CN110746465B - Osmium complex, preparation method and application thereof - Google Patents
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- 229910052762 osmium Inorganic materials 0.000 title claims abstract description 82
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 239000011259 mixed solution Substances 0.000 claims abstract description 25
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 239000002243 precursor Substances 0.000 claims abstract description 23
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 13
- NPNBNNLTZDQMMW-UHFFFAOYSA-N (5-chloro-2-phenyl-1H-pyridin-2-yl)-pyridin-2-yldiazene Chemical compound ClC=1C=CC(NC=1)(N=NC1=NC=CC=C1)C1=CC=CC=C1 NPNBNNLTZDQMMW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- YDHJLJIJUCHSBV-UHFFFAOYSA-M Cl[Os+3].N Chemical compound Cl[Os+3].N YDHJLJIJUCHSBV-UHFFFAOYSA-M 0.000 claims abstract description 10
- 150000001450 anions Chemical class 0.000 claims abstract description 4
- 238000010992 reflux Methods 0.000 claims description 7
- 238000001069 Raman spectroscopy Methods 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- 239000000523 sample Substances 0.000 claims description 5
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical group [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 23
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 238000003332 Raman imaging Methods 0.000 abstract description 5
- 201000011510 cancer Diseases 0.000 abstract description 5
- 230000003013 cytotoxicity Effects 0.000 abstract description 5
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 5
- 239000003446 ligand Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 9
- 150000002907 osmium Chemical class 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 6
- 210000003855 cell nucleus Anatomy 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 5
- 201000005202 lung cancer Diseases 0.000 description 5
- 208000020816 lung neoplasm Diseases 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001237 Raman spectrum Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- -1 anion salt Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 210000000805 cytoplasm Anatomy 0.000 description 3
- 238000002189 fluorescence spectrum Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HKEWOTUTAYJWQJ-UHFFFAOYSA-N 2-(1h-pyrazol-5-yl)pyridine Chemical compound N1N=CC=C1C1=CC=CC=N1 HKEWOTUTAYJWQJ-UHFFFAOYSA-N 0.000 description 1
- CPUDLFSMVVGOOP-UHFFFAOYSA-N 2-(triazol-1-yl)pyridine Chemical compound N1=NC=CN1C1=CC=CC=N1 CPUDLFSMVVGOOP-UHFFFAOYSA-N 0.000 description 1
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229910017673 NH4PF6 Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
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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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/002—Osmium compounds
- C07F15/0026—Osmium compounds without a metal-carbon linkage
-
- 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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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/65—Raman scattering
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/18—Metal complexes
- C09K2211/185—Metal complexes of the platinum group, i.e. Os, Ir, Pt, Ru, Rh or Pd
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Abstract
The invention relates to an osmium complex, a preparation method and application thereof. The method comprises the steps of adding ammonium chloroosmium and bipyridyl into an organic solvent for reaction to obtain a mixed solution; adding a reducing agent into the mixed solution to react to obtain an osmium complex precursor; adding the osmium complex precursor and 5-chloro-2-phenylazo pyridine into ethylene glycol according to a preset ratio, reacting under a preset reaction condition, and adding a target anion to obtain the osmium complex. The osmium complex provided by the invention has extremely high structural stability, hardly emits fluorescence, has strong cytotoxicity to tumor cells and selectivity to cancer cells, and can be applied to the field of Raman imaging of tumor cells.
Description
Technical Field
The invention relates to the technical field of transition metal complexes, and particularly relates to an osmium complex, and a preparation method and application thereof.
Background
The transition metal complex is one of the research hotspots in recent decades, and a great number of the complexes contain d6、d8And d10Transition metal complexes of electronic configuration were successfully synthesized and studied. The iridium and ruthenium complexes are most abundant and most widely used in the synthesized metal complexes. But studies have found that the complexes have a more infrared absorption. P.T.Chou et al synthesized a series of [ Os (II) (N-N)2(PR)2](N-2-pyridyltriazole or 2-pyridylpyrazole PR ═ PPh2Me or PPhMe2) And (3) a complex. Research shows that the lowest energy absorption of the complex belongs to the mixed transition of MLCT and ILCT, and the MLCT transition penetrates through the whole transition process and has the ultraviolet absorption with longer wavelength. Wherein, the MLCT absorption peak with longer wavelength correspondingly prolongs the excitation wavelength of the complex when measuring the resonance Raman spectrum, thereby being more suitable for the analysis of biological samples and enhancing the tissue penetration capability and biocompatibility.
In medicine, metal anticancer drugs such as platinum-containing anticancer drugs are widely used antitumor drugs in clinic, ruthenium and osmium complexes become one of the most promising anticancer drugs, and the molecular structure of the osmium complexes has good plasticity, so that other molecular active groups are easily introduced to ligands, and the performance of the osmium complexes also has plasticity, so that the synthesis of novel osmium complexes with excellent stability and antitumor activity has great significance in the fields of medicine and materials. The osmium complex prepared in the prior art has low stability and low anti-tumor activity.
Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide an osmium complex, a preparation method and an application thereof, and aims to solve the problems of poor stability and low anti-tumor activity of the existing osmium complex.
The technical scheme adopted by the invention for solving the technical problems is as follows:
an osmium complex, wherein the complex has the following general formula:
wherein: x is Cl-、Br-And I-Any one of (1), M-Is PF6 -。
A method for preparing an osmium complex, comprising the steps of:
adding ammonium chloroosmium and bipyridyl into an organic solvent for reaction to obtain a mixed solution;
adding a reducing agent into the mixed solution to react to obtain an osmium complex precursor;
adding the osmium complex precursor and 5-chloro-2-phenylazo pyridine into ethylene glycol according to a preset ratio, reacting under a preset reaction condition, and adding a target anion to obtain the osmium complex.
The preparation method of the osmium complex is characterized in that the reducing agent is sodium hydrosulfite or sodium sulfite.
The preparation method of the osmium complex comprises the following steps of adding ammonium chloroosmium and bipyridyl into an organic solvent to react to obtain a mixed solution, and specifically comprises the following steps:
adding ammonium chloroosmium and bipyridyl into an organic solvent, carrying out reflux reaction for a first preset time under the protection of inert gas, and obtaining a mixed solution after reaction.
The preparation method of the osmium complex, wherein in the step, a reducing agent is added into the mixed solution to react to obtain an osmium complex precursor, and specifically comprises the following steps:
and adding an aqueous solution of a reducing agent into the mixed solution, putting the mixed solution into a refrigerator at 4 ℃, and standing overnight to obtain an osmium complex precursor.
The preparation method of the osmium complex is characterized in that the predetermined ratio is that the molar ratio of the osmium complex precursor to 5-chloro-2-phenylazo pyridine is 1: 1-1.2.
The preparation method of the osmium complex is characterized in that the preset reaction condition is that the temperature is set to be 120-140 ℃ under the protection of inert gas.
The preparation method of the osmium complex, wherein the first preset time is 4 to 8 hours.
A Raman probe is prepared from an osmium complex.
An application of osmium complex, wherein the osmium complex is used for preparing an anti-tumor drug taking cell nucleus as an action target.
Has the advantages that: the osmium complex provided by the invention has extremely high structural stability, hardly emits fluorescence, has strong cytotoxicity to tumor cells and selectivity to cancer cells, and can be applied to the field of Raman imaging of tumor cells.
Drawings
FIG. 1 is a flow chart of a method for preparing an osmium complex provided by an embodiment of the present invention.
FIG. 2 is a diagram of a synthetic pathway for osmium complexes provided by an example of the present invention.
FIG. 3 is a graph of the ultraviolet and fluorescence spectra of osmium complexes provided in accordance with an embodiment of the present invention.
Fig. 4 is an infrared spectrum of an osmium complex provided by an embodiment of the present invention.
FIG. 5 is a histogram of the content distribution of hunger complexes at different locations in cells according to an embodiment of the present invention.
FIG. 6 is a Raman spectrum of hunger complex in solution and in cells provided by an embodiment of the present invention.
Fig. 7 is a raman image of hungry complexes in lung cancer cells, B is the C-H peak representing the entire cell area, C, D is the peak of the N ═ N bond in the bpy ancillary ligand and the primary ligand, respectively, and E is a superimposed plot of B, C, D.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer and clearer, the present invention is further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention provides an osmium complex, which has a structure shown as the following formula:
wherein X is Cl-、Br-And I-Any one of (1), M-Is PF6 -。
In the structure of the osmium complex, osmium is connected with a ligand through an osmium-nitrogen bond, so that the stability between a matrix and the ligand is enhanced. Meanwhile, osmium in the structure is divalent, so that the structure of the complex is more stable, and the complex is suitable for preparing a Raman probe.
Referring to fig. 1, the present invention further provides a method for preparing an osmium complex, comprising the steps of:
s10, adding ammonium chloroosmium and bipyridyl into an organic solvent for reaction to obtain a mixed solution;
specifically, the mixed solution is prepared by dissolving ammonium chloroosmium and dipyridyl in an organic solvent, wherein the organic solvent may be DMF, ethylene glycol, or the like.
S20, adding a reducing agent into the mixed solution to react to obtain an osmium complex precursor;
specifically, the mixture obtained in step S10 is subjected to a reflux reaction under the protection of an inert gas, after the reflux reaction is completed, a certain amount of reducing agent is added to the mixed solution, the mixture is uniformly stirred, the mixed solution is placed in a refrigerator at 4 ℃, the mixture is allowed to stand overnight, a black precipitate is obtained after suction filtration, and the black precipitate is washed with water and diethyl ether, so that an osmium complex precursor is obtained. The reducing agent is sodium hydrosulfite, ammonium sulfite and the like.
The specific reaction mechanism in this step is: a typical process, which is similar to S, is repeated after leaving the chloride ion, which is an intermediate formed by the electron donation from the nitrogen atom with higher electron cloud density on the 2, 2-bipyridine ligand and the ammonium chlorososmate via a metal ligand bond (i.e., osmium-nitrogen bond)N2 nucleophilic substitution bimolecular association mechanism in which trivalent-n osmium is reduced with sodium dithionite to form more stable divalent osmium, ultimately forming the osmium complex precursor [ Os (bpy)2Cl2]。
S30, adding the osmium complex precursor and 5-chloro-2-phenylazo pyridine into ethylene glycol according to a preset ratio, reacting under a preset reaction condition, and adding an anion salt to obtain the osmium complex.
Specifically, weighing an osmium complex precursor and 5-chloro-2-phenylazo pyridine (main ligand) according to a certain proportion, adding the osmium complex precursor and the 5-chloro-2-phenylazo pyridine (main ligand) into ethylene glycol, setting the reaction temperature to 120 ℃, heating and refluxing for a preset time under the protection of argon gas, cooling the solution to room temperature after the reaction is finished, adding an aqueous solution of ammonium hexafluorophosphate into the solution, and separating out a black solid, namely the osmium complex. Wherein, the osmium complex precursor: the molar ratio of the 5-chloro-2-phenylazo pyridine is 1:1-1.2, and the deviation caused by insufficient raw material purity can be caused by properly increasing the amount of the main ligand.
The specific reaction mechanism in this step is: main ligand (5-chloro-2-Phenylazo pyridine) to provide electrons, forming osmium-nitrogen bonds with vacancies of osmium precursors to generate hepta-coordinated intermediates, leaving chlorine, repeating the process by using another nitrogen atom, forming two osmium-nitrogen bonds with a right-side ligand into rings, and forming salts with hexafluorophosphate to form target osmium complexes based on S N2, a bimolecular association mechanism of nucleophilic substitution.
The invention also provides a Raman probe which is prepared from the osmium complex. The molecular probe has good light stability and hardly fluoresces.
The invention also provides application of the osmium complex to preparation of an anti-tumor medicament taking cell nucleus as an action target.
The preparation of the osmium complexes provided by the present invention is further illustrated by the following specific examples.
0.439g of ammonium osmate chloride solid and 0.328g of bipyridine powder are weighed and added into 15mL of DMF solution, reflux reaction is carried out for 5h under the protection of nitrogen, after cooling to room temperature, aqueous solution containing 6.8g of sodium hydrosulfite is added into the mixed solution, after uniform mixing, the mixed solution is placed into a refrigerator, after standing overnight, suction filtration is carried out, and black precipitate is washed with water and ether for several times, thus obtaining osmium complex precursor.
Then weighing [ Os (bpy) ] according to the metering molar ratio (1: 1)2Cl2]Reacting about 57.35mg with about 21.77mg of main ligand (5-chloro-2-phenylazopyridine), adding 10mL of ethylene glycol, setting the temperature at 120 ℃, under the protection of argon, heating and refluxing for 8h, cooling the solution, and adding NH4PF6Precipitating black solid from the aqueous solution, and vacuum filtering to obtain dark black solid. The specific synthetic route is shown in FIG. 2.
Analysis of dark black solids:
1、ESI(m/z):359.65[M-2PF6]2+/2.1H NMR(400MHz,DMSO-d6)δ9.23(d,J＝2.2Hz,1H),9.05(d,J＝8.2Hz,1H),8.95(d,J＝8.2Hz,1H),8.67(d,J＝8.1Hz,1H),8.55(d,J＝8.0Hz,1H),8.30(t,J＝7.9Hz,1H),8.21(dd,J＝13.8,6.6Hz,2H),7.93(dd,J＝11.3,4.5Hz,1H),7.79(d,J＝6.3Hz,1H),7.72(d,J＝5.3Hz,1H),7.70–7.58(m,4H),7.58–7.53(m,1H),7.43(dt,J＝10.9,6.3Hz,3H),7.25(t,J＝7.3Hz,1H),7.18(t,J＝7.5Hz,2H),6.82(d,J＝7.7Hz,2H).
2. the product was subjected to uv/fluorescence/ir spectroscopy:
the optical properties of the osmium complex are preliminarily characterized by using an ultraviolet spectrum and a fluorescence spectrum, and the absorption peak region and the position of a fluorescence emission peak are determined, as can be seen from FIG. 3, the complex has a strong absorption peak at 460-470nm, and the fluorescence spectrum is measured by using 460nm as an excitation wavelength, and the emission peak is found to be particularly weak and almost has no fluorescence emission.
The IR spectrum of the osmium complex powder was determined using the KBr pellet method, as shown in FIG. 4, in which about 1500cm-1Stretching vibration peak with C ═ C bond, 1620cm-1The peak of stretching vibration of C ═ N bond.
3. Cytotoxicity experiments:
the cytotoxicity of the osmium complex on a liver cancer cell strain (Hep-G2), a lung cancer cell strain (A549) and corresponding normal cell strains (LO2, MRC-5) is researched through an MTT (methanol to toluene) experiment. TABLE 1 IC 48h after osmium complex and cisplatin administration to various cell lines50The value is obtained. IC (integrated circuit)50Representing the concentration required for inhibiting half of cell proliferation, and inversely related to toxicity, Table 1 shows that the toxicity of osmium complex to Hep-G2 liver cancer cells and A549 lung cancer cells is higher than that of cisplatin, and the IC of osmium complex to two groups of normal cells50The value is much higher than the IC of cancer cells50The complex is selective to cancer cells, but basically has no toxicity to normal cells, so that the complex is expected to be a high-efficiency low-toxicity target medicament.
TABLE 1
| Hep-G2 | A549 | MRC-5 | LO2 | |
| Os | 6.3±0.7 | 13.4±1.7 | 102.4±2.7 | 75.2±3.9 |
| Cis-Pt | 9.5±1.7 | 10.2±1.8 | 13.5±1.5 | 13.2±1.3 |
4. Cell uptake experiments:
collecting lung cancer A549 cells after incubating complex (10 mu M, 8h), dividing into 2 parts, extracting a part of cell nucleus and the rest part of cytoplasm by using a cell nucleus extraction reagent, dividing into 3 parts of whole, cell nucleus and cytoplasm (subpackaging in a 1.5mL centrifuge tube), digesting with concentrated nitric acid for 2 days, adding ultrapure water to dilute to a clear solution with the nitric acid concentration of 5%, filtering with a filter membrane, taking 10mL of each solution as a final test sample, simultaneously using osmium standard solution, using ascorbic acid and thiourea as antioxidants (preventing metal osmium from being oxidized and avoiding errors) and preparing standard solution with the concentration gradient of 0,10,2020.99997) and the cell samples are sequentially tested, and the content of the complex in the nucleus and the cytoplasm of the cell are calculated to be about 89.9ng/cell and about 9.1ng/cell, for exampleFIG. 5 shows that the complex is mostly concentrated in the nucleus.
5. Raman imaging experiments:
firstly testing the powder and the solution of the osmium complex, obtaining a Raman spectrum by using 532nm excitation as shown in figure 6, then carrying out a Raman imaging test on lung cancer A549 cells incubated with the osmium complex (100 mu M,4h), selecting a cell area for scanning under 532nm laser excitation, obtaining an intuitive Raman image by later-stage Mapping treatment, and further showing that the complex can be gathered in cell nucleus as shown in figure 7.
In summary, the invention provides an osmium complex, a preparation method and an application thereof. The method comprises the steps of adding ammonium chloroosmium and bipyridyl into an organic solvent for reaction to obtain a mixed solution; adding a reducing agent into the mixed solution to react to obtain an osmium complex precursor; adding the osmium complex precursor and 5-chloro-2-phenylazo pyridine into ethylene glycol according to a preset ratio, reacting under a preset reaction condition, and adding a target anion to obtain the osmium complex. The osmium complex provided by the invention has extremely high structural stability, hardly emits fluorescence, has strong cytotoxicity to tumor cells and selectivity to cancer cells, and can be applied to the field of Raman imaging of tumor cells.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (10)
1. An osmium complex, characterized in that the complex has the following general formula:
wherein: x is any one of chlorine, bromine and iodine, M-Is PF6 -。
2. A method of preparing the osmium complex of claim 1, comprising the steps of:
adding ammonium chloroosmium and bipyridyl into an organic solvent for reaction to obtain a mixed solution;
adding a reducing agent into the mixed solution, and reacting to obtain an osmium complex precursor;
adding the osmium complex precursor and 5-chloro-2-phenylazo pyridine into ethylene glycol according to a preset ratio, reacting under a preset reaction condition, and adding a target anion to obtain the osmium complex.
3. The process for preparing an osmium complex according to claim 2, wherein the reducing agent is sodium dithionite or sodium sulfite.
4. The method for preparing osmium complex according to claim 2, wherein the step of adding ammonium chloroosmium and bipyridyl to an organic solvent for reaction to obtain a mixed solution includes:
adding ammonium chloroosmium and bipyridyl into an organic solvent, carrying out reflux reaction for a first preset time under the protection of inert gas, and obtaining a mixed solution after reaction.
5. The method for preparing the osmium complex according to claim 2, wherein the step of adding a reducing agent to the mixed solution to react to obtain an osmium complex precursor includes:
and adding an aqueous solution of a reducing agent into the mixed solution, putting the mixed solution into a refrigerator at 4 ℃, and standing overnight to obtain an osmium complex precursor.
6. The method for preparing an osmium complex according to claim 2, wherein the predetermined ratio is a molar ratio of the osmium complex precursor to 5-chloro-2-phenylazo pyridine of 1:1 to 1.2.
7. The method for preparing an osmium complex according to claim 2, wherein the predetermined reaction conditions are set to a temperature of 120 ℃ to 140 ℃ under the protection of an inert gas.
8. The method for preparing an osmium complex according to claim 4, wherein the first predetermined time is 4 to 8 hours.
9. A raman probe prepared using the osmium complex according to claim 1.
10. Use of the osmium complex according to claim 1 for producing a nuclear-targeted antitumor drug.
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