CN105601675A - Synthesis of phosphorescent iridium complex and application thereof in schistosome adult worm fluorescence labeling - Google Patents
Synthesis of phosphorescent iridium complex and application thereof in schistosome adult worm fluorescence labeling Download PDFInfo
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- CN105601675A CN105601675A CN201610060560.5A CN201610060560A CN105601675A CN 105601675 A CN105601675 A CN 105601675A CN 201610060560 A CN201610060560 A CN 201610060560A CN 105601675 A CN105601675 A CN 105601675A
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- schistosome
- phosphorescent
- iridium complex
- adult
- fluorescence
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- 229910052741 iridium Inorganic materials 0.000 title claims abstract description 34
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 24
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000001215 fluorescent labelling Methods 0.000 title claims abstract description 20
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 5
- 241000242678 Schistosoma Species 0.000 title abstract 10
- 238000003786 synthesis reaction Methods 0.000 title abstract 3
- 238000000799 fluorescence microscopy Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003446 ligand Substances 0.000 claims abstract description 9
- 239000007853 buffer solution Substances 0.000 claims abstract description 5
- 241000699670 Mus sp. Species 0.000 claims abstract description 4
- 241001442514 Schistosomatidae Species 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 241000754688 Cercaria Species 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 241000699666 Mus <mouse, genus> Species 0.000 claims description 15
- 210000001015 abdomen Anatomy 0.000 claims description 10
- 238000010790 dilution Methods 0.000 claims description 9
- 239000012895 dilution Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims description 4
- 241000565675 Oncomelania Species 0.000 claims description 3
- 239000012980 RPMI-1640 medium Substances 0.000 claims description 3
- 239000012930 cell culture fluid Substances 0.000 claims description 3
- 239000006059 cover glass Substances 0.000 claims description 3
- 238000005286 illumination Methods 0.000 claims description 3
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- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000002504 physiological saline solution Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 5
- 208000030852 Parasitic disease Diseases 0.000 abstract description 4
- -1 nitrogen-containing aromatic compounds Chemical class 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 238000013461 design Methods 0.000 abstract description 2
- 229910001873 dinitrogen Inorganic materials 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 150000001491 aromatic compounds Chemical class 0.000 abstract 1
- 238000002372 labelling Methods 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 9
- 238000000926 separation method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000000862 absorption spectrum Methods 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 201000004409 schistosomiasis Diseases 0.000 description 5
- 241000242677 Schistosoma japonicum Species 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000237858 Gastropoda Species 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 description 2
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
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- 239000012153 distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
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- 239000000463 material Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000013110 organic ligand Substances 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 229940072033 potash Drugs 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 230000010148 water-pollination Effects 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 0 CC*(C(C)(C)*(C)NC*)*(N)=C Chemical compound CC*(C(C)(C)*(C)NC*)*(N)=C 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000242711 Fasciola hepatica Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 241000935974 Paralichthys dentatus Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000004847 absorption spectroscopy Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000000347 anti-schistosomal effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000010165 autogamy Effects 0.000 description 1
- 230000006470 autoimmune attack Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000000886 photobiology Effects 0.000 description 1
- 229960002957 praziquantel Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 206010048282 zoonosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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
- C07F15/0033—Iridium compounds
- C07F15/004—Iridium compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- 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
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- 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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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Immunology (AREA)
- Analytical Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Optics & Photonics (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention belongs to the field of biological optical labeling for parasitic disease precention and treatment, and relates to synthesis of a phosphorescent iridium complex and application thereof in schistosome adult worm fluorescence labeling. Designing and synthesizing of the phosphorescent iridium complex and schistosome adult worm fluorescence labeling through the iridium complex are achieved. The phosphorescent iridium complex is coordinately synthesized by taking two nitrogen-containing aromatic compounds as main ligands and taking a dinitrogen-containing aromatic compound as an auxiliary ligand. A schistosome adult worm fluorescence labeling method comprises the following steps that 1, schistosome cercariae are obtained; 2, mice are infected with the cercariae; 3, schistosome adult worms are obtained; 4, schistosome adult worm fluorescence labeling is performed through a phosphorescent iridium complex PBS buffer solution with the concentration of 5 micromoles per liter at room temperature; 5, schistosome adult worm fluorescence imaging is performed by collecting phosphorescent signals through a laser confocal fluorescence microscope. Through design and synthesis, the phosphorescent iridium complex is used for schistosome adult worm fluorescence labeling by serving as a fluorescent probe, and the problems that in the schistosome adult worm fluorescence imaging process, the fluorescence labeling effect is poor, and the photobleaching resistance is poor are solved.
Description
Technical field
The invention belongs to the Photobiology marker field of preventing and treating verminosis, more specifically, the present invention relates to a class phosphorescence iridium and coordinateThing synthetic and for imago of blood fluke fluorescence labeling, the invention provides a kind of imago of blood fluke fluorescence labeling method of novelty,Such phosphorescent iridium complex has the fluorescently-labeled beneficial effect of imago of blood fluke.
Background technology
Snail fever is a kind of ancient parasitic disease, and the mankind's productive life is had to huge harm, is to be only second to of malariaTwo large tropical parasitic diseases. Schistosomiasis endemic is in 74 countries and regions, and estimating has 6.52 hundred million populations compromised at present, has1.93 hundred million the infecteds, have symptom case approximately 1.2 hundred million, and wherein 2,000 ten thousand is serious case, and China is the Major Epidemic of snail feverDistrict. Snail fever is a kind of Zoonosis parasitic disease of typically propagating through water source, and blood fluke cercaria is infect people and animals uniqueStage, after blood fluke cercaria enters human body, grow for the virgin worm stage, enter again adult rank by the time of 20 to 60 daysSection can cause acute and chronic snail fever and related complication in whole process, human body is caused to great injury, from skin mistakeQuick dermatitis, malnutrition, apocleisis, jaundice, even cirrhosis, late period, severe patient can causing death. Researcher passes throughConstantly research, has developed a series of antischistosomal drugs that fluke adult had to good killing effect, and wherein praziquantel is doneFor main representative, and because having safety, bad reaction is few, and instructions of taking is simple and easy to do, good effect, and people's vivo degradation is fast etc.Feature and at home so that the world applied widely. But due to extensively long-term a large amount of use the to praziquantel class medicine, bloodFluke produces drug resistance to it; The definite mechanism of action that such medicine of while kills adult is still not clear, so need to be to suchMedicine continues deep research. Explore these medicines according to traditional research method (being mainly the detection to dead polypide)The possible mechanism of action of thing, can not directly reflect the mode of action and the site of medicine on live body, and adapter ring festival-gathering affects resultAccuracy and confidence level, so need to seek some new research methods and make up the deficiency of current existence. At present, fluorescence imagingSensitive a, non-intrusion type, visual detection approach that expense is cheap, its resolution hundred nanometers, can realize from carefullyBorn of the same parents are to the living imaging of animal, fluorescence imaging means have sensitive monitoring, imaging rapidly, can observe polymolecular event etc. excellent simultaneouslyPoint, is therefore being with a wide range of applications aspect the research of control blood fluke medicine mechanism.
Imago of blood fluke body wall is made up of by lower floor body quilt, basement membrane and body, and plasomidum and flesh layer that body is formed by cell are staggered inTogether, and be connected with body by kytoplasm tubule, make body by lower floor by the body of the seedless acellular separation in top layer by cover, thereforeImago of blood fluke does not have cuticula. Imago of blood fluke parasitizes in blood vessel, and body surface directly contacts with host's blood, in order to escapeKeep away host's autoimmune attack, body has been capped a kind of specific carbohydrate identical with host's red blood cell ab antigen, so become polypideTable presents stronger hydrophily. At present, use traditional organic molecule fluorescent dye as fluorescence probe, organism to be groundStudy carefully, have following shortcoming: short wavelength's transmitting has the interference of archebiosis fluorescence, photostability to cause not observing for a long timeDeng. Meanwhile, most of organic molecule fluorescent dye hydrophily is poor, and its Color to imago of blood fluke is undesirable, thereforeDeveloping the fluorescent dye that imago of blood fluke is had to a good fluorescence mark effect is a challenge.
Phosphorescent iridium complex is compared other fluorescent materials, has MLCT feature greatly, has that luminous efficiency is high, light is steadyQualitative good, the advantage such as glow color is adjustable. The present invention is in conjunction with the excellent luminescent properties of phosphorescent iridium complex, and inventor coordinates by iridiumThing, is selected suitable organic ligand and organic ligand is carried out for the fluorescently-labeled application of imago of blood fluke as phosphorescence probeHydrophilic modification, can successfully solve in imago of blood fluke fluorescence imaging process fluorescence labeling weak effect and anti-light bleachability poorProblem.
Summary of the invention
The invention provides a class phosphorescent iridium complex, by this class complex is carried out to hydrophilic radical in chemical modification, make itThere is the performance of Schistosoma japonicum adult being carried out to phosphorescence mark, and improved such phosphorescent iridium complex luminous quantum efficiency,Can be used as Schistosoma japonicum adult phosphorescence labelled reagent.
The structure of complex of iridium of the present invention be by taking two nitrogenous aromatics as bidentate ligand, be aided with one containing dinitrogen virtueThe part coordination of aroma compounds is synthetic, and structure is as follows more specifically:
Wherein n=0,1,2,3,4
The compounds of this invention can be prepared according to following synthetic route:
Raw material and the agents useful for same of preparing the compounds of this invention are known compound, can on market, obtain, or available abilityThe method preparation that territory is known. In synthetic route second step can prepare by methods known in the art (referring to Nonoyama, K.Bull.Chem.Soc.Jpn.1974,47,467-468.)
PartIn acetonitrile alkaline solution, add hot reflux with PEG-Ts and can obtain the bidentate ligand containing hydrophilic groupItsMiddle PEG-Ts structural formula is as follows:
PartStructural formula is as follows:
By iridous chloride hydrate and the bidentate ligand that contains hydrophilic groupIn the mixed solution of cellosolvo and water, heatReact 12 to 48 hours, can synthesize and obtain corresponding iridium dichloro bridge complex; Then the iridium dichloro bridge complex, obtaining is organicIn solvent, water or mixed solvent with corresponding assistant ligandReact synthetic end-product 4 to 12 hours.
Above-mentioned any one phosphorescent iridium complex is as imago of blood fluke fluorescence labeling probe, and fluorescence labeling method comprises the steps:
(1) blood fluke cercaria obtains: fresh cercaria obtains from the positive oncomelania that infects miracidium, gets positive spiral shell in 100mLIn conical flask, add clear water to bottleneck, the illumination cercaria of overflowing about 2 hours under incandescent lamp.
(2) mouse infection: by six week age female mice four limbs be fixed on self-control shelf on, belly unhairing, gets the moistening mouse of warm waterSkin of abdomen, and the cover glass that contains 50 left and right cercarias is affixed on the plucked skin of abdomen of mouse, keep making for 20 minutes cercariaPenetrating mouse skin infects.
(3) imago of blood fluke obtains: metainfective mouse was raised after 6 weeks, used neck dislocation to put to death, in strict accordance with asepticOperation requirements, cuts skin of abdomen, peritonaeum successively open, takes perfusion to collect adult in liver portal-mesentcric vein. To collectAdult in physiological saline, after rinsing 3 times, be assigned in culture dish, add RPMI-1640 (RoswellParkMemorialInstitute) cell culture fluid was cultivated after 2 hours, and the active good polypide of microscopy screening is for fluorescence imaging.
(4) imago of blood fluke fluorescence imaging: dimethyl sulfoxide (DMSO) for phosphorescent complexes (DMSO) dissolves and is accurately mixed with 1mmolMother liquor, and then be diluted to the dilution of 5 μ M with PBS buffer solution. The dilution that pipettes 200 μ L joins in culture dish,Join in phosphorescent complexes dilution with tweezers picking adult,, after 5 minutes to 6 hours adult is transferred in incubated at roomFluorescence imaging vessel, excite the phosphorescence mark situation of lower confocal fluorescent microscopic examination cercaria at 405nm, gather 520-620The phosphorescent signal of nm is carried out fluorescence imaging.
Inventor with synthetic, is used for imago of blood fluke fluorescently-labeled research by phosphorescent iridium complex by design, can be successfullySolve fluorescence labeling weak effect and the poor deficiency of anti-light bleachability in adult fluorescence imaging process.
Brief description of the drawings
The absorption spectrum of Fig. 1 complex Ir-1 and phosphorescent emissions spectrum.
The absorption spectrum of Fig. 2 complex Ir-2 and phosphorescent emissions spectrum.
The laser co-focusing fluorescence imaging figure of Fig. 3 complex Ir-2 mark Schistosoma japonicum adult.
The laser co-focusing fluorescence imaging figure of Fig. 4 complex Ir-2 mark Schistosoma japonicum adult device.
Detailed description of the invention
Below provided the specific embodiment of the compounds of this invention, they use example in detail the present invention, but to not structure of the present inventionBecome any restriction. Raw material used in the present embodiment is known compound, can be obtained by commercial sources, maybe can be by relevant literary compositionOffer method for designing synthetic.
In the following embodiments, related physical and chemical parameter is by following Instrument measuring:1HNMR composes at BrukerThe upper employing of Mercuryplus 400MHz measure, with TMS be interior mark; Mass spectrometric data MALDI-TOF-MS is at ABSCIEXOn 5800 type mass spectrographs, obtain; Ultraviolet-visible absorption spectroscopy completes on ShimadzuUV-2700 uv-visible absorption spectra instrument;Phosphorescent emissions spectrum is by measuring on PerkinElmerLS-55 XRF; Cercaria Phosphorescence imaging is at OLYMPUSFV1000On type laser confocal fluorescence microscope, gather, it is the excitation source of 405nm that laser instrument provides wavelength, according to complex of iridiumPhosphorescent emissions character collect the transmitting phosphorescent signal within the scope of 520nm-620nm.
Embodiment 1
[Ir(HO-pq)2(phen)][PF6] (Ir-1) synthetic
(1) HO-pq's is synthetic: by the 4-phenolic group phenyl boric acid of 1mmol, the 2-chloroquinoline of 1mmol, four (3-of 7% equivalentPhenylphosphine) potash of palladium (0) and 1mmol joins in three-neck flask, then adds 30mLTHF and H2The mixing of OSolvent. Under the protection of nitrogen, reaction system is at 70 DEG C of reaction 24h. Be cooled to room temperature, reactant liquor dichloromethane extraction,Water, with dichloromethane extraction 3 times (10mL × 3), merges organic layer, and with anhydrous sodium sulfate drying, column chromatography for separation obtains.
(2) HO-pq iridium dichloro bridge complex is synthetic: bibliography (Nonoyama, K.Bull.Chem.Soc.Jpn.1974,47,467-468.) synthetic. The part HO-pq of the iridous chloride hydrate of 0.5mmol and 1mmol is dissolved in the 2-second of 25mLIn the mixed liquor of ethoxy-ethanol and water (v/v=3:1), 110 DEG C of reaction 24h, room temperature is cooling. Suction filtration is collected solid, respectivelyWith distilled water and absolute ethanol washing several, obtain HO-pq iridium dichloro bridge complex.
(3)[Ir(HO-pq)2(bpy)][PF6] (Ir-1) synthetic: by the HO-pq iridium dichloro bridge complex of 0.2mmol, 0.41 of mmol, 10-Phen adds in round-bottomed flask, then adds 30mL carrene and methyl alcohol (v/v=2:1). ?Under the protection of nitrogen, reaction system is at 50 DEG C of reaction 10h. Add again the KPF of 10 times of equivalents6, continue reaction 4h. Room temperatureCooling, decompress filter is collected filtrate, and column chromatography for separation obtains product. The Absorption and fluorescence spectrum of complex Ir-1 is as Fig. 1Shown in. Nuclear-magnetism characterization data:1HNMR(400MHz,d6-DMSO)δ9.49(s,2H),8.71(dd,J＝8.2,1.2Hz,2H),8.52(t,J＝12.8Hz,2H),8.34(q,J＝9.0Hz,4H),8.16(d,J＝8.7Hz,2H),8.09–7.97(m,4H),7.84–7.56(m,2H),7.14(t,J＝7.5Hz,2H),7.01(d,J＝8.9Hz,2H),6.78–6.69(m,2H),6.63(dd,J＝8.6,2.3Hz,2H),5.98(d,J＝2.2Hz,2H)。
Embodiment 2
[Ir(PEG-pq)2(phen)][PF6] (Ir-2) synthetic
(1) HO-pq's is synthetic: by the 4-phenol phenyl boric acid of 1mmol, and the 2-chloroquinoline of 1mmol, four (3-benzene of 7% equivalentBase phosphine) potash of palladium (0) and 1mmol joins in three-neck flask, then adds 30mLTHF and H2The mixing of O is moltenAgent. Under the protection of nitrogen, reaction system is at 70 DEG C of reaction 24h. Be cooled to room temperature, reactant liquor dichloromethane extraction,Water, with dichloromethane extraction 3 times (10mL × 3), merges organic layer, with anhydrous sodium sulfate drying, and column chromatography for separation.
Synthesizing of the single-ended p-methyl benzenesulfonic acid ester of (2) three diglycol ethylene: 1mmol tri-diglycol ethylenes are added to three-neck flaskIn, add the pyridine of 1mmoL, dissolve with the carrene of 20mL, in 0 DEG C of ice bath, stir. Slowly splash into dichloromethaneThe 1mmoL p-methyl benzene sulfonic chloride that alkane dissolves. React and use salt acid elution after 3 hours, get organic layer and add and be washed to the aqueous solution and beNeutral. Anhydrous sodium sulfate drying, column chromatography for separation obtains.
(3) part PEG-pq's is synthetic: by the single-ended p-methyl benzenesulfonic acid ester of 1mmol tri-diglycol ethylene, 1mmol carbonic acidPotassium, the TBAB of 10% equivalent adds in three-necked bottle, with the acetonitrile dissolving of 20mL. In 80 DEG C of oil baths, stir backStream. Slowly splash into the 1mmolHO-pq that acetonitrile dissolves. After reaction 10h, be cooled to room temperature. Reactant liquor dichloromethane extraction,Water, with dichloromethane extraction 3 times (10mL × 3), merges organic layer, and with anhydrous sodium sulfate drying, column chromatography for separation obtains.
(4) PEG-pq iridium dichloro bridge complex synthetic (referring to document Nonoyama, K.Bull.Chem.Soc.Jpn.1974,47,467-468.): the part PEG-pq of the iridous chloride hydrate of 0.5mmol and 1mmol is dissolved in the 2-ethoxy of 25mLIn the mixed liquor of base second alcohol and water (v/v=3:1), 110 DEG C are reacted 24 hours, finish cooling room temperature. Suction filtration is collected solid,Use respectively distilled water and absolute ethanol washing for several times, obtain PEG-pq iridium dichloro bridge complex.
(5)[Ir(PEG-pq)2(bpy)][PF6] (Ir-2) synthetic: by the PEG-pq iridium dichloro bridge complex of 0.2mmol,1 of 0.4mmol, 10-Phen adds in round-bottomed flask, then adds 30mL carrene and methyl alcohol (v/v=2:1).Under the protection of nitrogen, reaction system is at 50 DEG C of reaction 10h. Add again the KPF of 10 times of equivalents6, continue reaction 4h. ChamberTemperature is cooling, and decompress filter is collected filtrate, and column chromatography for separation obtains product. The Absorption and fluorescence spectrum of complex Ir-2 is as figureShown in 2. Complex Ir-2 characterization data:1HNMR(400MHz,CDCl3)δ8.73(dd,J＝8.2,1.2Hz,2H),8.51(dd,J＝5.1,1.2Hz,2H),8.45(d,J＝9.0Hz,2H),8.38(d,J＝8.9Hz,2H),8.30(d,J＝8.9Hz,2H),8.08(s,2H),8.02(dt,J＝13.9,7.0Hz,2H),7.75(d,J＝8.0Hz,2H),7.19(t,J＝7.7Hz,2H),7.03(d,J＝8.9Hz,2H),6.86(dd,J＝8.8,2.4Hz,2H),6.80–6.72(m,2H),5.96(d,J＝2.5Hz,2H),4.50(t,J＝5.5Hz,2H),3.95–3.78(m,2H),3.76–3.62(m,2H),3.68–3.61(m,8H),3.57(s,8H),3.55–3.50(m,4H)；MALDI-TOFMS:m/z1077.6443([M-PF6]+)。
Embodiment 3
Phosphorescent complexes Ir-2 is marked as picture to the phosphorescence of imago of blood fluke
(1) reagent and material
Reagent: dimethyl sulfoxide (DMSO) (Tianjin Kermel Chemical Reagent Co., Ltd.), the autogamy of PBS buffer solution.
Cercaria: Snails is overflowed and obtained, and Snails is provided by Jiangsu Prov. Bilharziasis Prevention and Control Inst..
Mouse: kunming mice, is provided by Gannan Medical College of Jiangxi Province.
(2) blood fluke cercaria obtains
Fresh cercaria obtains from the positive oncomelania that infects miracidium, gets positive spiral shell in 100mL conical flask, adds clear water to bottleMouthful, the illumination cercaria of overflowing about 2 hours under incandescent lamp.
(3) mouse infection
By six week age female mice four limbs be fixed on self-control shelf on, belly unhairing, gets the moistening mouse part skin of warm water, and willThe cover glass that contains 50 left and right cercarias is affixed on the plucked skin of abdomen of mouse, keeps within 20 minutes, making cercaria penetrate mouse skin and entersRow infects.
(4) obtain adult
Metainfective mouse was raised after 6 weeks, used neck dislocation to put to death, in strict accordance with sterile working requirement, cut successively belly openSkin, peritonaeum, take perfusion to collect adult in liver portal-mesentcric vein. By the adult of collecting rinsing in physiological salineAfter 3 times, be assigned in culture dish, add RPMI-1640 (RoswellParkMemorialInstitute) cell culture fluid to cultivate 2After hour, the active good polypide of microscopy screening is for fluorescence imaging.
(5) adult fluorescence labeling formation method
Choose phosphorescent complexes Ir-2 as fluorescence labeling probe, phosphorescent complexes is dimethyl sulfoxide (DMSO) (DMSO) dissolving standard for Ir-2Really be mixed with the mother liquor of 1mmol, be then diluted to the dilution of 5 μ M with PBS buffer solution. Pipetting 200 μ L dilutions addsIn culture dish, join in phosphorescent complexes dilution with tweezers picking adult, under room temperature, hatch after 5 minutes to 6 hours,Adult is transferred to fluorescence imaging special utensil, excite lower employing laser confocal fluorescence microscope to observe the phosphorus of cercaria at 405nmSignal situation, and the phosphorescent signal that gathers 520-620nm is carried out fluorescence imaging.
(6) fluorescence labeling result
Concrete mark result, referring to Fig. 3 and Fig. 4, can draw from fluorescence imaging figure: phosphorescent complexes Ir-2 can become blood flukeWorm carries out fluorescence labeling imaging.
Claims (5)
1. a phosphorescent iridium complex, is characterized in that: the phosphorescent compound with following formula structure:
Wherein n=0,1,2,3,4.
2. a kind of phosphorescent iridium complex according to claim 1, is characterized in that: the structural formula that phosphorescent compound is n=3.
3. a kind of phosphorescent iridium complex according to claim 1, is characterized in that: any one complex of iridium can pass through following roadLine is synthetic:
Wherein PEG-Ts structural formula is as follows:
Bidentate ligandStructural formula is as follows:
By iridous chloride hydrate and the bidentate ligand that contains hydrophilic groupIn the mixed solution of cellosolvo and water, heatReact the synthetic iridium dichloro bridge complex that obtains 12 to 48 hours; Then the iridium dichloro bridge complex, obtaining organic solvent,In water or mixed solvent with corresponding assistant ligandReact synthetic end-product 4 to 12 hours.
4. according to a kind of phosphorescent iridium complex described in claim 1-2 any one, it is characterized in that: any one phosphorescent iridium complexFor imago of blood fluke fluorescence labeling.
5. a kind of phosphorescent iridium complex according to claim 1, is characterized in that, imago of blood fluke fluorescence labeling formation method bagDraw together following steps:
Blood fluke cercaria obtains: fresh cercaria obtains from the positive oncomelania that infects miracidium, gets positive spiral shell in 100mL conical flaskIn, add clear water to bottleneck, the illumination cercaria of overflowing about 2 hours under incandescent lamp;
Mouse infection: by six week age female mice four limbs be fixed on self-control shelf on, belly unhairing, gets the moistening mouse web portion of warm waterSkin, and the cover glass that contains 45-55 bar cercaria is affixed on the plucked skin of abdomen of mouse, keep cercaria being penetrated in 20 minutes littleMouse skin infects;
Imago of blood fluke obtains: metainfective mouse was raised after 6 weeks, used neck dislocation to put to death, in strict accordance with sterile workingRequirement, cuts skin of abdomen, peritonaeum successively open, takes perfusion to collect adult in liver portal-mesentcric vein; By the one-tenth of collectingWorm is assigned in culture dish after rinsing 3 times in physiological saline, adds RPMI-1640 (RoswellParkMemorialInstitute) cell culture fluid was cultivated after 2 hours, and the active good polypide of microscopy screening is for fluorescence imaging;
Imago of blood fluke fluorescence imaging: dimethyl sulfoxide (DMSO) for phosphorescent complexes (DMSO) dissolves and is accurately mixed with 1mmol'sMother liquor, and then be diluted to the dilution of 5 μ M with PBS buffer solution; The dilution that pipettes 200 μ L joins in culture dish, usesTweezers picking adult joins in phosphorescent complexes dilution, after 5 minutes to 6 hours, adult is transferred to fluorescence in incubated at roomImaging vessel, excite the phosphorescence mark situation of lower confocal fluorescent microscopic examination cercaria, and gather 520-620nm at 405nmPhosphorescent signal carry out fluorescence imaging.
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| CN105061515A (en) * | 2015-08-08 | 2015-11-18 | 赣南师范学院 | Synthesis of phosphorescent iridium complex and application of phosphorescent iridium complex for fluorescence labeling of schistosome cercaria |
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