CN117285572A - 一类环金属化铂配合物及其制备方法和应用 - Google Patents
一类环金属化铂配合物及其制备方法和应用 Download PDFInfo
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 85
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims description 7
- 238000010668 complexation reaction Methods 0.000 title description 6
- 150000001450 anions Chemical class 0.000 claims abstract description 21
- 239000007850 fluorescent dye Substances 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- 239000002244 precipitate Substances 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 17
- 239000012498 ultrapure water Substances 0.000 claims description 17
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- 238000001035 drying Methods 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 239000002243 precursor Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 239000013067 intermediate product Substances 0.000 claims description 10
- 239000007791 liquid phase Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
- -1 bipyridine compound Chemical class 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
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- 125000003118 aryl group Chemical group 0.000 claims description 7
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- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 4
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- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 8
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- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 7
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
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- NBPGPQJFYXNFKN-UHFFFAOYSA-N 4-methyl-2-(4-methylpyridin-2-yl)pyridine Chemical compound CC1=CC=NC(C=2N=CC=C(C)C=2)=C1 NBPGPQJFYXNFKN-UHFFFAOYSA-N 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
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- ASIUQJZSEZTIRU-UHFFFAOYSA-N 2-(2,4-dimethylphenyl)pyridine Chemical compound CC1=CC(C)=CC=C1C1=CC=CC=N1 ASIUQJZSEZTIRU-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
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- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- SSABEFIRGJISFH-UHFFFAOYSA-N 2-(2,4-difluorophenyl)pyridine Chemical compound FC1=CC(F)=CC=C1C1=CC=CC=N1 SSABEFIRGJISFH-UHFFFAOYSA-N 0.000 description 3
- 229910020366 ClO 4 Inorganic materials 0.000 description 3
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- 239000012452 mother liquor Substances 0.000 description 3
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical class [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 3
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- 230000004044 response Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NRSBAUDUBWMTGL-UHFFFAOYSA-N 2-(1-benzothiophen-2-yl)pyridine Chemical compound S1C2=CC=CC=C2C=C1C1=CC=CC=N1 NRSBAUDUBWMTGL-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108010019160 Pancreatin Proteins 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
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
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- 125000001153 fluoro group Chemical group F* 0.000 description 2
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- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
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- 206010067997 Iodine deficiency Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- MXRWOZZHVSTPJP-UHFFFAOYSA-N S1C(=CC2=C1C=CC=C2)C2=NC=CC=C2.N2=CC=CC=C2 Chemical compound S1C(=CC2=C1C=CC=C2)C2=NC=CC=C2.N2=CC=CC=C2 MXRWOZZHVSTPJP-UHFFFAOYSA-N 0.000 description 1
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- 125000000539 amino acid group Chemical group 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
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- 235000006479 iodine deficiency Nutrition 0.000 description 1
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- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
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- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
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- 230000004083 survival effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 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
- C07F15/0086—Platinum compounds
-
- 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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- 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"
-
- 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"
- G01N21/643—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" non-biological material
-
- 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
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
- G01N21/6458—Fluorescence microscopy
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- 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
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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- 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
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
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- 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
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1092—Heterocyclic compounds characterised by ligands containing sulfur as the only heteroatom
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pathology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Optics & Photonics (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
本发明公开了环金属化铂配合物,其结构式如式Ⅰ所示:式Ⅰ
Description
技术领域
本发明涉及一类环金属化铂配合物,及其在检测阴离子、蛋白分子和生物成像方面的应用,属于生物医学检测和成像领域。
背景技术
磷光过渡金属配合物具有发射寿命长、吸收-发射斯托克斯位移大、激发态可调等特点。d8 Pt(II)配合物通常采用方形平面配位几何,允许分子间相互作用,可以显著改变基态和激发态性质,往往具有金属-金属-配体电荷转移(MMLCT)性质的转变,其转移的电荷转移能量更低。本发明环金属化铂配合物在水溶剂中没有荧光发射,而在受水溶液环境中阴离子、蛋白的诱导后具有强双色荧光发射,为体内外检测研究提供了新型的方法。
蛋白质在生命过程中具有重要作用,蛋白质结构的改变会极大地改变其生理功能,从而导致一系列疾病。牛血清白蛋白(BSA)是一种生物相容性蛋白,与人血清白蛋白(HSA)具有结构上的同源性,是生化研究中使用最广泛的模型蛋白。人体中各种微量的阴离子对调节人的生理生化功能具有重要意义。如碘离子缺乏或过量都会导致甲状腺疾病,如甲状腺肿大、甲退和甲亢;长期饮用含溴离子较高的水,在体内蓄积过多会导致人体膀胱和肾脏发生癌变;短时间摄入大量硝酸根和亚硝酸根可造成高铁血红蛋白血症,严重者导致缺氧性死亡;高氯酸根对甲状腺、生长发育及神经系统等具有潜在危害。因此设计用来高效检测蛋白质以及以上各类阴离子的荧光探针具有重要的意义。
目前用于检测阴离子的发光开关探针少见,只能在有机溶剂中进行荧光检测,多数探针结构中引入了具有生物毒性的重金属,因此极大地限制了此类探针在生物系统(水环境)中的应用。该类环金属化铂配合物能够在水溶液或生物环境中特异性识别阴离子,可应用于荧光探针、细胞成像和荧光显色材料等领域,具有较高灵敏度、较低检测成本、操作方便、测定快速以及实时检测等特点。
发明内容
针对现有技术的不足,本发明提供了一类具有抗肿瘤活性的环金属化铂配合物,该类环金属化铂配合物作为“开-关”磷光探针既能在水溶液中受到阴离子诱导,分子间产生Pt-Pt作用诱导自组装形成具有橙到红光发射的纳米颗粒,也能与BSA相互作用获得开关型的绿色荧光发射,实现了对阴离子、蛋白特异性的双功能荧光检测,也可作为活细胞中双荧光通道的荧光诊疗探针。
本发明环金属化铂配合物的结构式如式Ⅰ所示:
式Ⅰ其中,/>选自/> 选自/>当/>为/>时,/>为/>当/>为/>时,/>为/>当/>为/>时,/>为当/>为/>时,/>为/>
本发明所述环金属化铂配合物的制备方法,具体步骤如下:
(1)在保护性气氛条件下,将四氯铂酸钾与芳香环类化合物溶解于溶剂A中得到混合溶液A,混合溶液A在温度80-85℃下回流搅拌反应48~54h,析出沉淀,沉淀经洗涤、干燥得到铂桥联前体;
(2)在保护性气氛条件下,将步骤(1)得到的铂联前体与银盐溶解于溶剂B中得到混合溶液B,混合溶液B在室温下搅拌反应脱氯20-24h,固液相分离,液相为中间产物;
(3)在保护性气氛条件下,将步骤(2)得到的中间产物与联吡啶类化合物混合均匀,在温度60-70℃下回流搅拌反应24-36h,析出沉淀,沉淀洗涤干燥制得环金属化铂配合物。
所述芳香环类化合物选自2-苯基吡啶、2-(2,4-二甲基苯基)吡啶、2-(2,4-二氟苯基)吡啶、2-(2-吡啶基)苯并噻吩,即所述联吡啶类化合物选自2,2'-联吡啶、4,4'-二甲基-2,2'-联吡啶、1,10-菲罗啉、4,4'-二叔丁基-2,2'-联吡啶,即/>
第一组环金属铂配合物:由2-(2,4-二甲基苯基)吡啶的型环金属配体与2,2'-联吡啶为/>型辅助配体,1,10-菲罗啉为对照,三氟甲烷磺酸为阴离子共同络合形成环铂金属配合物1a、1b,其结构如下:
第二组环金属铂配合物:由4,4'-二甲基-2,2'-联吡啶的型辅助配体与2-苯基吡啶为/>型环金属配体,2-(2,4-二甲基苯基)吡啶为对照,三氟甲烷磺酸为阴离子共同络合形成环铂金属配合物2a、2b,其结构如下:
第三组环金属铂配合物:由2-(2-吡啶基)苯并噻吩吡啶的型环金属配体与2,2'-联吡啶为/>型辅助配体,1,10-菲罗啉为对照,三氟甲烷磺酸为阴离子共同络合形成环铂金属配合物3a、3b,其结构如下:
第四组环金属铂配合物:由2-(2,4-二氟苯基)吡啶的型环金属配体与4,4'-二甲基-2,2'-联吡啶为/>型辅助配体,4,4'-二叔丁基-2,2'-联吡啶为对照,三氟甲烷磺酸为阴离子共同络合形成环铂金属配合物4a、4b,其结构如下:
优选的,所述四氯铂酸钾与芳香环类化合物的摩尔比为1:2-2.5,铂桥联前体与银盐的摩尔比为1:2,铂桥联前体与联吡啶类化合物的摩尔比为1:2-2.5。
优选的,所述保护性气氛为N2、Ar或He。
优选的,所述溶剂A为乙二醇乙醚和超纯水的混合溶剂,乙二醇乙醚和超纯水的体积比为2:1;溶剂B为乙腈、二氯甲烷、甲醇或N,N-二甲基甲酰胺。
所述环金属化铂配合物可作为荧光探针应用在检测阴离子中;所述环金属化铂配合物可应用在制备细胞诊疗成像试剂中;所述环金属化铂配合物可应用在制备抗肿瘤药物中。
附图说明
图1是配合物1a的核磁共振氢谱(1H-NMR,d6-DMSO)图;
图2是配合物1b的核磁共振氢谱(1H-NMR,d6-DMSO)图;
图3是配合物1a的高分辨质谱图;
图4是配合物1b的高分辨质谱图;
图5-12分别是配合物1a、1b、2a、2b、3a、3b、4a、4b(20μM/L)在六种不同溶剂(FBS、BSA、PBS、H2O、CH3CN、CH2Cl2)中的紫外与荧光光谱图;A图为紫外光谱图,B图为荧光光谱图和紫外光下的溶液颜色;
图13-19分别是配合物1a、1b、2a、2b、3a、3b、4a(20μM/L)在不同阴离子水溶液中(离子浓度为5mM/L)的荧光发射图谱,其中左图为荧光发射光谱图,右图为相应的荧光强度柱状图;
图20是配合物1a与牛血清白蛋白(BSA)分子对接模拟示意图;
图21是配合物1a与HeLa细胞共孵育的双通道时间摄取定位共聚焦成像图;
图22是配合物2a在离子溶液中的动态光散射(DLS)数据分析与Zeta电位图。
具体实施方式
下面通过实施例对本发明作进一步详细说明,但本发明保护范围不局限于所述内容。
本发明实施例中制备的化合物采用核磁共振氢谱、质谱确定化合物的结构;实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用材料或设备未注明生产厂商者,均为可以通过购买获得的常规产品,使用的方法如无特殊说明均为常规方法。
实施例1:配合物1a的合成
(1)在氮气气氛下,按摩尔比1:2.1的比例,将四氯铂酸钾与2-(2,4-二甲基苯基)吡啶(dmppy)混合后,在乙二醇乙醚和超纯水的混合溶剂(乙二醇乙醚和超纯水的体积比为2:1)中溶解得到溶液A,溶液A在温度80℃下回流搅拌配位反应48h,反应结束后,加入大量超纯水,冰浴至出现墨绿色絮状沉淀,过滤沉淀,得到的固体用超纯水和乙醚分别洗3次,50℃干燥,得到绿色铂前体[Pt(dmppy)Cl];
(2)在氮气气氛下,将[Pt(dmppy)Cl]2(60mg,0.073mmol)和AgCF3SO3(37.34mg,0.145mmol)溶解于15-20ml乙腈中得到溶液B,溶液B常温反应24h,固液相分离,除去AgCl沉淀,液相为中间产物;
(3)在氮气气氛下,中间产物中加入2,2’-联吡啶(bpy)(22.70mg,0.145mmol),在60℃下冷凝回流反应24h;反应结束后,旋蒸浓缩溶液至1-2mL,加入乙醚,析出沉淀,过滤,沉淀依次经水和乙醚洗涤,60℃烘干,得到橙红色固体配合物1a;产率40.2%;配合物1a的核磁共振氢谱图见图1,高分辨质谱图见图3;
所述配合物1a的结构式为核磁氢谱和质谱数据如下:1HNMR(600MHz,DMSO-d6)δ9.31(d,J=5.2Hz,1H),9.06(d,J=5.1Hz,1H),8.94(d,J=5.2Hz,1H),8.74–8.68(m,2H),8.49(t,J=7.6Hz,1H),8.44(t,J=7.6Hz,1H),8.17(t,J=7.4Hz,1H),8.07(d,J=8.2Hz,1H),7.97–7.93(m,1H),7.88(t,J=6.3Hz,1H),7.46(t,J=6.5Hz,1H),6.94(s,1H),6.85(s,1H),2.62(s,3H),2.30(s,3H).ESI-MS m/z:[M]+533.13.
实施例2:配合物1b的合成
所述步骤(1)和步骤(2)与实施例1的步骤(1)和步骤(2)相同;
在氮气气氛下,中间产物中加入1,10-菲罗啉(phen)(26.13mg,0.145mmol),在60℃冷凝回流反应24h;反应结束后,旋蒸浓缩溶液至1-2mL,加入乙醚,析出沉淀,过滤,沉淀依次经水和乙醚洗涤,60℃烘干,得到橙黄色固体配合物1b;产率47.8%;配合物1b的核磁共振氢谱图见图2,高分辨质谱图见图4;
所述配合物1b的结构式为核磁氢谱和质谱数据如下:1HNMR(600MHz,DMSO-d6)δ9.61(d,J=5.0Hz,1H),9.41(d,J=4.4Hz,1H),9.10(d,J=4.0Hz,1H),8.97–8.94(m,1H),8.69(d,J=8.0Hz,1H),8.28(q,J=8.7Hz,1H),8.19–8.15(m,1H),8.14(s,1H),8.04–8.00(m,1H),7.93(dd,J=8.0,4.4Hz,1H),7.77(d,J=8.2Hz,1H),7.31(t,J=6.3Hz,1H),6.92(s,1H),6.70(s,1H),2.45(s,3H),2.27(s,3H).ESI-MS m/z:[M]+557.13.
实施例3:配合物2a的合成
(1)在氮气气氛下,按摩尔比1:2的比例,将四氯铂酸钾与2-苯基吡啶(ppy)混合后,在乙二醇乙醚和超纯水的混合溶剂(体积比为2:1)中溶解得到溶液A,溶液A在温度80℃下回流搅拌配位反应48h,反应结束后,加入大量超纯水,冰浴至出现绿色絮状沉淀,过滤沉淀,得到的固体依次经超纯水和乙醚分别洗3次,50℃干燥,得到绿色铂前体[Pt(ppy)Cl];
(2)在氮气气氛下,将[Pt(ppy)Cl]2(60mg,0.078mmol)和AgCF3SO3(40.16mg,0.156mmol)溶解至15-20ml乙腈得到溶液B,溶液B常温反应20h,固液相分离,除去AgCl沉淀,液相为中间产物;
(3)在氮气气氛下,中间产物中加入4,4'-二甲基-2,2'-联吡啶(dmbpy)(28.74mg,0.156mmol),在60℃冷凝回流反应24h;反应结束后,旋蒸浓缩溶液至1-2mL,加入乙醚,析出沉淀,过滤,沉淀依次经水和乙醚洗涤,60℃烘干,得到橙色固体配合物2a;产率62.0%;
所述配合物2a的结构式为核磁氢谱和质谱数据如下:1HNMR(600MHz,DMSO-d6)δ9.06(d,J=5.8Hz,1H),8.78(dd,J=13.3,5.6Hz,2H),8.46(s,1H),8.42(s,1H),8.16(t,J=7.6Hz,1H),8.10(d,J=7.9Hz,1H),7.74–7.72(m,1H),7.68(d,J=5.2Hz,1H),7.58(d,J=5.3Hz,1H),7.38(t,J=6.4Hz,1H),7.22(d,J=5.8Hz,1H),7.19–7.16(m,2H),2.52(d,J=4.7Hz,6H).ESI-MS m/z:[M]+533.51.
实施例4:配合物2b的合成
所述步骤(1)和步骤(2)与实施例1的步骤(1)和步骤(2)相同;
在氮气气氛下,中间产物中加入4,4'-二甲基-2,2'-联吡啶(dmbpy)(26.8mg,0.145mmol),在60℃冷凝回流反应24h;反应结束后,旋蒸浓缩溶液至1-2mL,加入乙醚,析出沉淀,过滤,沉淀依次经水和乙醚洗涤,60℃烘干,得到橙黄色固体配合物2b;产率63.6%;
所述配合物2b的结构式为核磁氢谱和质谱数据如下:1HNMR(600MHz,DMSO-d6)δ8.86(d,J=18.3Hz,1H),8.73(d,J=4.4Hz,1H),8.60(dd,J=18.1,5.7Hz,1H),8.43(d,J=8.0Hz,1H),8.20–8.07(m,1H),8.06–7.96(m,2H),7.95–7.77(m,1H),7.64(d,J=33.9Hz,1H),7.56–7.53(m,1H),7.41–7.31(m,2H).ESI-MS m/z:[M]+563.17.
实施例5:配合物3a的合成
(1)在氮气气氛下,按摩尔比1:2.5的比例,将四氯铂酸钾与2-(2-吡啶基)苯并噻吩(Btppy)混合后,在乙二醇乙醚和超纯水的混合溶剂(体积比为2:1)中溶解得到溶液A,溶液A在温度85℃下回流搅拌反应54h,反应结束后,加入大量超纯水,冰浴至出现橙色絮状沉淀,过滤沉淀,得到的固体用超纯水和乙醚分别洗3次,55℃干燥,得到橙色铂前体[Pt(Btppy)Cl]2;
(2)在氮气气氛下,将[Pt(Btppy)Cl]2(60mg,0.068mmol)和AgCF3SO3(34.91mg,0.136mmol)溶解于15-20ml乙腈中得到溶液B,溶液B常温反应24h,固液相分离,除去AgCl沉淀,液相为中间产物;
(3)在氮气气氛下,中间产物中加入2,2’-联吡啶(bpy)(21.21mg,0.136mmol),在温度70℃冷凝回流反应28h,反应结束后,旋蒸浓缩溶液至1-2mL,加入乙醚,析出沉淀,过滤,沉淀依次经水和乙醚洗涤,60℃烘干,得到红色固体配合物3a,产率:56.6%;
所述配合物3a的结构式为核磁氢谱和质谱数据如下:1HNMR(600MHz,DMSO-d6)δ9.69(s,1H),9.26(s,1H),8.86(d,J=20.3Hz,2H),8.60(d,J=17.1Hz,2H),8.49–8.39(m,2H),8.11(s,1H),8.02(d,J=7.3Hz,1H),7.81(s,1H),7.64(d,J=35.0Hz,2H),7.40(t,J=7.3Hz,1H),7.35(t,J=7.3Hz,2H).ESI-MS m/z:[M]+561.07.
实施例6:配合物3b的合成
所述步骤(1)和步骤(2)与实施例5的步骤(1)和步骤(2)相同;
在氮气气氛下,中间产物中加入1,10-菲罗啉(phen)(24.51mg,0.136mmol),在温度70℃冷凝回流反应28h,反应结束后,旋蒸浓缩溶液至1-2mL,加入乙醚,析出沉淀,过滤,沉淀依次经水和乙醚洗涤,60℃烘干,得到红色固体配合物3b,产率:51.2%;
所述配合物3b的结构式为核磁氢谱和质谱数据如下:1HNMR(600MHz,DMSO-d6)δ10.14–9.87(m,1H),9.37–9.17(m,1H),9.15–8.93(m,2H),8.61(s,1H),8.52(d,J=9.5Hz,1H),8.43(d,J=16.0Hz,2H),8.39–8.31(m,1H),8.06–7.93(m,2H),7.88–7.65(m,2H),7.47(dt,J=84.7,7.5Hz,1H),7.35–7.09(m,2H).ESI-MS m/z:[M]+585.56.
实施例7:配合物4a的合成
(1)在氮气气氛下,按摩尔比1:2.2的比例,将四氯铂酸钾与2-(2,4-二氟苯基)吡啶(dfppy)混合后,在乙二醇乙醚和超纯水的混合溶剂(体积比为2:1)中溶解得到溶液A,溶液A在温度80℃下回流搅拌反应50h,反应结束后,加入大量超纯水,冰浴至出现墨绿色絮状沉淀,过滤沉淀,得到的固体用超纯水和乙醚分别洗3次,55℃干燥,得到墨绿色铂前体[Pt(dfppy)Cl]2;
(2)在氮气气氛下,将[Pt(dfppy)Cl]2(60mg,0.071mmol)和AgCF3SO3(36.35mg,0.142mmol)溶解于15-20ml乙腈中得到溶液B,溶液B常温反应24h,固液相分离,除去AgCl沉淀,液相为中间产物;
(3)在氮气气氛下,中间产物中加入4,4'-二甲基-2,2'-联吡啶(dmbpy)(25.13mg,0.136mmol),在60℃冷凝回流反应24h,反应结束后,旋蒸浓缩溶液至1-2mL,加入乙醚,析出沉淀,过滤,沉淀依次经水和乙醚洗涤,60℃烘干,得到黄色固体配合物4a,产率:51.3%;所述配合物4a的结构式为核磁氢谱和质谱数据如下:1H NMR(600MHz,DMSO-d6)δ8.98(s,1H),8.78(d,J=35.1Hz,2H),8.45(d,J=19.2Hz,2H),8.18(tt,J=17.8,8.5Hz,1H),8.05–7.97(m,1H),7.67(s,1H),7.53(s,1H),7.38(s,1H),7.12(dd,J=6.7,3.4Hz,1H),6.81(s,1H),2.55(s,5H),2.42(s,1H).ESI-MS m/z:[M]+569.11.
实施例8:配合物4b的合成
所述步骤(1)和步骤(2)与实施例5的步骤(1)和步骤(2)相同;
将中间产物旋蒸至溶液挥干,加入少量N,N-二甲基甲酰胺(3ml)溶解,再加入4,4'-二叔丁基-2,2'-联吡啶(bbbpy)(47.9mg,0.177mmol),氮气气氛下,75℃冷凝回流反应36h,反应结束后,加入大量超纯水,析出沉淀,过滤,沉淀依次经水和乙醚洗涤,60℃烘干,得到黄绿色固体配合物4b,产率:40.2%;
所述配合物4b的结构式为核磁氢谱和质谱数据如下:1H NMR(600MHz,DMSO-d6)δ9.13(d,J=6.1Hz,1H),8.92(d,J=5.8Hz,1H),8.87(d,J=6.0Hz,1H),8.63–8.60(m,1H),8.17(t,J=7.9Hz,1H),7.98(d,J=8.3Hz,1H),7.83(dd,J=5.9,2.1Hz,1H),7.70(dd,J=6.1,2.2Hz,1H),7.52(dd,J=5.3,2.0Hz,1H),7.41(t,J=6.8Hz,1H),7.09(ddd,J=11.7,9.0,2.2Hz,1H),6.90(dd,J=9.0,2.3Hz,1H),1.45(s,9H),1.35(s,9H).ESI-MS m/z:[M]+653.66.
实施例9:环金属化铂(II)配合物在不同溶剂下的紫外吸收和荧光发射及蛋白选择性响应
分别称取实施例1-8中合成配合物0.5mg,加入二甲基亚砜中配制成20mmol/L的母液,取3μL加入到离心管中,加入27μL的二甲基亚砜,再分别加入BSA水溶液(50g/L)、FBS水溶液(30g/L)、H2O、CH3CN、CH2Cl2、PBS缓冲液(pH7.0-7.4)稀释到20μmol/L,上述溶液在400nm激发光下测定荧光获得荧光光谱图;结果如图5至图12所示,除配合物1a、4b外,所有配合物在水溶液中发射较弱或无发射,而在PBS溶液中配合物的荧光发射明显增强,1b、3a、3b最大发射波长在600-650nm处,365nm紫外灯照射下具有红色荧光;2a、2b、4a最大发射波长为580nm,在365nm紫外灯照射下具有橙色荧光。说明在PBS溶液中的阴离子能诱导配合物产生配位与静电作用从而增加了荧光发射。此外配合物1a、1b在CH2Cl2溶液中最大发射波长蓝移至485nm处,呈蓝色发射,CH3CN溶液中2b、4a分别呈绿色(λemmax=490nm)和橙色(λemmax=560nm)荧光发射;
配合物1a、1b、2a、2b、4a、4b均对BSA有较强的荧光响应性,最大发射波长为493nm,在365nm紫外灯照射下具有明亮的绿色发光,波峰范围在470-500nm;结构中含苯并噻吩基团的配合物3a、3b最大发射波长蓝移到460nm,在365nm紫外灯照射下具有蓝色发光,说明配合物通过氢键作用以及静电相互作用与带有负电荷的牛血清蛋白(BSA)发生作用;同时与配合物1a相比,1b对蛋白的荧光发射强度下降,说明芳环的增加降低了配合物对蛋白的荧光响应;
使用配合物Pt1a结构与牛血清白蛋白(BSA)进行分子对接(PDB:3v03),1a的结构通过Chem3D 20.0优化,使能量最小化;结果显示(图20)Pt1a配合物与BSA中氨基酸残基如:ILE521A,VAL551A,LYS563A等可以形成很强的氢键作用力,并且结合能为-6.35Kcal/mol。因此表明当配合物与BSA等生物分子在溶液中相互作用时有明显的荧光增强现象。
实施例10:环金属化铂(II)配合物的不同阴离子选择性测试
分别称取0.5mg实施例1-8中合成配合物加入二甲基亚砜配制成20mmol/L的母液,取3μL母液到5mL的离心管里,再加入27μL的二甲基亚砜,用水稀释到20μmol/L,分别加入F-、Cl-、Br-、I-、NO2 -、NO3 -、SO4 2-、HSO3 -、CO3 2-、HCO3 -、H2PO4 -、CH3COO-、ClO-、ClO4 -等离子,离子最终浓度为5mmol/L,上述溶液在400nm激发光下测定荧光获得荧光光谱图;
结果见图13至图19,配合物1a、1b、2b对Br-、ClO4 -、NO3 -具有较好的红色荧光选择性,2a、4a对Br-、I-具有特异的荧光选择性;
荧光光谱显示,波长在460nm的吸收带属于配体中心(LC)π-π*跃迁,而长波长区域较强的吸收带属于电荷转移(CT)跃迁,包括金属-配体电荷转移(MLCT)和金属-金属-配体电荷转移(MMLCT)跃迁。实施例1、2中CN配体含有给电子基团-甲基的时候,最大发射波长在600nm左右,发射峰红移;
实施例3中CN配体上面没有取代基的配合物的则蓝移到580nm左右,具有橙色荧光发射。实施例3、4中NN配体中含有甲基给电子基团,环键被削弱,电子密度重分布,吡啶基氮上的电荷变得更负,增强了二聚体分子间相互作用,最终使得荧光强度上升;
实施例7中CN配体中含有氟原子这样的吸电子取代基的时候则蓝移到570nm,具有黄色荧光发射;吸收带表明蓝移说明CN配体上吸电子基的存在则增加了HOMO和LUMO之间的带隙;可能由于氟原子在二聚体分子间能与甲基上的氢相互作用,也增强其荧光强度;
配合物1a(配体芳环少位阻小)对Br-有显著的选择性,在600nm处具有最强的红色荧光发射,同时NN配体芳环多位阻大的配合物1b对所有离子的选择性较弱一些,说明增加双齿氮氮配体中芳环的数量会诱导分子间的铂-铂相互作用减弱,对离子的选择性能降低。对于2a、2b,3a、3b,4a同样满足这一条规律,及当配体的取代基增大,位阻增强,降低了铂-铂相互作用,导致配合物的荧光发射降低。
实施例11:环金属化铂(II)配合物的抗肿瘤活性测定
利用实施例1、2、3、4、5、6、7、8制备得到的环金属化Pt(II)配合物为实验组,以顺铂为对照组,分别测定其对HeLa(人宫颈癌细胞株)细胞毒性,具体测定方法如下:
采用四唑盐(MTT)比色法测定,将受试肿瘤细胞分别用胰酶消化成单细胞悬液,采用血球计数板进行计数,调整细胞浓度为5×104/mL,接种于96孔板,每孔160μL,培养24h后,再加入不同浓度的药物,置于在5% CO2、37℃的培养箱中孵育48h,于孵育结束前4h加入MTT 20μL/孔;4h后弃上清液,加入DMSO 150μL/孔,振动5min后用酶标仪测定OD值,波长设置为492nm;
计算受试肿瘤细胞的存活率,同时作图并求出IC50值,评价配合物的抗肿瘤活性。结果见表1,
表1本发明制备得到的环金属Pt(II)配合物对HeLa细胞的IC50值
实结果说明随着配合物配体中芳环数量或取代基位阻的增大,毒性增大,其中配合物1b对HeLa细胞毒性最高,是对照组顺铂的10.9倍。
实施例12:双通道荧光监测纳米颗粒在肿瘤细胞中的摄取与定位情况
将生长状态良好的HeLa(人宫颈癌细胞株)用胰酶消化下来,接种于共聚焦培养皿中,用含有5% CO2的培养箱37℃培养,当HeLa细胞的密度培养至70%时,加入配合物1a,最终药物孵育细胞的浓度为20μmol/L,分别继续培养2h、12h、24h、48h,之用PBS洗涤两次,立刻用激光共聚焦显微镜观察。结果见图21,显示配合物1a与HeLa细胞共孵育2h后,可在细胞核中观察到强烈的绿色荧光,红色荧光不太明显并主要定位在细胞质中;当培养时间延长到12h以后时,细胞质中均观察到强烈的绿色与红色荧光,表明配合物1a在12h主要定位在细胞质中。
实施例13:水溶液中阴离子诱导环金属化铂配合物自组装成纳米颗粒
称取0.5mg配合物2a加入二甲基亚砜中配制成20mmol/L的母液,取3μL加入到离心管中,加入27μL的二甲基亚砜,再加BSA水溶液(50g/L)、FBS水溶液(30g/L)、H2O、DMEM培养基、PBS缓冲液(pH7.0-7.4)稀释到20μmol/L,再在各溶液中分别加入ClO4 -,ClO4 -最终浓度为5mmol/L;
结果图22A所示,配合物2a在FBS和BSA溶液中不能形成纳米结构,但当高浓度的ClO4 -存在时,与未添加阴离子的水溶液相比,使用红外光照射该溶液出现了明显的“丁达尔效应”,且在365nm紫外灯照射下发出强烈橙光,DLS测量其平均粒径为615.1±2nm,说明了加入ClO4 -离子可以成功使制备的环金属铂配合物自组装成纳米颗粒。
Claims (7)
1.一类环金属化铂配合物,其特征在于:其结构式如式Ⅰ所示:
式Ⅰ
其中,选自/>
选自/>
当为/>时,/>为/>
当为/>时,/>为/>
当为/>时,/>为/>
当为/>时,/>为/>或/>
2.权利要求1所述的环金属化铂配合物的制备方法,其特征在于,具体步骤如下:
(1)在保护性气氛条件下,将四氯铂酸钾与芳香环类化合物溶解于溶剂A中得到混合溶液A,混合溶液A在温度80-85℃下回流搅拌反应48~54h,析出沉淀,沉淀经洗涤、干燥得到铂桥联前体;
(2)在保护性气氛条件下,将步骤(1)得到的铂联前体与银盐溶解于溶剂B中得到混合溶液B,混合溶液B在室温下搅拌反应脱氯20-24h,固液相分离,液相为中间产物;
(3)在保护性气氛条件下,将步骤(2)得到的中间产物与联吡啶类化合物混合均匀,在温度60-70℃下回流搅拌反应24-36h,析出沉淀,沉淀洗涤干燥制得环金属化铂配合物。
3.根据权利要求2所述的环金属化铂配合物的制备方法,其特征在于:四氯铂酸钾与芳香环类化合物的摩尔比为1:2-2.5,铂桥联前体与银盐的摩尔比为1:2,铂桥联前体与联吡啶类化合物的摩尔比为1:2-2.5。
4.根据权利要求2所述的环金属化铂配合物的制备方法,其特征在于:溶剂A为乙二醇乙醚和超纯水的混合溶剂;溶剂B为乙腈、二氯甲烷、甲醇或N,N-二甲基甲酰胺。
5.权利要求1所述的环金属化铂配合物作为荧光探针在检测阴离子中的应用。
6.权利要求1所述的环金属化铂配合物在制备细胞诊疗成像试剂中的应用。
7.权利要求1所述的环金属化铂配合物在制备抗肿瘤药物中的应用。
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