WO2023134120A1 - 含有aie和acq基团的双吡啶配体及两亲性菱形超分子金属环和应用 - Google Patents

含有aie和acq基团的双吡啶配体及两亲性菱形超分子金属环和应用 Download PDF

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WO2023134120A1
WO2023134120A1 PCT/CN2022/100793 CN2022100793W WO2023134120A1 WO 2023134120 A1 WO2023134120 A1 WO 2023134120A1 CN 2022100793 W CN2022100793 W CN 2022100793W WO 2023134120 A1 WO2023134120 A1 WO 2023134120A1
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compound
aggregation
reaction
acq
aie
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尹守春
范逸錡
李洋
何田
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杭州师范大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • 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
    • 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

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  • the invention belongs to the field of pharmaceutical preparations, and relates to a bipyridine ligand containing AIE and ACQ groups, an amphipathic rhombic supramolecular metal ring and its application.
  • Discrete supramolecular coordination complexes are discrete supramolecular systems self-assembled through coordination interactions between metal centers and organic ligands.
  • organic ligands generally have multiple binding sites, which can be connected to the metal center at a specific angle.
  • various shapes including two-dimensional polygonal metal rings and three-dimensional polyhedral metal cages
  • size-controllable supramolecular assemblies CN112142811A
  • a kind of amphiphilic diamond-shaped supramolecular metal macrocycle and its preparation method and application are the previous research of the inventor.
  • This patent proposes an amphiphilic diamond-shaped supramolecular metal macrocycle, which is formed by self-assembly of directional coordination bonds , modified with glucose groups to increase water solubility and biocompatibility, and then applied in the field of drug carriers, but it is not suitable for bioimaging.
  • the present invention proposes to use a 120° bipyridine ligand containing aggregation-induced emission (AIE) and aggregation fluorescence quenching (ACQ) groups to self-assemble with a 60° hydrophilic chain double platinum receptor to form an amphipathic diamond-shaped supramolecular metal ring , which mainly includes: (1) modifying the double platinum receptor with a hydrophilic chain, so that the diamond-shaped supramolecular metallocycle of the present invention has good water solubility; (2) introducing a fluorescent group into the bipyridine ligand, making the The diamond-shaped supramolecular metallocycle has good photophysical properties; (3) It can be used in the field of biological imaging.
  • AIE aggregation-induced emission
  • ACQ aggregation fluorescence quenching
  • the first purpose of the present invention is to provide a 120° bispyridine ligand containing aggregation-induced emission (AIE) and aggregation fluorescence quenching (ACQ) groups for the deficiencies of the prior art.
  • AIE aggregation-induced emission
  • ACQ aggregation fluorescence quenching
  • the 120 ° bispyridine ligand containing aggregation-induced emission (AIE) and aggregation fluorescence quenching (ACQ) groups the chemical structural formula is as follows:
  • R1 group is one of
  • the second object of the present invention is to provide the above-mentioned 120° synthetic method containing bipyridine ligands of aggregation-induced emission (AIE) and aggregation fluorescence quenching (ACQ) groups; its synthetic route is:
  • the ratio of compound 4, compound 5, potassium carbonate, and tetrakis(triphenylphosphine) palladium is 1:0.3 ⁇ 0.6:1.8:0.004;
  • the ratio of compound 6 and iodine monochloride is 1:8-10;
  • the catalyst adopts one or more of tetrakis(triphenylphosphine) palladium, palladium acetate, triphenylphosphine, cuprous iodide;
  • the pyridine compound adopts one or more of pyridine-4-boronic acid, 4-vinylpyridine, and 4-ethynylpyridine hydrochloride;
  • the acid-binding agent adopts one or both of potassium carbonate and triethylamine
  • the post-treatment method is: the reactant is extracted with dichloromethane and water, the organic phase is collected, dried and filtered to obtain the crude product, and then the volume ratio of sherwood oil and ethyl acetate is 6 : The mixture of 1 was used as the eluent, and compound 6 was obtained by separation and purification on a silica gel chromatography column.
  • the post-treatment method is: the reactant is extracted with dichloromethane and water, the organic phase is collected, dried and filtered to obtain the crude product, and then the volume ratio of sherwood oil/ethyl acetate is 20 : The mixed solution of 1 was used as the eluent, and compound 7 was obtained by separation and purification on a silica gel chromatography column.
  • the post-treatment method is: the reactant is extracted with dichloromethane and water, the organic phase is collected, dried and filtered to obtain the crude product, and then the dichloromethane/methanol volume ratio is 30: The mixed solution of 1 was used as the eluent, and the bispyridine ligand was obtained by separation and purification on a silica gel column.
  • the third object of the present invention is to provide a 60 ° hydrophilic chain double platinum acceptor, its chemical structural formula is as follows:
  • the 4th object of the present invention is to provide a kind of synthetic method of 60 ° hydrophilic chain double platinum acceptor, and its synthetic route is:
  • the ratio of compound 8, compound 9, and potassium carbonate is 1:2 to 3:5;
  • the ratio of compound 10 and tetrakis(triethylphosphine)platinum is 1:0.2 ⁇ 0.4;
  • the ratio of compound 13 and silver trifluoromethanesulfonate is 1:6-10.
  • the post-treatment method is: the reactant is extracted with dichloromethane and water, the organic phase is collected, dried and filtered to obtain the crude product, and then the dichloromethane/methanol volume ratio is 20: The mixture of 1 was used as the eluent, and compound 10 was obtained by separation and purification through silica gel chromatography.
  • the post-treatment method is: the reactant is extracted with dichloromethane and water, the organic phase is collected, dried and filtered to obtain the crude product, and then the dichloromethane/methanol volume ratio is 30: The mixture of 1 was used as the eluent, and compound 11 was obtained by separation and purification through silica gel chromatography.
  • the post-treatment method is as follows: the reaction solution is filtered and then concentrated by a nitrogen flow to obtain a 60° hydrophilic chain double platinum acceptor 2 .
  • the fifth object of the present invention is to provide a 120° amphiphilic rhombic supramolecular metal ring containing aggregation-induced emission (AIE) and aggregation fluorescence quenching (ACQ) groups.
  • AIE aggregation-induced emission
  • ACQ aggregation fluorescence quenching
  • R2 group is one of
  • the 6th object of the present invention is to provide the synthetic method of the amphiphilic diamond-shaped supramolecular metallocycle that contains aggregation-induced emission (AIE) and aggregation fluorescence quenching (ACQ) groups at 120 °, and its synthetic route is:
  • the alcoholic solvent is anhydrous methanol
  • the reaction temperature is 40-60°C, and the reaction time is 10-15 hours;
  • the amount ratio of the bispyridine ligand 1 and the bisplatinum receptor 2 is 1:1.
  • the post-treatment method is: filtering and concentrating to obtain a crude product.
  • the crude product was dissolved in 1 mL of anhydrous dichloromethane, and then 7 mL of anhydrous diethyl ether was added to mix well, and then a solid precipitated out, which was separated by centrifugation and dried to obtain the amphiphilic diamond-shaped supramolecular metallocycle 3.
  • the seventh object of the present invention is to provide a 120° amphiphilic diamond-shaped supramolecular metal ring containing aggregation-induced emission (AIE) and aggregation fluorescence quenching (ACQ) groups as a fluorescent dye for biological imaging.
  • AIE aggregation-induced emission
  • ACQ aggregation fluorescence quenching
  • the invention integrates multiple fluorophores with different luminescence properties into a single molecule scaffold, and obtains coordinated fluorescence emission.
  • the invention provides the application of the amphiphilic diamond-shaped supramolecular metal ring as a fluorescent dye.
  • the amphiphilic rhombic supramolecular metal ring has good biocompatibility and coordinated fluorescence emission, and its own properties can support the realization of convenient cell imaging without resorting to commercially available carriers.
  • the metal rings of the present invention can all be taken up by cells, and 3b can realize the clearest cell imaging effect.
  • Fig. 1 is the proton nuclear magnetic resonance spectrogram of compound 6 synthesized in the embodiment one (deuterated dimethyl sulfoxide is solvent);
  • Fig. 2 is the carbon nuclear magnetic resonance spectrogram of compound 6 synthesized in embodiment one (deuterated dimethyl sulfoxide is solvent);
  • Fig. 3 is the high-resolution mass spectrogram of compound 6 synthesized in embodiment one;
  • Fig. 4 is the proton nuclear magnetic resonance spectrogram of the compound 7 synthesized in embodiment one (deuterated dimethyl sulfoxide is solvent);
  • Fig. 5 is the carbon nuclear magnetic resonance spectrogram of compound 7 synthesized in the embodiment 1 (deuterated dimethyl sulfoxide is solvent);
  • Fig. 6 is the high-resolution mass spectrogram of the compound 7 synthesized in the embodiment one;
  • Fig. 7 is the proton nuclear magnetic resonance spectrogram of the compound 1a synthesized in the embodiment one (deuterated chloroform is solvent);
  • Fig. 8 is the carbon nuclear magnetic resonance spectrogram of the compound 1a synthesized in the embodiment one (deuterated chloroform is solvent);
  • Fig. 9 is the high-resolution mass spectrogram of compound 1a synthesized in embodiment one;
  • Fig. 10 is the proton nuclear magnetic resonance spectrogram of compound 1b synthesized in the embodiment one (deuterated chloroform is solvent);
  • Fig. 11 is the carbon nuclear magnetic resonance spectrogram of the compound 1b synthesized in the embodiment 1 (deuterated chloroform is solvent);
  • Fig. 12 is the high-resolution mass spectrogram of compound 1b synthesized in Example 1;
  • Figure 13 is the proton nuclear magnetic resonance spectrogram of the compound 1c synthesized in Example 1 (deuterated chloroform is a solvent);
  • Figure 14 is the carbon nuclear magnetic resonance spectrogram of the compound 1c synthesized in Example 1 (deuterated chloroform is a solvent);
  • Fig. 15 is the high-resolution mass spectrogram of the compound 1c synthesized in Example 1;
  • Fig. 16 is the proton nuclear magnetic resonance spectrogram of compound 10 synthesized in the embodiment two (deuterated chloroform is solvent);
  • Fig. 17 is the carbon nuclear magnetic resonance spectrogram of the compound 10 synthesized in the embodiment two (deuterated chloroform is solvent);
  • Fig. 18 is the high-resolution mass spectrogram of the compound 10 synthesized in the embodiment two;
  • Fig. 19 is the proton nuclear magnetic resonance spectrogram of the compound 11 synthesized in the embodiment two (deuterated chloroform is solvent);
  • Fig. 20 is the carbon nuclear magnetic resonance spectrogram of the compound 11 synthesized in the embodiment two (deuterated chloroform is solvent);
  • Fig. 21 is the high-resolution mass spectrogram of compound 11 synthesized in Example 2.
  • Fig. 22 is the proton nuclear magnetic resonance spectrogram of compound 2 synthesized in embodiment two (deuterated chloroform is solvent);
  • Fig. 23 is the carbon nuclear magnetic resonance spectrogram of the compound 2 synthesized in the embodiment two (deuterated chloroform is solvent);
  • Fig. 24 is the nuclear magnetic resonance phosphorus spectrogram of the compound 2 synthesized in the embodiment two (deuterated chloroform is solvent);
  • Fig. 25 is the high-resolution mass spectrogram of compound 2 synthesized in embodiment two;
  • Fig. 26 is the proton nuclear magnetic resonance spectrogram of the metal ring 3a synthesized in the embodiment three (deuterated dichloride is a solvent);
  • Fig. 27 is the nuclear magnetic resonance phosphorus spectrogram of the metallocycle 3a synthesized in the embodiment three (deuterated dichloride is a solvent);
  • Figure 28 is the time-of-flight mass spectrogram of the metal ring 3a synthesized in Example 3;
  • Figure 29 is the proton nuclear magnetic resonance spectrogram of the metallocycle 3b synthesized in Example 3 (deuterated dichloride is the solvent);
  • Fig. 30 is the nuclear magnetic resonance phosphorus spectrogram of the metallocycle 3b synthesized in the embodiment three (deuterated dichloride is a solvent);
  • Figure 31 is the time-of-flight mass spectrogram of the metal ring 3b synthesized in Example 3;
  • Figure 32 is the proton nuclear magnetic resonance spectrogram of the metallocycle 3c synthesized in Example 3 (deuterated dichloride is the solvent);
  • Figure 33 is the nuclear magnetic resonance phosphorus spectrum of the metallocycle 3c synthesized in Example 3 (deuterated dichloride is the solvent);
  • Figure 34 is the time-of-flight mass spectrogram of the metal ring 3c synthesized in Example 3;
  • Fig. 35 is a confocal fluorescence imaging image of the metal ring (the cells are CT26 cells).
  • the inventor of this case proposed the technical solution of the present invention after long-term research and extensive practice, which is mainly based on at least including: (1) combining aggregation-induced emission (AIE) and aggregation fluorescence Quenching (ACQ) groups are integrated into a single-molecule scaffold, and single-molecule coordinated fluorescence emission is obtained; (2) discrete supramolecular ligands self-assembled through coordination interactions between metal centers and organic ligands Coordination complexes, supramolecular coordination complexes as a functional platform, can achieve single-molecule coordinated fluorescence emission through rational molecular design, and apply it in biological imaging.
  • AIE aggregation-induced emission
  • ACQ aggregation fluorescence Quenching
  • the 120 ° bispyridine ligand containing aggregation-induced emission (AIE) and aggregation fluorescence quenching (ACQ) group of the present invention its synthetic route is:
  • the ratio of compound 4, compound 5, potassium carbonate, and tetrakis(triphenylphosphine) palladium is 1:0.3 ⁇ 0.6:1.8:0.004;
  • the ratio of compound 6 and iodine monochloride is 1:8-10;
  • the catalyst adopts one or more of tetrakis(triphenylphosphine) palladium, palladium acetate, triphenylphosphine, cuprous iodide;
  • the pyridine compound adopts one or more of pyridine-4-boronic acid, 4-vinylpyridine, and 4-ethynylpyridine hydrochloride;
  • the acid-binding agent adopts one or both of potassium carbonate and triethylamine
  • a kind of 60 ° hydrophilic chain double platinum acceptor of the present invention, its synthetic route is:
  • the ratio of compound 8, compound 9, and potassium carbonate is 1:2 to 3:5;
  • the ratio of compound 10 and tetrakis(triethylphosphine)platinum is 1:0.2 ⁇ 0.4;
  • the ratio of compound 13 and silver trifluoromethanesulfonate is 1:6-10.
  • amphiphilic diamond-shaped supramolecular metallocycle containing aggregation-induced emission (AIE) and aggregation fluorescence quenching (ACQ) groups at 120° of the present invention has a synthetic route as follows:
  • the alcoholic solvent is anhydrous methanol
  • the reaction temperature is 40-60°C, and the reaction time is 10-15 hours;
  • the amount ratio of the bispyridine ligand 1 and the bisplatinum receptor 2 is 1:1.
  • Example 1-1 Bispyridine ligand 1a
  • Step (3) preparation of 60 ° hydrophilic chain double platinum receptor 2:
  • Example 3-1 Preparation of amphiphilic diamond-shaped supramolecular metallocycle 3a:
  • Example 3-2 Preparation of amphiphilic diamond-shaped supramolecular metallocycle 3b:
  • Example 4-1 Cell imaging of the amphiphilic diamond-shaped supramolecular metallocycle 3a:
  • CT26 cells were seeded in 24-well plates and cultured for 12 hours. A DMEM solution of metalloid 3a was added and incubated for 24 hours. Add DiO (green fluorescent probe for cell membrane) and incubate for about 20 minutes. After washing with PBS, observe with confocal laser scanning microscope (CLSM).
  • CLSM confocal laser scanning microscope
  • Example 4-2 Cell imaging of the amphiphilic diamond-shaped supramolecular metallocycle 3b:
  • CT26 cells were seeded in 24-well plates and cultured for 12 hours. A DMEM solution of metalloid 3b was added and incubated for 24 hours. Add DiO and incubate for about 20 minutes. After washing with PBS, observe with CLSM.
  • Example 4-2 Cell imaging of the amphiphilic diamond-shaped supramolecular metallocycle 3c:
  • CT26 cells were seeded in 24-well plates and cultured for 12 hours. A DMEM solution of metal ring 3c was added and incubated for 24 hours. Add DiO and incubate for about 20 minutes. After washing with PBS, observe with CLSM.

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Abstract

本发明公开含有AIE和ACQ基团的双吡啶配体及两亲性菱形超分子金属环和应用。将含有AIE和ACQ基团的双吡啶配体1和双铂受体2溶解在醇类溶剂中，40-60℃加热反应10-15小时；反应结束后，经后处理得到两亲性菱形超分子金属环3。120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的两亲性菱形超分子金属环作为荧光染料在生物成像上的应用。

Description

含有AIE和ACQ基团的双吡啶配体及两亲性菱形超分子金属环和应用 技术领域
本发明属于药物制剂领域，涉及一种含有AIE和ACQ基团的双吡啶配体及两亲性菱形超分子金属环和应用。
背景技术
近年来，具有可协调荧光发射的材料引起了越来越多的关注，在有机可调二极管、生物成像、荧光传感器和光伏电池中都有广泛的应用。这类材料通常有两种设计方法：(1)混合具有不同颜色发射的染料；(2)通过共价键或非共价键连接不同发射的多个荧光团得到单分子染料。与混合染料相比，单分子具有更好的重现性、稳定性以及制造简单等优点。然而，单分子的原位可协调发射仍然具有挑战，因为很难将具有不同染色的多个荧光团集成到一个单分子支架中。此外，根据卡莎规则，更容易得到最低振动态对应的单色发射。
离散型超分子配位络合物是一种通过金属中心与有机配体之间的配位相互作用而自组装得到的离散超分子体系。其中有机配体一般具有多个结合位点，可以和金属中心以特定角度连接，结合对组分计量比的控制，可以得到形貌多变(包括二维的多边形金属环和三维的多面体金属笼)且尺寸可控的超分子组装体。CN112142811A一种两亲性菱形超分子金属大环及其制备方法和应用，是发明人之前的研究，该专利提出一种两亲性菱形超分子金属大环，其通过定向配位键自组装形成，以葡萄糖基团修饰，增加水溶性与生物相容性，进而应用在药物载体领域，但是其并不能适用于生物成像。故本发明提出利用120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的双吡啶配体与60°亲水链双铂受体自组装形成两亲性菱形超分子金属环，其主要是：(1)以亲水链修饰双铂受体，使本发明的菱形超分子金属环具有良好的水溶性；(2)荧光基团引入双吡啶配体中，使本发明的菱形超分子金属环具有良好的光物理性质；(3)应用于生物成像领域。
发明内容
本发明的第一个目的是针对现有技术的不足，提供一种120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的双吡啶配体。
所述120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的双吡啶配体，化学结构式如下：
Figure PCTCN2022100793-appb-000001
其中R1基团为
Figure PCTCN2022100793-appb-000002
中的一种；
本发明的第二个目的是提供上述120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的双吡啶配体的合成方法；其合成路线为：
Figure PCTCN2022100793-appb-000003
所述合成方法为：
(1)将化合物4、化合物5、碳酸钾、四(三苯基膦)钯溶于1,4-二氧六环与水的混合溶剂中，然后用液氮和氮气冻抽三次除氧，在氩气保护下75～80℃加热反应36～48小时；反应结束后，经后处理得到化合物6；
所述化合物4、化合物5、碳酸钾、四(三苯基膦)钯的物质的量之比为1：0.3～0.6：1.8：0.004；
(2)将化合物6溶解于无水二氯甲烷中，然后在常温下将一氯化碘溶液逐滴加入得到紫黑的溶液；滴加 完毕后，在氩气保护下40～50℃加热反应4～6小时，经后处理得到化合物7；
所述化合物6、一氯化碘的物质的量之比为1：8～10；
(3)将化合物7、催化剂、吡啶类化合物、缚酸剂，溶于溶剂中，然后用液氮和氮气冻抽三次除氧，在氩气保护下80～90℃加热反应36～48小时；反应结束后，经后处理得到双吡啶配体；
所述催化剂采用四(三苯基膦)钯、醋酸钯、三苯基膦、碘化亚铜中的一种或多种；
所述吡啶类化合物采用吡啶-4-硼酸、4-乙烯基吡啶、4-乙炔基吡啶盐酸盐中的一种或多种；
所述缚酸剂采用碳酸钾、三乙胺中的一种或两种；
作为优选，步骤(1)中，所述后处理的方法为：反应物用二氯甲烷和水萃取，收集有机相，干燥过滤后得到粗产物，然后以石油醚与乙酸乙酯体积比为6：1的混合液为洗脱剂，通过硅胶层析柱分离纯化得到化合物6。
作为优选，步骤(2)中，所述后处理的方法为：反应物用二氯甲烷和水萃取，收集有机相，干燥过滤后得到粗产物，然后以石油醚/乙酸乙酯体积比为20：1的混合液为洗脱剂，通过硅胶层析柱分离纯化得到化合物7。
作为优选，步骤(3)中，所述后处理的方法为：反应物用二氯甲烷和水萃取，收集有机相，干燥过滤后得到粗产物，然后以二氯甲烷/甲醇体积比为30：1的混合液为洗脱剂，通过硅胶层析柱分离纯化得到双吡啶配体。
本发明的第三个目的是提供一种60°亲水链双铂受体，其化学结构式如下：
Figure PCTCN2022100793-appb-000004
本发明的第四个目的是提供一种60°亲水链双铂受体的合成方法，其合成路线为：
Figure PCTCN2022100793-appb-000005
所述合成方法为：
(1)将化合物8，化合物9，碳酸钾溶解于无水二甲基甲酰胺中，在氩气保护下85～100℃加热反应20～24小时；反应结束后，经后处理得到化合物10；
化合物8、化合物9、碳酸钾的物质的量之比为1：2～3：5；
(2)将化合物10，四(三乙基膦)铂溶解于无水甲苯中，90～100℃加热反应65～72小时；反应结束后，经后处理得到化合物11；
化合物10、四(三乙基膦)铂的物质的量之比为1：0.2～0.4；
(3)将化合物11、三氟甲烷磺酸银用无水二氯甲烷溶解，室温且避光反应过夜，经后处理得到60°亲水链双铂受体；
化合物13、三氟甲烷磺酸银的物质的量之比为1：6～10。
作为优选，步骤(1)中，所述后处理的方法为：反应物用二氯甲烷和水萃取，收集有机相，干燥过滤后得到粗产物，然后以二氯甲烷/甲醇体积比为20：1的混合液为洗脱剂，通过硅胶层析柱分离纯化得到化合物10。
作为优选，步骤(2)中，所述后处理的方法为：反应物用二氯甲烷和水萃取，收集有机相，干燥过滤后得到粗产物，然后以二氯甲烷/甲醇体积比为30：1的混合液为洗脱剂，通过硅胶层析柱分离纯化得到化合物11。
作为优选，步骤(3)中，所述后处理的方法为：将反应液过滤后通过氮气流浓缩，得到60°亲水链双铂受体2。
本发明的第五个目的是提供一种120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的两亲性菱形超分子金属环。
Figure PCTCN2022100793-appb-000006
其中R2基团为
Figure PCTCN2022100793-appb-000007
中的一种；
本发明的第六个目的是提供120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的两亲性菱形超分子金属环的合成方法，其合成路线为：
Figure PCTCN2022100793-appb-000008
所述合成方法为：
将双吡啶配体1和双铂受体2溶解在醇类溶剂中进行自组装反应；反应结束后，经后处理得到两亲性菱形超分子金属环3；
作为优选，所述醇类溶剂为无水甲醇；
作为优选，反应温度为40-60℃，反应时间为10-15小时；
作为优选，双吡啶配体1、双铂受体2的物质的量之比为1：1。
作为优选，所述后处理的方法为：过滤浓缩得到粗产物。将粗产物溶解在1mL无水二氯甲烷中，再加入7mL无水乙醚混合均匀之后有固体沉淀析出，离心分离，干燥后得到两亲性菱形超分子金属环3。
本发明的第七个目的是提供120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的两亲性菱形超分子金属环作为荧光染料在生物成像上的应用。
本发明的有益效果是：
本发明将具有不同发光性质的多个荧光团集成到一个单分子支架中，并获得可协调荧光发射。
本发明提供以两亲性菱形超分子金属环作为荧光染料的应用。所述两亲性菱形超分子金属环具有良好的生物相容性与可协调荧光发射，无需借助商售载体，自身性质即可支持实现方便的细胞成像。
本发明所述金属环，均能被细胞摄取，其中3b能够实现最为清晰的细胞成像效果。
附图说明
图1为实施例一中合成的化合物6的核磁共振氢谱谱图(氘代二甲基亚砜为溶剂)；
图2为实施例一中合成的化合物6的核磁共振碳谱谱图(氘代二甲基亚砜为溶剂)；
图3为实施例一中合成的化合物6的高分辨质谱谱图；
图4为实施例一中合成的化合物7的核磁共振氢谱谱图(氘代二甲基亚砜为溶剂)；
图5为实施例一中合成的化合物7的核磁共振碳谱谱图(氘代二甲基亚砜为溶剂)；
图6为实施例一中合成的化合物7的高分辨质谱谱图；
图7为实施例一中合成的化合物1a的核磁共振氢谱谱图(氘代氯仿为溶剂)；
图8为实施例一中合成的化合物1a的核磁共振碳谱谱图(氘代氯仿为溶剂)；
图9为实施例一中合成的化合物1a的高分辨质谱谱图；
图10为实施例一中合成的化合物1b的核磁共振氢谱谱图(氘代氯仿为溶剂)；
图11为实施例一中合成的化合物1b的核磁共振碳谱谱图(氘代氯仿为溶剂)；
图12为实施例一中合成的化合物1b的高分辨质谱谱图；
图13为实施例一中合成的化合物1c的核磁共振氢谱谱图(氘代氯仿为溶剂)；
图14为实施例一中合成的化合物1c的核磁共振碳谱谱图(氘代氯仿为溶剂)；
图15为实施例一中合成的化合物1c的高分辨质谱谱图；
图16为实施例二中合成的化合物10的核磁共振氢谱谱图(氘代氯仿为溶剂)；
图17为实施例二中合成的化合物10的核磁共振碳谱谱图(氘代氯仿为溶剂)；
图18为实施例二中合成的化合物10的高分辨质谱谱图；
图19为实施例二中合成的化合物11的核磁共振氢谱谱图(氘代氯仿为溶剂)；
图20为实施例二中合成的化合物11的核磁共振碳谱谱图(氘代氯仿为溶剂)；
图21为实施例二中合成的化合物11的高分辨质谱谱图；
图22为实施例二中合成的化合物2的核磁共振氢谱谱图(氘代氯仿为溶剂)；
图23为实施例二中合成的化合物2的核磁共振碳谱谱图(氘代氯仿为溶剂)；
图24为实施例二中合成的化合物2的核磁共振磷谱谱图(氘代氯仿为溶剂)；
图25为实施例二中合成的化合物2的高分辨质谱谱图；
图26为实施例三中合成的金属环3a的核磁共振氢谱谱图(氘代二氯为溶剂)；
图27为实施例三中合成的金属环3a的核磁共振磷谱谱图(氘代二氯为溶剂)；
图28为实施例三中合成的金属环3a的飞行时间质谱图；
图29为实施例三中合成的金属环3b的核磁共振氢谱谱图(氘代二氯为溶剂)；
图30为实施例三中合成的金属环3b的核磁共振磷谱谱图(氘代二氯为溶剂)；
图31为实施例三中合成的金属环3b的飞行时间质谱图；
图32为实施例三中合成的金属环3c的核磁共振氢谱谱图(氘代二氯为溶剂)；
图33为实施例三中合成的金属环3c的核磁共振磷谱谱图(氘代二氯为溶剂)；
图34为实施例三中合成的金属环3c的飞行时间质谱图；
图35为所述金属环的共聚焦荧光成像图(细胞为CT26细胞)。
具体实施方式
如前所述，鉴于现有技术的不足，本案发明人经长期研究和大量实践，提出了本发明的技术方案，其主要是依据至少包括：(1)将聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团集成到一个单分子支架中，并获得单分子可协调荧光发射；(2)通过金属中心与有机配体之间的配位相互作用而自组装得到的离散超分子配位络合物，以超分子配位络合物作为功能平台，通过合理的分子设计可以实现单分子可协调荧光发射，并将其应用于生物成像中。
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。此外，下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
本发明120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的双吡啶配体，其合成路线为：
Figure PCTCN2022100793-appb-000009
(1)将化合物4、化合物5、碳酸钾、四(三苯基膦)钯溶于1,4-二氧六环与水的混合溶剂中，然后用液氮和氮气冻抽三次除氧，在氩气保护下75～80℃加热反应36～48小时；反应结束后，经后处理得到化合物 6；
所述化合物4、化合物5、碳酸钾、四(三苯基膦)钯的物质的量之比为1：0.3～0.6：1.8：0.004；
(2)将化合物6溶解于无水二氯甲烷中，然后在常温下将一氯化碘溶液逐滴加入得到紫黑的溶液；滴加完毕后，在氩气保护下40～50℃加热反应4～6小时，经后处理得到化合物7；
所述化合物6、一氯化碘的物质的量之比为1：8～10；
(3)将化合物7、催化剂、吡啶类化合物、缚酸剂，溶于溶剂中，然后用液氮和氮气冻抽三次除氧，在氩气保护下80～90℃加热反应36～48小时；反应结束后，经后处理得到双吡啶配体；
所述催化剂采用四(三苯基膦)钯、醋酸钯、三苯基膦、碘化亚铜中的一种或多种；
所述吡啶类化合物采用吡啶-4-硼酸、4-乙烯基吡啶、4-乙炔基吡啶盐酸盐中的一种或多种；
所述缚酸剂采用碳酸钾、三乙胺中的一种或两种；
本发明一种60°亲水链双铂受体，其合成路线为：
Figure PCTCN2022100793-appb-000010
其合成方法为：
(1)将化合物8，化合物9，碳酸钾溶解于无水二甲基甲酰胺中，在氩气保护下85～100℃加热反应20～24小时；反应结束后，经后处理得到化合物10；
化合物8、化合物9、碳酸钾的物质的量之比为1：2～3：5；
(2)将化合物10，四(三乙基膦)铂溶解于无水甲苯中，90～100℃加热反应65～72小时；反应结束后，经后处理得到化合物11；
化合物10、四(三乙基膦)铂的物质的量之比为1：0.2～0.4；
(3)将化合物11、三氟甲烷磺酸银用无水二氯甲烷溶解，室温且避光反应过夜，经后处理得到60°亲水链双铂受体；
化合物13、三氟甲烷磺酸银的物质的量之比为1：6～10。
本发明120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的两亲性菱形超分子金属环，其合成路线为：
Figure PCTCN2022100793-appb-000011
将双吡啶配体1和双铂受体2溶解在醇类溶剂中进行自组装反应；反应结束后，经后处理得到两亲性菱形超分子金属环3；
作为优选，所述醇类溶剂为无水甲醇；
作为优选，反应温度为40-60℃，反应时间为10-15小时；
作为优选，双吡啶配体1、双铂受体2的物质的量之比为1：1。
以下结合若干较佳实施例对本发明的技术方案作进一步的解释说明，但其中的实验条件和设定参数不应视为对本发明基本技术方案的局限。并且本发明的保护范围不限于下述的实施例。
实施例一、制备120°含有聚集诱导发光(AIE)和聚集荧光猝灭(ACQ)基团的双吡啶配体
实施例1-1：双吡啶配体1a
Figure PCTCN2022100793-appb-000012
步骤(1)、化合物6的制备：
将化合物4(1000.0mg,5.61mmol)，化合物5(1139.8mg,3.03mmol)，碳酸钾(1396.0mg,10.10mmol)，四(三苯基膦)钯(26.4mg,0.02mmol)添加到250mL的舒伦克瓶中，加入混合溶剂(1,4-二氧六环/水,4/1,v/v)溶解，然后用液氮和氮气冻抽三次除氧，在氩气保护下80℃加热反应48小时。反应结束后，冷却到室温，用旋转蒸发仪减压浓缩，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤后得到粗产物，通过硅胶层析柱分离纯化(石油醚/乙酸乙酯，6/1，v/v)，最终得到黄色固体(705.0mg,43.4％)，熔点：247.7-250.1℃。
图1-3所示： 1H NMR(500MHz,CD 3SOCD 3,298K)δ(ppm):7.61(q,J＝8.6Hz,4H),7.49(d,J＝8.3Hz,2H),7.41(d,J＝8.5Hz,2H),7.19–7.10(m,9H),7.04(t,J＝8.2Hz,6H),7.01–6.97(m,2H),6.66(d,J＝8.5Hz,2H),5.27(s,2H). 13C NMR(125MHz,CD 3SOCD 3,298K)δ(ppm):149.0,143.7,143.7,142.5,141.2,140.6,140.1,138.1,136.7,131.8,131.2,131.2,128.4,128.3,128.3,127.5,127.1,127.1,127.0,126.1,126.0,114.7.ESI-HRMS[6+H] +:calcd.for[C 38H 30N] +500.2373,found 500.2391.
步骤(2)、化合物7的制备：
将化合物6(500.0mg,1.00mmol)溶解于无水二氯甲烷(100mL)中，加入到配有恒压滴液漏斗和冷凝回流管的三颈烧瓶中，然后在常温下用恒压滴液漏斗将一氯化碘溶液(1mol/L in CH 2Cl 2)逐滴加入得到紫黑的溶液。滴加完毕后，在氩气保护下40℃加热反应6小时。待到反应结束后冷却，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤后得到粗产物，通过硅胶层析柱分离纯化(石油醚/乙酸乙酯，20/1，v/v)，最终得到白色固体(100.0mg,20.8％)，熔点：181.2-183.8℃。
图4-6所示： 1H NMR(500MHz,CD 3SOCD 3,298K)δ(ppm):7.98(s,2H),7.56(d,J＝68.4Hz,6H),7.23–6.93(m,17H),5.23(s,2H). 13C NMR(125MHz,CD 3SOCD 3,298K)δ(ppm):147.1,143.6,142.8,141.2,140.6,138.2,137.7,137.3,136.7,132.2,131.8,131.2,131.1,128.4,128.4,128.3,127.3,127.2,127.1,126.7,126.1,82.8.ESI-HRMS[7+K] +:calcd.for[C 38H 28I 2NK] +789.9864,found 789.4427.
步骤(3)、双吡啶配体1a的制备：
将化合物7(100.0mg,0.13mmol)，吡啶-4-硼酸(81.9mg,0.67mmol)，碳酸钾(183.0mg,1.33mmol)，四(三苯基膦)钯(15.3mg,0.01mmol)添加到100mL的舒伦克瓶中，加入混合溶剂(1,4-二氧六环/水,4/1,v/v)溶解，然后用液氮和氮气冻抽三次除氧，在氩气保护下80℃加热反应48小时。反应结束后，冷却到室温，用旋转蒸发仪减压浓缩，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤得到粗产物，通过硅胶层析柱分离纯化(二氯甲烷/甲醇，30/1，v/v)，最终得到白色固体(30.0mg,30.9％)，熔点：173.7-176.1℃。
图7-9所示： 1H NMR(500MHz,CDCl 3,298K)δ(ppm):8.75(s,4H),7.61(d,J＝8.6Hz,4H),7.52(s,4H),7.45(s,2H),7.38(d,J＝8.3Hz,2H),7.15–7.03(m,17H),3.95(s,2H). 13C NMR(125MHz,CDCl 3,298K)δ(ppm):150.7,147.3,143.8,143.7,143.7,142.9,141.2,140.5,139.7,139.2,138.6,138.2,131.9,131.4,131.4,128.9,127.8,127.7,127.7,127.3,126.6,126.5,126.0,125.8.ESI-HRMS[1a+K] +:calcd.for[C 48H 36N 3] +654.2904,found 654.2981.
实施例1-2：双吡啶配体1b
Figure PCTCN2022100793-appb-000013
步骤(1)、化合物6的制备：
将化合物4(1000.0mg,5.61mmol)，化合物5(1139.8mg,3.03mmol)，碳酸钾(1396.0mg,10.10mmol)，四(三苯基膦)钯(26.4mg,0.02mmol)添加到250mL的舒伦克瓶中，加入混合溶剂(1,4-二氧六环/水,4/1,v/v)溶解，然后用液氮和氮气冻抽三次除氧，在氩气保护下80℃加热反应48小时。反应结束后，冷却到室温，用旋转蒸发仪减压浓缩，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤后得到粗产物，通过硅胶层析柱分离纯化(石油醚/乙酸乙酯，6/1，v/v)，最终得到黄色固体(705.0mg,43.4％)，熔点：247.7-250.1℃。
图1-3所示： 1H NMR(500MHz,CD 3SOCD 3,298K)δ(ppm):7.61(q,J＝8.6Hz,4H),7.49(d,J＝8.3Hz,2H),7.41(d,J＝8.5Hz,2H),7.19–7.10(m,9H),7.04(t,J＝8.2Hz,6H),7.01–6.97(m,2H),6.66(d,J＝8.5Hz,2H),5.27(s,2H). 13C NMR(125MHz,CD 3SOCD 3,298K)δ(ppm):149.0,143.7,143.7,142.5,141.2,140.6,140.1,138.1,136.7,131.8,131.2,131.2,128.4,128.3,128.3,127.5,127.1,127.1,127.0,126.1,126.0,114.7.ESI-HRMS[6+H] +:calcd.for[C 38H 30N] +500.2373,found 500.2391.
步骤(2)、化合物7的制备：
将化合物6(500.0mg,1.00mmol)溶解于无水二氯甲烷(100mL)中，加入到配有恒压滴液漏斗和冷凝回流管的三颈烧瓶中，然后在常温下用恒压滴液漏斗将一氯化碘溶液(1mol/L in CH 2Cl 2)逐滴加入得到紫黑的溶液。滴加完毕后，在氩气保护下40℃加热反应6小时。待到反应结束后冷却，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤后得到粗产物，通过硅胶层析柱分离纯化(石油醚/乙酸乙酯，20/1，v/v)，最终得到白色固体(100.0mg,20.8％)，熔点：181.2-183.8℃。
图4-6所示： 1H NMR(500MHz,CD 3SOCD 3,298K)δ(ppm):7.98(s,2H),7.56(d,J＝68.4Hz,6H),7.23–6.93(m,17H),5.23(s,2H). 13C NMR(125MHz,CD 3SOCD 3,298K)δ(ppm):147.1,143.6,142.8,141.2,140.6,138.2,137.7,137.3,136.7,132.2,131.8,131.2,131.1,128.4,128.4,128.3,127.3,127.2,127.1,126.7,126.1,82.8.ESI-HRMS[7+K] +:calcd.for[C 38H 28I 2NK] +789.9864,found 789.4427.
步骤(3)、双吡啶配体1b的制备：
将化合物7(100.0mg,0.13mmol)，4-乙烯基吡啶(54.9mg,0.52mmol)，三乙胺(5mL)，醋酸钯(2.2mg,0.01mmol)和三苯基膦(10.5mg,0.04mmol)添加到100mL的舒伦克瓶中，加入无水二甲基甲酰胺溶解，然后用液氮和氮气冻抽三次除氧，在氩气保护下100℃加热反应48小时。反应结束后，冷却到室温，用旋转蒸发仪减压浓缩，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤得到粗产物，通过硅胶层析柱分离纯化(二氯甲烷/甲醇，30/1，v/v)，最终得到橘黄色固体(23.0mg,23.0％)，熔点：147.3-149.9℃。
图10-12所示： 1H NMR(500MHz,CDCl 3,298K)δ(ppm):8.61(s,4H),7.65(d,J＝8.7Hz,6H),7.43(m,J＝19.3,11.1Hz,8H),7.18–6.93(m,19H),4.20(s,2H). 13C NMR(125MHz,CDCl 3,298K)δ(ppm):150.3,144.5,143.7,143.7,142.9,141.9,141.2,140.5,139.2,139.1,138.2,131.9,131.4,131.4,131.3,129.0,128.6,127.8,127.7,127.6,127.2,126.8,126.6,126.5,126.0,124.0,120.9.ESI-HRMS[1b+H] +:calcd.for[C 52H 40N 3] +706.3217,found 706.3317.
实施例1-3：双吡啶配体1c
Figure PCTCN2022100793-appb-000014
步骤(1)、化合物6的制备：
将化合物4(1000.0mg,5.61mmol)，化合物5(1139.8mg,3.03mmol)，碳酸钾(1396.0mg,10.10mmol)，四(三苯基膦)钯(26.4mg,0.02mmol)添加到250mL的舒伦克瓶中，加入混合溶剂(1,4-二氧六环/水,4/1,v/v)溶解，然后用液氮和氮气冻抽三次除氧，在氩气保护下80℃加热反应48小时。反应结束后，冷却到室温，用旋转蒸发仪减压浓缩，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤后得到粗产物，通过硅胶层析柱分离纯化(石油醚/乙酸乙酯，6/1，v/v)，最终得到黄色固体(705.0mg,43.4％)，熔点：247.7-250.1℃。
图1-3所示： 1H NMR(500MHz,CD 3SOCD 3,298K)δ(ppm):7.61(q,J＝8.6Hz,4H),7.49(d,J＝8.3Hz,2H),7.41(d,J＝8.5Hz,2H),7.19–7.10(m,9H),7.04(t,J＝8.2Hz,6H),7.01–6.97(m,2H),6.66(d,J＝8.5Hz,2H),5.27(s,2H). 13C NMR(125MHz,CD 3SOCD 3,298K)δ (ppm):149.0,143.7,143.7,142.5,141.2,140.6,140.1,138.1,136.7,131.8,131.2,131.2,128.4,128.3,128.3,127.5,127.1,127.1,127.0,126.1,126.0,114.7.ESI-HRMS[6+H] +:calcd.for[C 38H 30N] +500.2373,found 500.2391.
步骤(2)、化合物7的制备：
将化合物6(500.0mg,1.00mmol)溶解于无水二氯甲烷(100mL)中，加入到配有恒压滴液漏斗和冷凝回流管的三颈烧瓶中，然后在常温下用恒压滴液漏斗将一氯化碘溶液(1mol/L in CH 2Cl 2)逐滴加入得到紫黑的溶液。滴加完毕后，在氩气保护下40℃加热反应6小时。待到反应结束后冷却，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤后得到粗产物，通过硅胶层析柱分离纯化(石油醚/乙酸乙酯，20/1，v/v)，最终得到白色固体(100.0mg,20.8％)，熔点：181.2-183.8℃。
图4-6所示： 1H NMR(500MHz,CD 3SOCD 3,298K)δ(ppm):7.98(s,2H),7.56(d,J＝68.4Hz,6H),7.23–6.93(m,17H),5.23(s,2H). 13C NMR(125MHz,CD 3SOCD 3,298K)δ(ppm):147.1,143.6,142.8,141.2,140.6,138.2,137.7,137.3,136.7,132.2,131.8,131.2,131.1,128.4,128.4,128.3,127.3,127.2,127.1,126.7,126.1,82.8.ESI-HRMS[7+K] +:calcd.for[C 38H 28I 2NK] +789.9864,found 789.4427.
步骤(3)、双吡啶配体1c的制备：
将化合物7(100.0mg,0.13mmol)，4-乙炔基吡啶盐酸盐(53.6mg,0.52mmol)，碘化亚铜(1.9mg,0.01mmol)，三乙胺(5mL)和四(三苯基膦)钯(15.3mg,0.01mmol)添加到100mL的舒伦克瓶中，加入无水四氢呋喃溶解，然后用液氮和氮气冻抽三次除氧，在氩气保护下60℃加热反应48小时。反应结束后，冷却到室温，用旋转蒸发仪减压浓缩，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤得到粗产物，通过硅胶层析柱分离纯化(二氯甲烷/甲醇，30/1，v/v)，最终得到淡黄色固体(20.0mg,20.0％)，熔点：153.6-155.4℃。
图13-15所示： 1H NMR(500MHz,CDCl 3,298K)δ(ppm):8.65(s,4H),7.72(d,J＝3.8Hz,2H),7.60(dd,J＝18.7,8.6Hz,4H),7.41(dd,J＝8.4,6.7Hz,6H),7.16–7.00(m,17H),4.99(s,2H). 13C NMR(125MHz,CDCl 3,298K)δ(ppm):149.9,148.6,143.8,143.7,143.0,141.2,140.5,139.4,138.2,138.0,132.7,132.1,131.9,131.4,131.4,131.0,130.4,127.9,127.8,127.7,127.7,127.3,126.5,126.0,125.4,107.1,92.7,89.8.ESI-HRMS[1c+H] +:calcd.for[C 52H 36N 3] +702.2904,found 702.4691.
实施例二：60°亲水链双铂受体2的制备
步骤(1)、化合物10的制备：
将化合物8(500.0mg,1.36mmol)，化合物9(1305.1mg,2.99mmol)，碳酸钾(938.4mg,6.80mmol)加入到250mL的圆底烧瓶，然后加入100mL无水二甲基甲酰胺溶解，在氩气保护下85℃加热反应24小时。反应结束后，冷却到室温，用旋转蒸发仪减压浓缩，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤得到粗产物，通过硅胶层析柱分离纯化(二氯甲烷/甲醇，20/1，v/v)，最终得到黄色油状液体(961.3mg,57.6％)。
图16-18所示： 1H NMR(500MHz,CDCl 3,298K):δ(ppm):8.54(d,J＝1.6Hz,1H),8.14(d,J＝8.8Hz,1H),7.62(m,J＝8.8,1.7Hz,1H),4.35–4.24(m,2H),3.76(m,J＝5.0,3.6Hz,3H),3.69–3.45(m,23H). 13C NMR(125MHz,CDCl 3,298K)δ(ppm):δ141.9,129.5,127.9,127.5,124.2,123.7,119.5,71.5,69.6,69.5,69.5,69.4,69.4,69.1,60.5.ESI-HRMS[10+H] +:calcd.for[C 38H 57Br 2O 14] +895.2110,found 895.2735.
步骤(2)、化合物11的制备：
将化合物10(500.0mg,1.36mmol)，四(三乙基膦)铂(293.3mg,0.44mmol)在氩气保护下加入到250mL的舒伦克瓶，用注射器往瓶中加入50mL无水甲苯溶解，90℃加热反应72小时。反应结束后，冷却到室温，用旋转蒸发仪减压浓缩，经过二氯甲烷萃取三次之后，收集有机相，干燥过滤得到粗产物，通过硅胶层析柱分离纯化(二氯甲烷/甲醇，30/1，v/v)，最终得到黄色油状液体(445.9mg,91.1％)。
图19-21所示： 1H NMR(500MHz,CDCl 3,298K)δ(ppm):8.46(s,2H),7.76(d,J＝8.1Hz,2H),7.56(d,J＝7.9Hz,2H),4.35(s,4H),3.88(s,4H),3.75–3.62(m,36H),3.60–3.56(m,4H),1.72–1.56(m,24H),1.06(dt,J＝15.4,7.5Hz,36H). 13C NMR(125MHz,CDCl 3,298K)δ(ppm):141.1,136.5,135.4,129.3,128.3,124.7,120.6,72.6,72.1,70.8,70.7,70.7,70.6,70.5,70.3,61.7,14.2,14.1,13.9,13.7,13.4,13.3,7.8,7.8.ESI-HRMS[11+Na] +:calcd.for[C 62H 116Br 2O 14P 4Pt 2Na] +1769.4773,found 1769.5153.
步骤(3)、60°亲水链双铂受体2的制备：
将化合物11(100.0mg,0.06mmol)，三氟甲磺酸银(87.7mg,0.30mmol)添加到20mL圆底烧瓶中，加入无水二氯甲烷溶解。室温且避光反应过夜。反应结束后，过滤，通过氮气流浓缩，最终得到褐色油状液体(92.4mg,92.3％)。
图22-25所示： 1H NMR(500MHz,CD 2Cl 2,298K)δ(ppm):8.34(s,2H),7.76(d,J＝7.5Hz,2H),7.56(d,J＝8.2Hz,2H),4.39(s,4H),3.96(s,4H),3.76(m,J＝59.1,24.8,16.2Hz,36H),3.61(s,4H),1.59(s,24H),1.11(d,J＝6.8Hz,36H). 13C NMR(125MHz,CD 2Cl 2,298K)δ(ppm):141.6,135.6,128.5,128.3,125.2,121.9,121.0,119.3,72.8,71.7,71.0,70.9,70.4,70.3,70.3,70.1,69.8,69.7,69.5,14.0,13.8,13.7,12.8,7.6. 31P{ 1H}NMR(202MHz,CD 2Cl 2,298K)δ(ppm):19.51ppm(s, 195Pt satellites  1J Pt-P＝2831.4Hz).ESI-TOF-MS[2-OTf] +:calcd.for[C 63H 116F 3O 17P 4Pt 2S] +1746.6110,found 1746.6113.
实施例三：两亲性菱形超分子金属环
实施例3-1：两亲性菱形超分子金属环3a的制备：
Figure PCTCN2022100793-appb-000015
将化合物1a(5.17mg,7.90μmol)和化合物2(15.00mg,7.90μmol)溶解在2mL无水甲醇中，55℃加热反应12小时。反应结束后，冷却到室温，然后过滤浓缩得到粗产物。将粗产物溶解在1mL无水二氯甲烷中，再加入7mL无水乙醚混合均匀之后有固体沉淀析出，离心干燥，最终得到淡黄色固体(15.93mg,79.4％)。
图26-28所示： 31P{ 1H}NMR(202MHz,CDCl 3,298K)δ(ppm):12.51ppm(s, 195Pt satellites, 1J Pt- P＝2685.2Hz). 1H NMR(500MHz,CD 2Cl 2)δ(ppm):9.16(d,J＝5.7Hz,2H),8.71(d,J＝6.0Hz,6H),8.44(d,J＝5.0Hz,2H),7.99(d,J＝8.2Hz,4H),7.86(d,J＝5.4Hz,3H),7.67(m,J＝22.1,11.8,5.9Hz,18H),7.43(dd,J＝12.5,8.5Hz,5H),7.19–6.99(m,38H),4.43(s,8H),3.98(s,8H),3.88–3.57(m,80H),1.39(s,48H),1.21–1.13(m,72H).ESI-TOF-MS[1a-3OTf+3Na-3H] 3+:calcd.for[C 221H 299F 3N 6Na 3O 31P 8Pt 4S] 3+1574.94,found 1574.46.
实施例3-2：两亲性菱形超分子金属环3b的制备：
Figure PCTCN2022100793-appb-000016
将化合物1b(5.58mg,7.90μmol)和化合物2(15.00mg,7.90μmol)溶解在2mL无水甲醇中， 55℃加热反应12小时。反应结束后，冷却到室温，然后过滤浓缩得到粗产物。将粗产物溶解在1mL无水二氯甲烷中，再加入7mL无水乙醚混合均匀之后有固体沉淀析出，离心干燥，最终得到橘黄色固体(17.29mg,84.3％)。
图29-31所示： 31P{ 1H}NMR(202MHz,CD 2Cl 2,298K)δ(ppm):13.26ppm(s, 195Pt satellites, 1J Pt-P＝2698.2Hz). 1H NMR(500MHz,CD 2Cl 2,298K)δ(ppm):8.81(d,J＝5.8Hz,3H),8.70–8.48(m,8H),8.40(d,J＝5.4Hz,3H),8.15–7.93(m,10H),7.92–7.30(m,26H),7.21–7.06(m,36H),4.41(s,8H),3.95(s,8H),3.79–3.57(m,80H),1.40(s,48H),1.19(m,J＝15.5,7.6Hz,72H).ESI-TOF-MS[3b-3OTf+3Na-3H] 3+:calcd.for[C 229H 307F 3N 6Na 3O 31P 8Pt 4S] 3+1609.62,found 1609.49.
实施例3-3两亲性菱形超分子金属环3c的制备：
Figure PCTCN2022100793-appb-000017
将化合物1c(5.54mg,7.90μmol)和化合物2(15.00mg,7.90μmol)溶解在2mL无水甲醇中，55℃加热反应12小时。反应结束后，冷却到室温，然后过滤浓缩得到粗产物。将粗产物溶解在1mL无水二氯甲烷中，再加入7mL无水乙醚混合均匀之后有固体沉淀析出，离心干燥，最终得到深黄色固体(16.64mg,81.2％)。
图32-34所示： 31P{ 1H}NMR(202MHz,CD 2Cl 2,298K)δ(ppm):13.04ppm(s, 195Pt satellites, 1J Pt-P＝2680.6Hz). 1H NMR(500MHz,CD 2Cl 2,298K)δ(ppm):8.91(d,J＝5.6Hz,3H),8.72–8.52(m,8H),8.16(d,J＝5.5Hz,3H),8.04(d,J＝8.2Hz,5H),7.88(s,5H),7.80–7.58(m,16H),7.47(d,J＝8.1Hz,6H),7.20–7.06(m,32H),4.41(s,8H),3.95(s,8H),3.81–3.54(m,80H),1.39(d,J＝2.7Hz,48H),1.26–1.07(m,72H).ESI-TOF-MS[3c-3OTf] 3+:calcd.for[C 229H 302F 3N 6O 31P 8Pt 4S] 3+1583.95,found 1583.83.
实施例四：两亲性菱形超分子金属环的细胞成像
实施例4-1两亲性菱形超分子金属环3a的细胞成像：
将CT26细胞种于24孔板中，培养12小时。加入金属环3a的DMEM溶液，共培育24小时。加入DiO(细胞膜绿色荧光探针)共培育约20分钟。用PBS清洗后，用激光共聚焦扫描显微镜(confocal laser scanning microscope,CLSM)观察。
实施例4-2两亲性菱形超分子金属环3b的细胞成像：
将CT26细胞种于24孔板中，培养12小时。加入金属环3b的DMEM溶液，共培育24小时。加入DiO共培育约20分钟。用PBS清洗后，用CLSM观察。
实施例4-2两亲性菱形超分子金属环3c的细胞成像：
将CT26细胞种于24孔板中，培养12小时。加入金属环3c的DMEM溶液，共培育24小时。加入DiO共培育约20分钟。用PBS清洗后，用CLSM观察。
如图35所示：细胞内观察到金属环的荧光，证明金属环可以被细胞摄取，实现细胞成像。

Claims (10)

120°含有聚集诱导发光AIE和聚集荧光猝灭ACQ基团的双吡啶配体，其特征在于化学结构式如下：
Figure PCTCN2022100793-appb-100001
其中R1基团为
Figure PCTCN2022100793-appb-100002
中的一种。
权利要求1所述的120°含有聚集诱导发光AIE和聚集荧光猝灭ACQ基团的双吡啶配体的合成方法；其特征在于其合成路线为：
Figure PCTCN2022100793-appb-100003
所述合成方法为：
(1)将化合物4、化合物5、碳酸钾、四(三苯基膦)钯溶于1,4-二氧六环与水的混合溶剂中，然后用液氮和氮气冻抽三次除氧，在氩气保护下75～80℃加热反应36～48小时；反应结束后，经后处理得到化合物6；
(2)将化合物6溶解于无水二氯甲烷中，然后在常温下将一氯化碘溶液逐滴加入得到紫黑的溶液；滴加完毕后，在氩气保护下40～50℃加热反应4～6小时，经后处理得到化合物7；
(3)将化合物7、催化剂、吡啶类化合物、缚酸剂，溶于溶剂中，然后用液氮和氮气冻抽三次除氧，在氩气保护下80～90℃加热反应36～48小时；反应结束后，经后处理得到双吡啶配体。
如权利要求1所述的方法，其特征在于所述催化剂采用四(三苯基膦)钯、醋酸钯、三苯基膦、碘化亚铜中的一种或多种；
所述吡啶类化合物采用吡啶-4-硼酸、4-乙烯基吡啶、4-乙炔基吡啶盐酸盐中的一种或多种；
所述缚酸剂采用碳酸钾、三乙胺中的一种或两种。
如权利要求1所述的方法，其特征在于所述化合物4、化合物5、碳酸钾、四(三苯基膦)钯的物质的量之比为1：0.3～0.6：1.8：0.004；
所述化合物6、一氯化碘的物质的量之比为1：8～10。
一种60°亲水链双铂受体，其特征在于化学结构式如下：
Figure PCTCN2022100793-appb-100004
一种120°含有聚集诱导发光AIE和聚集荧光猝灭ACQ基团的两亲性菱形超分子金属环，其特征在于化学结构式如下：
Figure PCTCN2022100793-appb-100005
其中R2基团为
Figure PCTCN2022100793-appb-100006
中的一种。
120°含有聚集诱导发光AIE和聚集荧光猝灭ACQ基团的两亲性菱形超分子金属环的合成方法，其特征在于其合成路线为：
Figure PCTCN2022100793-appb-100007
将权利要求1所述的120°含有聚集诱导发光AIE和聚集荧光猝灭ACQ基团的双吡啶配体和权利要求5所述的60°亲水链双铂受体溶解在醇类溶剂中进行自组装反应；反应结束后，经后处理得到两亲性菱形超分子金属环3。
如权利要求7所述的方法，其特征在于双吡啶配体1、双铂受体2的物质的量之比为1：1。
如权利要求7或8所述的方法，其特征在于反应温度为40-60℃，反应时间为10-15小时。
权利要求6所述的一种120°含有聚集诱导发光AIE和聚集荧光猝灭ACQ基团的两亲性菱形超分子金属环作为荧光染料在生物成像上的应用。
PCT/CN2022/100793 2022-01-17 2022-06-23 含有aie和acq基团的双吡啶配体及两亲性菱形超分子金属环和应用 WO2023134120A1 (zh)

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