2. fluorescence quenching spectrum titrates.It is excited with the wavelength of 530 nm, record DNA-EB compound systems are at 598 nm
Complex (0-3.3 μM) is gradually added in fluorescence emission wavelengths and intensity into DNA-EB systems, is recorded not after vibrating 6 min
With ligand concentration to the fluorescence quenching spectrum of DNA-EB compound systems.By classical stern-volmer equations F0/F=1+Kq[Q]
To inquire into its quenching mechanism, F0It is the fluorescence intensity of DNA-EB compound systems before and after complex is added respectively with F, [Q] is cooperation
The concentration of object, with F0/ F maps to [Q], and slope is binding constant Kq.Experimental result：Excitation wavelength is as seen from Figure 3
When 530 nm, with the increase of complex concentration, fluorescence intensity of the DNA-EB systems at 598 nm of wavelength significantly decreases,
Illustrate that dicopper complex4-amino-3 can be combined instead of EB with DNA, it was confirmed that the combination of complex and DNA are intercalation model.By
Stern-volmer equations determine dicopper complex4-amino-3 and the binding constant K of HS-DNAqFor：2.6×105 M-1, illustrate double-core copper
The binding ability of complex and HS-DNA are stronger.
Two, the cytotoxic activity experiment of two kinds of cancer cells of complex pair.
Logarithmic growth phase cell, with 4 × 104A cell/mL is inoculated in 96 well culture plates, and 100 μ L are loaded per hole.
200 μ L various concentration complexs are separately added into after cultivating 24 h, continues after cultivating 24 h, 5 mg/ is added under the conditions of being protected from light per hole
The 20 μ L of MTT solution of mL continue to be incubated 4 h.Supernatant is removed in centrifugation, and 100 μ L DMSO are added, after complete molten colour developing, with enzyme mark
Instrument measures OD values at 490 nm.Inhibitory rate of cell growth（%） = [1-（Medicine group OD values-blank group OD values）/（Control groups
OD values-blank group OD values）] × 100% utilizes statistical software prism calculation of half inhibitory concentration IC50Value.
Experimental result：The dicopper complex4-amino-3 has human cervical carcinoma cell Hela and human esophagus cancer cell Eca-109
Good inhibiting effect（To the IC of human cervical carcinoma cell Hela and human esophagus cancer cell Eca-10950Value respectively 6.66 ±
0.22 μM and 5.82 ± 0.59 μM）, and it is substantially better than business anti-cancer agent cisplatin（To human cervical carcinoma cell Hela and people's oesophagus
The IC of cancer cell Eca-10950Value is respectively 28.88 ± 3.27 μM and 47.66 ± 3.49 μM）, can be used as potential anticarcinogen
Object.
Claims (4)
1. the present invention, which disclose a kind of 1- phenyl -3- methyl -4-, to close copper to fluoro benzoyl -5- pyrazolone-shrinking salicylyl hydrazines and coordinates
The preparation of object and bioactivity, it is characterised in that copper complex has dual-core architecture, analyzes the copper by X-ray single crystal diffraction and matches
It includes two Cu (II) ions to close object, and two symmetrical ligand structure units and two DMF molecules, dicopper complex4-amino-3 can be inserted
Enter DNA base centering, and human cervical carcinoma cell Hela and human esophagus cancer cell Eca-109 are significantly inhibited.
2. copper complex described in claim 1 is the 1- phenyl -3- methyl -4- by equimolar amounts to fluoro benzoyl -5- pyrroles
Oxazoline ketone shrink poplar hydrazide ligands are prepared with metallic copper acetate by solwution method.
3. copper complex described in claim 1, it is characterised in that there is dual-core architecture, detected by X-ray single crystal diffraction method
Copper complex contains two Cu (II) ions, two symmetrical ligand structure units and two DMF molecules, Cu (II) ions with
One oxygen atom of two oxygen atoms of one ligand, a nitrogen-atoms and DMF is coordinated, the O2 atoms in two ligands
Two adjacent metal copper ions of bridging, form the coordination environment of CuNO5.
4. the application of copper complex described in claim 1, it is characterised in that copper complex can be inserted into DNA base pair, influence DNA
Duplication, transcription, human cervical carcinoma cell Hela and human esophagus cancer cell Eca-109 proliferation can be inhibited, and effect is better than business
Anticancer drug cis-platinum, the copper complex are applied to prepare anti-human cervical cancer cell Hela cells and human esophagus cancer cell Eca-
In the drug of 109 proliferation.
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| CN112079850B (en) * | 2020-09-21 | 2023-04-25 | 广西民族师范学院 | Novel copper binuclear structure metal complex, preparation method and application thereof |
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