CN114573608A - Schiff base pyridine metal complex and preparation method and application thereof - Google Patents
Schiff base pyridine metal complex and preparation method and application thereof Download PDFInfo
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- CN114573608A CN114573608A CN202210268729.1A CN202210268729A CN114573608A CN 114573608 A CN114573608 A CN 114573608A CN 202210268729 A CN202210268729 A CN 202210268729A CN 114573608 A CN114573608 A CN 114573608A
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- base pyridine
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- 239000002262 Schiff base Substances 0.000 title claims abstract description 149
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 73
- -1 Schiff base pyridine metal complex Chemical class 0.000 title claims abstract description 65
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000019253 formic acid Nutrition 0.000 claims abstract description 8
- 229910052761 rare earth metal Inorganic materials 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 6
- 150000004753 Schiff bases Chemical class 0.000 claims description 112
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 239000003446 ligand Substances 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 16
- 229910002651 NO3 Inorganic materials 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 14
- 230000000259 anti-tumor effect Effects 0.000 claims description 13
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 11
- 239000002246 antineoplastic agent Substances 0.000 claims description 10
- 229940041181 antineoplastic drug Drugs 0.000 claims description 10
- 229910052693 Europium Inorganic materials 0.000 claims description 8
- 210000002919 epithelial cell Anatomy 0.000 claims description 8
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 4
- 229910052692 Dysprosium Inorganic materials 0.000 claims description 3
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 3
- 229910052771 Terbium Inorganic materials 0.000 claims description 3
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 claims description 3
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 3
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 claims description 3
- XIEPJMXMMWZAAV-UHFFFAOYSA-N cadmium nitrate Inorganic materials [Cd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XIEPJMXMMWZAAV-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 238000001027 hydrothermal synthesis Methods 0.000 claims description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical group OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000004729 solvothermal method Methods 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 230000001093 anti-cancer Effects 0.000 abstract description 6
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 69
- NUMLHMCQZAXQDW-UHFFFAOYSA-N cadmium;pyridine Chemical compound [Cd].C1=CC=NC=C1 NUMLHMCQZAXQDW-UHFFFAOYSA-N 0.000 description 59
- 238000006243 chemical reaction Methods 0.000 description 24
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- 206010058467 Lung neoplasm malignant Diseases 0.000 description 16
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- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 13
- 201000005202 lung cancer Diseases 0.000 description 13
- 208000020816 lung neoplasm Diseases 0.000 description 13
- IRJGZWIEFFOYJN-UHFFFAOYSA-N copper;pyridine Chemical compound [Cu].C1=CC=NC=C1 IRJGZWIEFFOYJN-UHFFFAOYSA-N 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- IGDZUYKQDZJKFY-UHFFFAOYSA-N europium;pyridine Chemical compound [Eu].C1=CC=NC=C1 IGDZUYKQDZJKFY-UHFFFAOYSA-N 0.000 description 11
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 10
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- 201000007270 liver cancer Diseases 0.000 description 10
- 208000014018 liver neoplasm Diseases 0.000 description 10
- 229960004316 cisplatin Drugs 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 229910052793 cadmium Inorganic materials 0.000 description 8
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000002001 anti-metastasis Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000004699 copper complex Chemical class 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
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- 239000000203 mixture Substances 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
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- 108010087230 Sincalide Proteins 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
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- SZDVDUDLIIZMKX-UHFFFAOYSA-N copper;pyridine Chemical compound [Cu].C1=CC=NC=C1.C1=CC=NC=C1.C1=CC=NC=C1.C1=CC=NC=C1.C1=CC=NC=C1.C1=CC=NC=C1 SZDVDUDLIIZMKX-UHFFFAOYSA-N 0.000 description 2
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- 229910021645 metal ion Inorganic materials 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- WRHZTTISLCLBBE-OQLLNIDSSA-N n-[(e)-pyridin-2-ylmethylideneamino]pyridine-4-carboxamide Chemical compound C=1C=NC=CC=1C(=O)N\N=C\C1=CC=CC=N1 WRHZTTISLCLBBE-OQLLNIDSSA-N 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- OWXTVFSTYDVTPL-UHFFFAOYSA-N pyridine;terbium Chemical compound [Tb].C1=CC=NC=C1 OWXTVFSTYDVTPL-UHFFFAOYSA-N 0.000 description 2
- 238000006748 scratching Methods 0.000 description 2
- 230000002393 scratching effect Effects 0.000 description 2
- 229940007046 shigella dysenteriae Drugs 0.000 description 2
- 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 2
- 239000002904 solvent Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
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- 125000004429 atom Chemical group 0.000 description 1
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- DLGYNVMUCSTYDQ-UHFFFAOYSA-N azane;pyridine Chemical compound N.C1=CC=NC=C1 DLGYNVMUCSTYDQ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 239000013522 chelant Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 239000010949 copper Substances 0.000 description 1
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- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- LWNYCAIOTGOMGB-UHFFFAOYSA-N europium pyridine Chemical compound N1=CC=CC=C1.N1=CC=CC=C1.N1=CC=CC=C1.[Eu] LWNYCAIOTGOMGB-UHFFFAOYSA-N 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
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- 150000002466 imines Chemical class 0.000 description 1
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- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical compound [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
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- 150000002910 rare earth metals Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
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Abstract
The invention discloses a Schiff base pyridine metal complex and a preparation method and application thereof, belonging to the technical field of application of pyridyl Schiff base derivatives. The Schiff base pyridine metal complex has a chemical formula of [ Cd (HL)) (NO3)2]nOr [ CuL (NO) ]3)]nOr [ ML (HCOOH)) (H2O)(NO3)2]Wherein M is a rare earth metal ion, N is a natural number from 1 to plus infinity, and L is N' - [ (1E) -pyridine-2-methyleneBase of]Pyridine-4-carbohydrazide anion; the structural formula is shown as follows. The Schiff base pyridine metal complex prepared by the invention has a definite structure, low toxicity and good antibacterial and anticancer activities.
Description
Technical Field
The invention relates to the technical field of application of pyridyl schiff base derivatives, in particular to a schiff base pyridine metal complex and a preparation method and application thereof.
Background
Cancer, a general term for malignant tumors, refers to a disease of uncontrolled proliferation of cells due to disruption or dysfunction of the normal tightly controlled regulatory signaling pathways, and is one of the leading causes of human death worldwide. The development of platinum-containing metal-based anticancer drugs provides a good prospect for the research of metal-based drugs for anticancer, and the research of the medical application of the metal-based anticancer drugs aims to fill the blank of tumor chemotherapy, wherein the blank comprises the steps of reducing adverse side effects to the maximum extent, overcoming the problem of drug resistance and expanding the activity range to more tumor types.
The emergence of superbacteria, the development of resistance by bacteria, has been a clinical problem. In order to solve the drug resistance problem and improve the curative effect of antibacterial and anticancer drugs, people are trying to find new antibacterial and anticancer drugs. Antibacterial and anticancer drugs are always the research focus of drug synthesis, so the research and development of new drugs with antibacterial and anticancer activities is a difficult task and has important research significance.
Schiff bases are compounds containing imine or azomethine groups, are usually formed by simple condensation of primary amine and carbonyl, and are important organic ligands in the synthesis of novel drug molecules. The Schiff base metal complex is easy to chelate with metal ions, and the complex formed by the Schiff base metal complex and different metal ions has biological activities such as antibiosis, antitumor, tuberculosis resistance and the like, so that the Schiff base metal complex with good activity can be obtained. However, the currently synthesized Schiff base medicines either cannot obtain a determined structure, or have poor antibacterial and antitumor activities, or have high toxic and side effects. Therefore, research and development of new drugs with definite structures, low toxicity, antibacterial and anticancer activities are the problems to be solved urgently.
Disclosure of Invention
Aiming at the problems, the invention provides a Schiff base pyridine metal complex and a preparation method and application thereof, and the prepared Schiff base pyridine metal complex has a definite structure, low toxicity and good antibacterial and anticancer activities.
The first object of the invention is to provide a Schiff base pyridine metal complex, which has a chemical formula of [ Cd (HL) (NO)3)2]nOr [ CuL (NO) ]3)]nOr [ ML (HCOOH)) (H2O)(NO3)2]Wherein M is rare earth metal ion, N is natural number from 1 to positive infinity, and L is N' - [ (1E) -pyridine-2-methylene]Pyridine-4-carbohydrazide negative ions;
the structural formula is as follows:
preferably, M is one of europium, dysprosium, gadolinium and terbium.
A second object of the present invention is to provide a method for preparing the above schiff-base pyridine metal complex, which comprises the following steps:
dissolving a Schiff base pyridine ligand and nitrate in a mixed solvent, and uniformly mixing at room temperature to obtain a mixed solution; the mixed solvent is obtained by mixing methanol and ethanol;
and carrying out solvothermal reaction on the mixed solution at the temperature of 60-80 ℃ to obtain the Schiff base pyridine metal complex.
Preferably, the dosage ratio of the Schiff base pyridine ligand to the nitrate to the mixed solution is 1 mmol: 1 mmol: 3-5 mL.
Preferably, the nitrate is cadmium nitrate or copper nitrate or rare earth nitrate.
Preferably, the volume ratio of the methanol to the ethanol in the mixed solvent is 2-3: 1-2.
Preferably, the hydrothermal reaction is carried out at 60-80 ℃ for 36-48 h.
The third purpose of the invention is to provide the application of the Schiff base pyridine metal complex in preparing antitumor drugs.
Preferably, the Schiff base pyridine metal complex has no toxicity to human normal mammary epithelial cells MCF-10A and nasopharyngeal epithelial cell line NP69-SV 40T.
The fourth purpose of the invention is to provide the application of the Schiff base pyridine metal complex in preparing antibacterial drugs.
Compared with the prior art, the method has the following beneficial effects:
(1) the Schiff base pyridine cadmium complex has a molecular structure completely different from that of the existing antitumor drugs, and the Schiff base pyridine cadmium complex has antitumor activity superior to that of a positive control drug cisplatin on human liver cancer cells SMMC-7721 and human lung cancer cells A549, and provides a new idea for research and development of the antitumor drugs;
(2) the Schiff base pyridine cadmium complex disclosed by the invention shows good antibacterial activity, and has important significance for effectively developing and utilizing series antibacterial and anticancer drugs;
(3) the preparation method of the Schiff base pyridine cadmium complex is used for preparing the Schiff base pyridine cadmium complex with high purity and high yield under the conditions of low temperature, absolute ethyl alcohol and other solvents, and has the advantages of simple process, pure product, high yield and convenient post-treatment;
(4) the preparation method of the Schiff base pyridine cadmium complex adopts a one-pot synthesis method, the synthesis solvent is green, no catalyst is needed, and the product has a definite structure;
(5) the Schiff base pyridine cadmium complex does not show toxicity to normal human mammary epithelial cells MCF-10A and nasopharyngeal epithelial cell lines NP69-SV 40T;
(6) the Schiff base pyridine cadmium complex can also synthesize a copper complex with a similar structure under similar conditions. The Schiff base pyridine copper complex has strong antitumor activity on human hepatoma cells SMMC-7721, and the IC of the complex50More effective than the positive control drug cisplatin and the ligand;
(7) the Schiff base pyridine cadmium complex can also synthesize a europium complex with a monomolecular structure under similar conditions. The europium complex has strong antitumor activity on human breast cancer cells MDA-MB-231, and IC thereof50Is more positive thanThe control drug cisplatin and the ligand were more effective. The rare earth ion europium can be replaced by other rare earth metal ions such as dysprosium, gadolinium, terbium and the like.
Drawings
FIG. 1 is a flow chart of the preparation of Schiff base pyridine ligand provided in example 1 of the present invention;
FIG. 2 is a flow chart of the preparation of the Schiff base pyridine cadmium complex provided in example 1 of the present invention;
FIG. 3 is a flow chart of the preparation of Schiff base copper pyridine complex provided in example 4 of the present invention;
FIG. 4 is a flowchart of the preparation of Schiff base pyridine europium complex provided in embodiment 5 of the present invention;
FIG. 5 is a molecular structural unit diagram of a Schiff base pyridine cadmium complex prepared in example 1 of the present invention;
FIG. 6 is a diagram of the molecular structural unit of a Schiff base copper pyridine complex prepared in example 4 of the present invention;
FIG. 7 is a molecular structure diagram of a Schiff base europium-pyridine complex prepared in example 5 of the present invention;
FIG. 8 is a one-dimensional chain structure diagram of a Schiff base pyridine cadmium complex prepared in example 1 of the present invention;
FIG. 9 is a graph of the results of morphological observation experiments on human hepatoma cells SMMC-7721 and human lung carcinoma cells A549 of the Schiff base pyridine cadmium complex prepared in example 1. Wherein, fig. 9A is a morphological observation graph of schiff base pyridine cadmium complex on human hepatoma cells SMMC-7721, fig. 9B is a morphological observation experiment result statistical analysis graph of schiff base pyridine cadmium complex on human hepatoma cells SMMC-7721, fig. 9C is a morphological observation graph of cadmium complex on human lung cancer cells a549, and fig. 9D is a morphological observation experiment result statistical analysis graph of schiff base pyridine cadmium complex on human lung cancer cells a 549;
FIG. 10 is a graph showing the results of transwell experiments on human hepatoma cells SMMC-7721 and human lung carcinoma cells A549 with the Schiff base pyridine cadmium complex prepared in example 1. Wherein, fig. 10A is a diagram of statistical analysis of the transwell experimental results of schiff base pyridine cadmium complex on human hepatoma cells SMMC-7721, and fig. 10B is a diagram of statistical analysis of the transwell experimental results of schiff base pyridine cadmium complex on human lung cancer cells a 549;
FIG. 11 is a graph showing the results of the scratch test on human hepatoma cells SMMC-7721 and human lung carcinoma cells A549 with the Schiff base pyridine cadmium complex prepared in example 1. Wherein, fig. 11A is a statistical analysis chart of the scratch experiment result of the schiff base pyridine cadmium complex on the human liver cancer cell SMMC-7721, and fig. 11B is a statistical analysis chart of the scratch experiment result of the schiff base pyridine cadmium complex on the human lung cancer cell a 549;
FIG. 12 is a graph of the results of the inhibition zone experiment of the Schiff base pyridine cadmium complex prepared in example 1. Wherein, FIG 12A is the experiment result of Schiff base pyridine cadmium complex to Staphylococcus aureus zone, and FIG 12B is the experiment result of Schiff base pyridine cadmium complex to dysentery bacillus zone.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The Schiff base pyridine ligand is prepared according to the preparation flow chart of figure 1, and is specifically synthesized according to the following steps:
3.6g of (E) -2- (hydrazinomethyl) pyridine (0.03mol) and 3.3g of isonicotinal (0.03mol) were mixed, ethanol was added thereto, and the mixture was refluxed at 80 ℃ for 8 hours, cooled to room temperature, and a white solid was precipitated. The product is recrystallized by ethanol to obtain Schiff base pyridine ligand, namely N' - [ (1E) -pyridine-2-methylene ] pyridine-4-carbohydrazide with the yield of 70%.
The Schiff base pyridine cadmium complex is prepared according to a preparation flow chart shown in figure 2, and is specifically synthesized according to the following steps:
(1) 30mg of N' - [ (1E) -pyridine-2-methylene are weighed]Pyridine-4-carbohydrazide (i.e., 0.13mmol), 5mL of a mixed solvent (consisting of 3mL of methanol and 2mL of anhydrous ethanol), 40mg of Cd (NO)3)3·4H2O (0.13mmol) is placed in a reaction flask and the solution is stirred and mixed at room temperature. Transferring the solution into a polytetrafluoroethylene reaction kettle in a high-pressure reaction kettle, reacting at 70 ℃ for 48 hours, and slowly cooling to room temperature.
(2) And (2) carrying out solid-liquid separation on the material obtained in the step (1), and fully washing the solid with absolute ethyl alcohol to obtain the Schiff base pyridine cadmium complex.
The prepared Schiff base pyridine cadmium complex crystal is subjected to X-ray single crystal diffraction measurement to obtain crystal structure parameters. The Schiff base pyridine cadmium complex belongs to a monoclinic system, P21A space group of/c, cell parameters of
Beta is 105.6860(10) ° and unit cell volume is
Z＝4，Dc＝1.997g/cm3。
The chemical formula of the Schiff base pyridine cadmium complex is [ Cd (HL)) (NO3)2]nWherein N is a natural number from 1 to plus infinity, and L is N' - [ (1E) -pyridin-2-ylmethylene]Pyridine-4-carbohydrazide negative ions.
As shown in fig. 5, the smallest asymmetric unit contains one cadmium atom, one ligand, two coordinated nitrate ions. The cadmium atom is heptadentate. The Cd atom connects 4 oxygen atoms from the nitrate radical, 3 nitrogen atoms (two pyridine nitrogens, one schiff base nitrogen atom). Each ligand is connected with two cadmium atoms, and each cadmium atom is connected with two ligands, so that the whole structure is in a one-dimensional zigzag chain-shaped configuration, as shown in fig. 8. Between the one-dimensional chains there is N-H … ONitro radicalIntermolecular hydrogen bonding. There is also a weak pi-pi interaction between the one-dimensional chains. The whole molecule one-dimensional chain is connected into a three-dimensional structure by intermolecular hydrogen bonds and pi-pi action.
Example 2
The Schiff base pyridine ligand is synthesized by the following steps:
3.6g of (E) -2- (hydrazinomethyl) pyridine (0.03mol) and 3.3g of isonicotinal (0.03mol) were mixed, ethanol was added thereto, and the mixture was refluxed at 80 ℃ for 6 hours, cooled to room temperature, and a white solid was precipitated. The product is recrystallized by ethanol to obtain Schiff base pyridine ligand, namely N' - [ (1E) -pyridine-2-methylene ] pyridine-4-carbohydrazide.
The Schiff base pyridine cadmium complex is synthesized by the following steps:
(1) 30mg of N' - [ (1E) -pyridine-2-methylene are weighed]Pyridine-4-carbohydrazide (0.13mmol), 4mL of a mixed solvent consisting of 2.5mL of methanol and 1.5mL of anhydrous ethanol, and 40mg of Cd (NO)3)3·4H2O (i.e., 0.13mmol) was placed in a reaction flask and the solution was stirred and mixed at room temperature. Transferring the solution into a polytetrafluoroethylene reaction kettle in a high-pressure reaction kettle, reacting at 60 ℃ for 48 hours, and slowly cooling to room temperature.
(2) And (2) carrying out solid-liquid separation on the material obtained in the step (1), and fully washing the solid with absolute ethyl alcohol to obtain the Schiff base pyridine cadmium complex.
Example 3
The Schiff base pyridine ligand is synthesized by the following steps:
3.6g of (E) -2- (hydrazone methyl) pyridine (0.03mol) and 3.3g of isonicotinal (0.03mol) were mixed, ethanol was added thereto, and the mixture was refluxed at 80 ℃ for 6 hours, cooled to room temperature, and a white solid was precipitated. The product is recrystallized by ethanol to obtain Schiff base pyridine ligand, namely N' - [ (1E) -pyridine-2-methylene ] pyridine-4-carbohydrazide.
The Schiff base pyridine cadmium complex is synthesized by the following steps:
(1) 30mg of N' - [ (1E) -pyridine-2-methylene are weighed]Pyridine-4-carbohydrazide (i.e., 0.13mmol), 3mL of a mixed solvent (consisting of 2mL of methanol and 1mL of anhydrous ethanol), and 40mg of Cd (NO)3)3·4H2O (i.e., 0.13mmol) was placed in a reaction flask and the solution was stirred and mixed at room temperature. Transferring the solution into a polytetrafluoroethylene reaction kettle in a high-pressure reaction kettle, reacting at 80 ℃ for 36 hours, and slowly cooling to room temperature.
(2) And (2) after solid-liquid separation is carried out on the material obtained in the step (1), fully washing the solid with absolute ethyl alcohol to obtain the Schiff base pyridine cadmium complex.
Example 4
The synthesis of schiff base pyridine ligands was the same as in example 1.
The Schiff base pyridine copper complex is prepared according to the preparation flow chart of figure 3, and is specifically synthesized according to the following steps:
(1) 30mg of N' - [ (1E) -pyridin-2-ylmethylene are weighed out]Pyridine-4-carbohydrazide (i.e., 0.13mmol), 5mL of a mixed solvent (consisting of 3mL of methanol and 2mL of anhydrous ethanol), and 39mg of Cu (NO)3)3·6H2O (i.e., 0.13mmol) was placed in a reaction flask and the solution was stirred and mixed at room temperature. Transferring the solution into a polytetrafluoroethylene reaction kettle in a high-pressure reaction kettle, reacting at 70 ℃ for 48 hours, and slowly cooling to room temperature.
(2) And (2) carrying out solid-liquid separation on the material obtained in the step (1) to obtain the Schiff base pyridine copper complex.
The prepared Schiff base pyridine copper complex crystal is subjected to X-ray single crystal diffraction measurement to obtain crystal structure parameters. The Schiff base pyridine copper complex crystal belongs to a triclinic system, the space group is P-1, and the unit cell parameter is
88.831(2), 83.151(2), and 82.229(2) unit cell volume
Z＝4，Dc＝1.839g/cm3。
The chemical formula of the Schiff base pyridine copper complex is [ CuL (NO)3)2]nWherein N is a natural number from 1 to plus infinity, and L is N' - [ (1E) -pyridin-2-ylmethylene]Pyridine-4-carbohydrazide negative ions.
X-ray single crystal diffraction measurement shows that the copper complex structure is similar to the cadmium complex structure and is a one-dimensional zigzag chain structure. The molecular structure unit diagram of the Schiff base pyridine copper complex is shown in figure 6, and X-ray single crystal diffraction measurement shows that the minimum asymmetric unit of the Schiff base pyridine copper complex contains one copper atom, one ligand and one coordinated nitrate ion.
The anti-tumor activity experiment proves that the copper complex has the anti-tumor activity IC on human hepatoma cells SMMC-77215011.87 +/-0.7, better than positive control cisplatin (IC)5016.33. + -. 0.8), but no cadmium complex is very active (IC)50＝6.33±0.7)。
Example 5
The synthesis of schiff base pyridine ligands was the same as in example 1.
The Schiff base pyridine europium complex is prepared according to the preparation flow chart of figure 4, and is specifically synthesized according to the following steps:
(1) 30mg of N' - [ (1E) -pyridin-2-ylmethylene are weighed out]Pyridine-4-carbohydrazide (i.e., 0.13mmol), 5mL of a mixed solvent (consisting of 3mL of methanol and 2mL of absolute ethanol), and 58mg of Eu (NO)3)3·6H2O (i.e., 0.13mmol) was placed in a reaction flask and the solution was stirred and mixed at room temperature. Transferring the solution into a polytetrafluoroethylene reaction kettle in a high-pressure reaction kettle, reacting at 70 ℃ for 48 hours, and slowly cooling to room temperature.
(2) And (2) carrying out solid-liquid separation on the material obtained in the step (1) to obtain the Schiff base pyridine europium complex.
The prepared Schiff base pyridine europium complex crystal is subjected to X-ray single crystal diffraction measurement to obtain crystal structure parameters. Monoclinic system, space group C2/C, unit cell parameters
Beta is 116.1130(10) ° and unit cell volume is
Z＝8，Dc＝1.897g/cm3。
The Schiff base pyridine europium complex has a chemical formula of [ EuL (HCOOH)) (H2O)(NO3)2]Wherein HCOOH is formic acid, L is N' - [ (1E) -pyridine-2-methylene]Pyridine-4-carbohydrazide negative ions.
X-ray single crystal diffraction measurement shows that the Schiff base pyridine europium complex belongs to a monoclinic system, C2/C space group. The structure of the Schiff base pyridine europium complex is shown in figure 7, and the minimum asymmetric unit contains one europium atom, one ligand, two coordinated nitrate ions, one coordinated formic acid molecule and one coordinated water molecule. The europium atom is in nine coordination. The europium atom links 4 oxygen atoms from nitrate, 3 oxygen atoms from formic acid, water molecules and carbonyl, 2 nitrogen atoms (one pyridine nitrogen, one schiff base nitrogen atom). The Schiff base pyridine europium complex has a monomolecular structure.
Example 6
The synthesis of schiff base pyridine ligands was the same as in example 1.
The Schiff base pyridine dysprosium complex is synthesized according to the following steps:
(1) 30mg of N' - [ (1E) -pyridine-2-methylene are weighed]Pyridine-4-carbohydrazide (i.e., 0.13mmol), 5mL of a mixed solvent (composed of 3mL of methanol and 2mL of anhydrous ethanol), and 59mg of Dy (NO)3)3·6H2O (i.e., 0.13mmol) was placed in a reaction flask and the solution was stirred and mixed at room temperature. Transferring the solution into a polytetrafluoroethylene reaction kettle in a high-pressure reaction kettle, reacting at 60 ℃ for 48 hours, and slowly cooling to room temperature.
(2) And (2) carrying out solid-liquid separation on the material obtained in the step (1) to obtain the Schiff base pyridine dysprosium complex.
Example 7
The synthesis of schiff base pyridine ligands was the same as in example 1.
The Schiff base pyridine gadolinium complex is synthesized by the following steps:
(1) 30mg of N' - [ (1E) -pyridine-2-methylene are weighed]Pyridine-4-carbohydrazide (i.e., 0.13mmol), 5mL of mixed solvent (consisting of 3mL of methanol and 2mL of absolute ethanol), and 59mg of Gd (NO)3)3·6H2O (i.e., 0.13mmol) was placed in a reaction flask and the solution was stirred and mixed at room temperature. Transferring the solution into a polytetrafluoroethylene reaction kettle in a high-pressure reaction kettle, reacting at 60 ℃ for 48 hours, and slowly cooling to room temperature.
(2) And (2) carrying out solid-liquid separation on the material obtained in the step (1) to obtain the Schiff base pyridine gadolinium complex.
Example 8
The synthesis of schiff base pyridine ligands was the same as in example 1.
The Schiff base terbium pyridine complex is synthesized by the following steps:
(1) 30mg of N' - [ (1E) -pyridin-2-ylmethylene are weighed out]Pyridine-4-carbohydrazide (i.e., 0.13mmol), 5mL of a mixed solvent (composed of 3mL of methanol and 2mL of absolute ethanol), and 59mg of Tb (NO)3)3·6H2O (i.e., 0.13mmol) was placed in a reaction flask and the solution was stirred and mixed at room temperature. Transferring the solution into a polytetrafluoroethylene reaction kettle in a high-pressure reaction kettle, reacting at 80 ℃ for 36 hours, and slowly cooling to room temperature.
(2) And (2) carrying out solid-liquid separation on the material obtained in the step (1) to obtain the Schiff base terbium pyridine complex.
Example 9
The Schiff base pyridine metal complex provided by the invention has antitumor activity.
The schiff base pyridine metal complexes are the schiff base pyridine cadmium complex prepared in example 1, the schiff base pyridine copper complex prepared in example 4 and the schiff base pyridine europium complex prepared in example 5 respectively.
Cells were seeded in 96-well plates (100. mu.l/well) and the media was selected for different cells. SMMC-7721 used DMEM medium, MDA-MB-231 used 1640 medium, A549 used F12 main specific medium, each medium supplemented with 10% fetal bovine serum. 5% CO at 37 ℃2The cells were cultured in an atmosphere for 24 hours to allow the cells to adhere. The old medium was then removed, replaced with fresh medium containing the test complex (previously dissolved in DMSO), and incubated at increasing concentrations (0. mu.M, 4. mu.M, 8. mu.M, 16. mu.M, 32. mu.M, 64. mu.M, 128. mu.M) at 37 ℃ for a further 24 hours, with each treatment being performed in triplicate in three independent experiments. After 24 hours, adding 10 mu L/hole of CCK-8 reagent, incubating for 1-4 hours at 37 ℃, measuring ultraviolet visible absorbance at 450nm by using an enzyme-labeling instrument, and calculating the survival rate of cells under the action of complexes with different concentrations and the IC of each complex sample on different cells50Values (table 1). The activity of Schiff base pyridine ligand L, cisplatin and Schiff base pyridine cadmium complex in inhibiting tumor cell proliferation is determined through a CCK-8 experiment. The experiment result proves that the Schiff base pyridine cadmium complex has the strongest activity and is compared with positive control medicaments of cis-platinum and cis-platinumThe ligand is more effective.
As can be seen from Table 1, the Schiff base pyridine cadmium complex has the strongest antitumor activity on human liver cancer cells SMMC-7721 and human lung cancer cells A549, and the IC of the Schiff base pyridine cadmium complex is IC506.33 + -0.7 mu M and 14.16 + -0.8 mu M respectively, and is more effective than cisplatin and the ligand (IC) as positive control drugs5016.33. + -. 0.8. mu.M and 25.67. + -. 0.4. mu.M, respectively).
The Schiff base pyridine europium complex has strong anti-tumor activity on human liver cancer cell SMMC-7721 and human breast cancer cell MDA-MB-231, and IC of the complex5010.61 + -0.3 μ M and 7.39 + -0.2 μ M, respectively, are more effective than the positive control cisplatin and the ligand (IC)5016.33. + -. 0.8. mu.M and 9.56. + -. 1.3. mu.M).
The Schiff base pyridine copper complex has strong antitumor activity on human hepatoma cells SMMC-7721, and the IC of the complex5011.87 + -0.7. mu.M, respectively, was more potent than the positive control cisplatin and ligand (IC)5016.33. + -. 0.8. mu.M, respectively).
Anti-cancer Activity of the Compounds of Table 1 against SMMC-7721, MAD-MB-231 and A549 cells (IC)50)
The Schiff base pyridine cadmium complex, the Schiff base pyridine europium complex and the Schiff base pyridine copper complex of the invention do not show toxicity to normal human mammary epithelial cells MCF-10A and nasopharyngeal epithelial cell lines NP69-SV 40T.
In order to further prove the anti-tumor effect of the Schiff base pyridine cadmium complex on tumor cells, a morphological observation experiment of the tumor cells is carried out. The results of morphological observation experiments of the Schiff base pyridine cadmium complex on human liver cancer cells SMMC-7721 and human lung cancer cells A549 are shown in figure 9. In FIG. 9, denotes p<0.05, represents p<0.01, represents p<0.001. The cell morphology is directly observed by using a microscope for discovery,control cells (not exposed to drug) remained flat and smooth, indicating normal healthy cells. However, cells treated with drugs (schiff-pyridine cadmium complex, cisplatin, and schiff-pyridine ligand) undergo dramatic changes in morphology. Cells after drug incubation were round, showing cell atrophy, a characteristic of apoptosis. The survival data of SMMC-7721 cells showed that the cell survival rates of 4. mu.M, 8. mu.M, 16. mu.M, 32. mu.M, 64. mu.M, and 128. mu.M Schiff base pyridine cadmium complex treated cells were about 64.13%, 41.04%, 35.86%, 22.17%, 19.48%, and 20.22%, respectively (p.sub.M, p.sub.m, p.sub.sub.sub.m, p.sub.sub.m, p.sub.m, p.m, p.sub.sub.sub.sub.m, p.sub.sub.m<0.0001). Also for a549 cells, schiff base pyridine cadmium complexes at 4 μ M, 8 μ M,16 μ M,32 μ M,64 μ M and 128 μ M doses resulted in a significant decrease in cell viability of 84.08%, 54.72%, 42.663%, 27.93%, 26.83%, 27.11%, respectively (P) compared to control group<0.0001), as in fig. 9A to 9D. Schiff base pyridine cadmium complex IC in SMMC-7721 cells and A549 cells50The lowest values were 6.33. mu.M and 14.16. mu.M, respectively. These results indicate that treatment with schiff base pyridine cadmium complexes significantly reduced cell viability of selected cancer cell lines in a dose-dependent manner.
In order to further prove the anti-metastasis capability of the Schiff base pyridine cadmium complex to tumor cells, the anti-metastasis capability of the Schiff base pyridine cadmium complex to human liver cancer cells SMMC-7721 and human lung cancer cells A549 is further researched through cell invasion and migration experiments. The transwell experiment results of the Schiff base pyridine cadmium complex on human liver cancer cells SMMC-7721 and human lung cancer cells A549 are shown in FIG. 10. In fig. 10, p <0.05, p <0.01, and p < 0.001. The result shows that the selected Schiff base pyridine cadmium complex obviously inhibits human hepatoma cells SMMC-7721 and human lung cancer cells A549, and the invasion capacity of the cells is obviously reduced under the action of the medicament (Schiff base pyridine cadmium complex). In the effect of the Schiff base pyridine cadmium complex on human liver cancer cells SMMC-7721 and human lung cancer cells A549, when the concentration of the Schiff base pyridine cadmium complex is 0.5 mu M, 2 mu M and 8 mu M, the number of cell invasion is reduced from 847 and 464 of a control group (with the drug concentration of 0) to 650, 587, 437 and 376, 275 and 99 respectively. The experimental results are shown in fig. 10A and 10B.
The result of the scratching experiment of the Schiff base pyridine cadmium complex on human liver cancer cells SMMC-7721 and human lung cancer cells A549 is shown in figure 11. In fig. 11, p <0.05, p <0.01, and p < 0.001. In a cell scratching experiment, the healing area of the two cells under the action of the coordination compound is also found to be obviously reduced, which indicates that the migration capability of the cells is also inhibited. Wherein, when the Schiff base pyridine cadmium complex acts on SMMC-7721 cells at the concentration of 0 μ M, 0.5 μ M, 2 μ M and 8 μ M, the healing rate percentages are 53.89%, 42.61%, 37.11% and 28.33%, respectively; incubation of a549 cells with CdL at concentrations of 0 μ M, 0.5 μ M, 2 μ M, 8 μ M, respectively, resulted in healing rates of 70.74%, 60.23%, 53.79%, and 24.52, respectively. The results of the experiment are shown in FIGS. 11A and 11B. The experiment shows that the Schiff base pyridine cadmium complex has good anti-metastasis capacity on human liver cancer cells SMMC-7721 and human lung cancer cells A549.
Example 10
The Schiff base pyridine metal complex provided by the invention has antibacterial performance.
The schiff base pyridine metal complex used was the schiff base pyridine cadmium complex prepared in example 1.
The test was carried out by the in vitro paper diffusion method. The test bacteria are also evenly smeared on a flat plate of an agar culture medium, a sterilized paper sheet (6mm) is flatly laid on the culture medium containing the bacteria, and the solution to be tested is respectively injected. After culturing for 24 hours at 37 ℃ in a thermostat, the size of the inhibition zone is observed. The sizes of the inhibition zones of the Schiff base pyridine cadmium complex and the ligand on staphylococcus aureus and dysentery bacillus are respectively detected. The inhibition zone experimental result of the Schiff base pyridine cadmium complex is shown in a figure 12. FIGS. 12A and 12B are graphs showing the results of the measurement of the inhibition zones of the Schiff base pyridine cadmium complex for Staphylococcus aureus and Shigella dysenteriae, and the statistical results are shown in Table 2. As can be seen from FIG. 12A, FIG. 12B and Table 2, the diameters of the inhibition zones of the Schiff base pyridine cadmium complex on Staphylococcus aureus and Shigella dysenteriae reach 22mm and 24mm respectively, and good antibacterial activity is shown, while the ligand has no obvious antibacterial effect.
TABLE 2 zone of inhibition determination (mm)
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (10)
1. A Schiff base pyridine metal complex which is characterized in that the chemical formula is [ Cd (HL) (NO)3)2]nOr [ CuL (NO) ]3)]nOr [ ML (HCOOH)) (H2O)(NO3)2]Wherein M is a rare earth metal ion, n is a natural number from 1 to positive infinity,
l is N' - [ (1E) -pyridine-2-methylene ] pyridine-4-carbohydrazide anion;
the structural formula is as follows:
2. a schiff base pyridine metal complex according to claim 1, wherein M is one of europium, dysprosium, gadolinium and terbium.
3. A process for the preparation of the schiff-base pyridine metal complex according to claim 1, wherein the schiff-base pyridine metal complex is prepared by the steps of:
dissolving Schiff base pyridine ligand and nitrate in a mixed solvent, and uniformly mixing at room temperature to obtain a mixed solution; the mixed solvent is obtained by mixing methanol and ethanol;
and carrying out solvothermal reaction on the mixed solution at the temperature of 60-80 ℃ to obtain the Schiff base pyridine metal complex.
4. The preparation method of the Schiff base pyridine metal complex as claimed in claim 3, wherein the dosage ratio of the Schiff base pyridine ligand to the mixed solution is 1 mmol: 1 mmol: 3-5 mL.
5. A method of preparing a schiff base pyridine metal complex according to claim 3, wherein the nitrate is cadmium nitrate or copper nitrate or rare earth nitrate.
6. The method for preparing a schiff base pyridine metal complex, according to claim 3, wherein the volume ratio of methanol to ethanol in the mixed solvent is 2-3: 1-2.
7. A preparation method of Schiff base pyridine metal complex according to claim 3, wherein the hydrothermal reaction is performed at 60-80 ℃ for 36-48 h.
8. Use of the schiff base pyridine metal complex according to claim 1 in the preparation of an anti-tumor medicament.
9. The use of schiff base pyridine metal complexes according to claim 8, wherein the schiff base pyridine metal complexes are non-toxic to human normal mammary epithelial cells MCF-10A and nasopharyngeal epithelial cell line NP69-SV40T in the preparation of anti-tumor drugs.
10. Use of the schiff base pyridine metal complex according to claim 1 for the preparation of an antibacterial medicament.
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