CN113248502A - Near-infrared two-region dye based on naphthalene diimide derivative and preparation and application thereof - Google Patents
Near-infrared two-region dye based on naphthalene diimide derivative and preparation and application thereof Download PDFInfo
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- HPJFXFRNEJHDFR-UHFFFAOYSA-N 22291-04-9 Chemical class C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=C2C(=O)N(CCN(C)C)C(=O)C1=C32 HPJFXFRNEJHDFR-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000002872 contrast media Substances 0.000 claims abstract description 23
- 150000002632 lipids Chemical class 0.000 claims abstract description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
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- 238000000034 method Methods 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
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- 239000000126 substance Substances 0.000 claims description 7
- 238000006555 catalytic reaction Methods 0.000 claims description 6
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- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 claims description 3
- 238000003745 diagnosis Methods 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
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- 229940079593 drug Drugs 0.000 claims 1
- 238000003384 imaging method Methods 0.000 abstract description 13
- 239000002105 nanoparticle Substances 0.000 abstract description 2
- 239000000975 dye Substances 0.000 description 19
- 150000003384 small molecules Chemical class 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- -1 hexyl-2, 6-dibromo-1, 4,5, 8-naphthalenetetracarboxylic acid diimine Chemical compound 0.000 description 6
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 5
- 238000000799 fluorescence microscopy Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- TWWQCBRELPOMER-UHFFFAOYSA-N [4-(n-phenylanilino)phenyl]boronic acid Chemical compound C1=CC(B(O)O)=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 TWWQCBRELPOMER-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- DZAWUQRUHPUQFU-UHFFFAOYSA-N 2,6-dibromonaphthalene-1,4,5,8-tetracarboxylic acid Chemical compound C1=C(Br)C(C(O)=O)=C2C(C(=O)O)=CC(Br)=C(C(O)=O)C2=C1C(O)=O DZAWUQRUHPUQFU-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
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- 238000001254 matrix assisted laser desorption--ionisation time-of-flight mass spectrum Methods 0.000 description 2
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- 238000012545 processing Methods 0.000 description 2
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- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical class C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical compound C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 description 1
- LTHNHFOGQMKPOV-UHFFFAOYSA-N 2-ethylhexan-1-amine Chemical compound CCCCC(CC)CN LTHNHFOGQMKPOV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005964 Acibenzolar-S-methyl Substances 0.000 description 1
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000012984 biological imaging Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
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- 239000012043 crude product Substances 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- YTVNOVQHSGMMOV-UHFFFAOYSA-N naphthalenetetracarboxylic dianhydride Chemical compound C1=CC(C(=O)OC2=O)=C3C2=CC=C2C(=O)OC(=O)C1=C32 YTVNOVQHSGMMOV-UHFFFAOYSA-N 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
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- C09B57/08—Naphthalimide dyes; Phthalimide dyes
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Abstract
The invention relates to a near-infrared two-region dye based on a naphthalene diimide derivative, and preparation and application thereof. And then the near-infrared two-region dye and amphiphilic lipid molecule DSPE-PEG5000 are self-assembled, and the obtained water-soluble nano-particles have good fluorescence intensity in the near-infrared two-region and can be used as a contrast agent to realize imaging application in the near-infrared two-region.
Description
Technical Field
The invention belongs to the technical field of nano biomedical imaging materials, and relates to a near-infrared two-region dye based on a naphthalene diimide derivative, and preparation and application thereof.
Background
Because the fluorescence imaging does not need ionizing radiation, the fluorescence imaging can be developed into a non-invasive or minimally invasive technology and is conveniently used for researching biological phenomena. Meanwhile, fluorescence imaging also has some key problems such as self-fluorescence quenching, photobleaching and low tissue penetration depth. And the near-infrared two-region (NIR-II, 1000-plus-1700 nm) luminescence has lower self-fluorescence absorption and tissue scattering, compared with the traditional visible light fluorescence imaging and near-infrared one-region (NIR-I, 650-plus-900 nm) fluorescence imaging, the near-infrared two-region imaging has the minimum scattering and the deepest penetration depth, can realize high resolution and high signal-to-noise ratio, and has huge application potential in the aspects of molecular diagnosis and treatment. The near-infrared two-region dye based on the organic micromolecules has the advantages of high biocompatibility, high excretion capacity, simple and quick preparation method and the like, and is a research hotspot in the field of biological imaging and chemical research at present. However, a large number of reported near-infrared two-region dyes based on small organic molecules are based on the structure that benzothiadiazole is an electron acceptor, so that the development of a near-infrared two-region dye contrast agent based on a naphthalene diimide derivative as an electron acceptor structure is of great significance in the biomedical field.
Disclosure of Invention
The invention aims to provide a near-infrared two-region dye based on a naphthalene diimide derivative, and preparation and application thereof, so as to improve the fluorescence intensity of a near-infrared two-region imaging contrast agent, realize in-vivo clear and accurate near-infrared two-region imaging effect and the like.
The purpose of the invention can be realized by the following technical scheme:
one of the technical schemes of the invention provides a near-infrared two-region dye based on a naphthalene diimide derivative, which has a chemical structural formula as follows:
wherein R is1Is alkyl of 1-20 carbon atoms, R2Is one of the following groups:
the second technical scheme of the invention provides a preparation method of a near-infrared two-region dye based on a naphthalene diimide derivative, which comprises the steps of taking naphthalene diimide as an acceptor structure unit, carrying out coupling reaction with a donor unit to obtain a target product, wherein,
the chemical structural formula of the naphthalimide is
The chemical structural formula of the donor unit is
X is Br, Cl or I;
the specific reaction process is as follows:
further, the preparation method specifically comprises the following steps:
(1) dissolving an acceptor structural unit naphthalene diimide and a donor unit in a mixed solution of toluene and water, and adding a phase transfer catalyst tetrabutylammonium bromide and a catalyst tetrakis (triphenylphosphine) palladium for catalytic reaction under the protection of inert gas;
(2) and after the reaction is finished, cooling, extracting by adopting dichloromethane, and performing column chromatography to obtain the target product.
Further, in the step (1), the addition amount ratio of the naphthalene diimide as an acceptor structural unit, the donor unit, Aliquat 336, potassium carbonate and tetrakis (triphenylphosphine) palladium is 1 mmol: (2.1-2.5) mmol: (10-50) mg: (5-10) mmol: (0.05-1) mmol. Furthermore, in the step (1), the temperature of the catalytic reaction is 90-130 ℃, and the time is 12-36 h.
The third technical scheme of the invention provides application of a near-infrared two-region dye based on a naphthalimide derivative, wherein the near-infrared two-region dye is used for preparing a contrast agent.
Further, the preparation process of the contrast agent specifically comprises the following steps:
s01: dissolving the near-infrared second-zone dye in dichloromethane to obtain a dichloromethane solution of the near-infrared second-zone dye;
s02: dissolving the amphiphilic lipid molecules in water to obtain an aqueous solution of the amphiphilic lipid molecules;
s03: mixing a dichloromethane solution of the near-infrared two-region dye and an aqueous solution of amphiphilic lipid molecules, stirring overnight at room temperature, and evaporating to remove excessive dichloromethane to obtain the target product contrast agent.
Furthermore, in step S01, the concentration of the dichloromethane solution of the near-infrared two-region dye is 0.5-2 mg/mL;
in step S02, the concentration of the aqueous solution of the amphiphilic lipid molecules is 2-8 mg/mL;
in the step S03, the mass ratio of the added near-infrared two-region dye to the amphiphilic lipid molecules is 1: 4-8.
Further, the amphiphilic lipid molecule is DSPE-PEG 5000.
Furthermore, the contrast agent is used for preparing a diagnosis and treatment medicine for tumor diseases.
The invention designs, synthesizes and prepares a near-infrared two-region dye contrast agent based on a naphthalene diimide derivative, which is formed by self-assembling a near-infrared two-region dye based on a naphthalene diimide structure and amphiphilic lipid molecules DSPE-PEG 5000. The synthetic route and the preparation method are very simple. The near-infrared two-region imaging agent can be used as a near-infrared two-region contrast agent to realize high-quality near-infrared two-region imaging of various focus parts in a living body, including whole body blood vessel imaging, lymphatic drainage imaging, rheumatoid arthritis imaging and transplanted tumor imaging, and can accurately guide surgical excision of transplanted tumors. Moreover, by changing the structure of the donor unit, a series of near-infrared two-region fluorescent dyes are efficiently synthesized, and the types and the selection space of the near-infrared two-region imaging contrast agents are increased.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of N, N '- (2' -ethyl) hexyl-2, 6-dibromo-1, 4,5, 8-naphthalenetetracarboxylic acid diimine in example 1 of the present invention;
FIG. 2 is a NMR spectrum of a near-infrared two-domain small molecule in example 1 of the present invention;
FIG. 3 is a MALDI-TOF mass spectrum of a near-infrared two-domain small molecule according to example 1 of the present invention;
FIG. 4 is a fluorescence spectrum of a near-infrared two-region small molecule in example 1 of the present invention;
FIG. 5 is a TEM image of the NIR small molecule contrast agent obtained in example 2 of the present invention;
FIG. 6 shows the NIR-II fluorescence in vivo imaging application of the near-infrared two-region small molecule contrast agent obtained in example 2 of the present invention on tumor-bearing mice;
FIG. 7 is a NMR spectrum of a small molecule obtained in comparative example 2 of the present invention;
FIG. 8 is a flow chart of the manufacturing process of the present invention.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
In each of the following examples,
if the starting reagents or processing techniques are not specifically mentioned, they are all conventional commercial products or conventional processing techniques in the art.
Example 1:
the structure of the near-infrared two-region small molecule provided in this embodiment is as follows:
the preparation method of the embodiment is shown in fig. 8, and specifically includes the following steps:
1) in a 250mL round bottom flask were added 5g of 1,4,5, 8-naphthalenetetracarboxylic dianhydride (18.64mmol, 1equiv) and 75mL of fuming sulfuric acid, a catalytic amount of iodine was added to the reaction system, 1.72mL of bromine (33.52mmol, 1.8equiv) was slowly added at room temperature, and then heated to 50 ℃ and the reaction was stirred for 48 hours. After cooling, slowly adding a saturated solution of sodium thiosulfate to remove redundant bromine, pouring the reaction solution into ice water to form yellow precipitate, filtering, washing with water to obtain bright yellow solid, namely 2, 6-dibromo-1, 4,5, 8-naphthalene tetracarboxylic dianhydride, and directly carrying out the next reaction.
2) 2g of 2, 6-dibromo-1, 4,5, 8-naphthalenetetracarboxylic dianhydride (4.69mmol, 1equiv) and 50mL of glacial acetic acid were added into a 100mL round-bottomed flask, 4mL of 2-ethylhexylamine (24.42mmol, 5.2equiv) was added into the reaction system, the mixture was heated to reflux and stirred for reaction for 1 hour, after cooling, the reaction mixture was concentrated under reduced pressure to about the original volume of 1/10, then water was added to form a reddish brown crude product, and column chromatography separation (eluent was a mixed solution of petroleum ether and ethyl acetate) was carried out to obtain a pale yellow solid, which was N, N '- (2' -ethyl) hexyl-2, 6-dibromo-1, 4,5, 8-naphthalenetetracarboxylic diimine, with a yield of 33%. The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 1.
3) A100 mL round bottom flask was charged with a mixed solution of 0.5g N, N '- (2' -ethyl) hexyl-2, 6-dibromo-1, 4,5, 8-naphthalenetetracarboxylic acid diimine (0.77mmol, 1equiv), 0.63g of pinacol 4- (diphenylamino) phenylboronic acid ester (1.70mmol, 2.2equiv), a catalytic amount of Aliquat 336, 0.55g of potassium carbonate (3.98mmol, 5.2equiv), 46mg of tetrakis (triphenylphosphine) palladium (0.04mmol, 0.05equiv), and 30mL of toluene and 5mL of water. The reaction was degassed for 20 minutes and then heated and stirred at 120 ℃ for 24 hours under an argon atmosphere. After cooling to room temperature, water was added, extraction was carried out with dichloromethane, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography (eluent is mixed solution of petroleum ether and dichloromethane) gave blue solid with 40% yield.
The obtained near-infrared two-region organic small molecules are characterized by a nuclear magnetic resonance hydrogen spectrum and a MALDI-TOF mass spectrum, and the results are respectively shown in FIG. 2 and FIG. 3. The emission spectrum test of the obtained near-infrared two-region organic small molecule is carried out, as shown in fig. 4, it can be seen that the emission peak is 1060 nanometers wave band, and belongs to near-infrared two-region material.
Example 2:
near-infrared two-region small molecule contrast agent
1mg of near-infrared two-region small molecule (prepared in example 1) was dissolved in 1mL of dichloromethane, 6mg of amphiphilic lipid molecule DSPE-PEG5000 was dissolved in 1mL of aqueous solution, the prepared dichloromethane solution and aqueous solution were mixed to obtain a mixed liquid, and further, the mixed liquid was stirred overnight at room temperature to evaporate off excess dichloromethane to obtain a near-infrared two-region small molecule contrast agent.
The obtained near-infrared two-region small-molecule contrast agent is characterized by a transmission electron microscope, and the result is shown in figure 5, wherein the appearance is spherical, and the size is about 50 nm.
Application example:
near-infrared two-region small molecule contrast agent for tumor targeting near-infrared two-region fluorescence living body imaging
The tumor-bearing nude mice were injected with near-infrared two-region small molecule contrast agent (prepared in example 2) via tail vein, and the mice were imaged with a near-infrared two-region imager, as shown in fig. 6, it can be seen that the contrast agent was significantly enriched in tumor sites 12 hours after tail vein injection, and the fluorescence intensity of the two regions was significantly higher than that of the surrounding tissues, demonstrating that it can image tumor lesions.
Comparative example 1:
compared with example 1, the same was observed for the most part, except that the amount of pinacol ester 4- (diphenylamino) phenylboronate added was changed to 0.9 mmol. Column chromatography (eluent is mixed solution of petroleum ether and dichloromethane) gives two blue solids, of which the less polar is the target product of coupling two 4- (diphenylamino) benzenes (yield 10%) and the more polar is the by-product of coupling one 4- (diphenylamino) benzene (yield: 27%), and the specific nuclear magnetic results are shown in fig. 7.
Comparative example 2:
compared to example 2, most of them are the same, except that the introduction of amphiphilic lipid molecules in the contrast agent is omitted. Namely, water-soluble nano particles cannot be obtained, and the subsequent near-infrared two-zone fluorescence living body imaging experiment cannot be carried out.
Example 3:
most of them were the same as in example 1 except that the amounts of pinacol ester of 4- (diphenylamino) phenylboronic acid, Aliquat 336, potassium carbonate and tetrakis (triphenylphosphine) palladium were adjusted so that the ratio of the amounts of N, N '- (2' -ethyl) hexyl-2, 6-dibromo-1, 4,5, 8-naphthalenetetracarboxylic acid diimine added to pinacol ester of 4- (diphenylamino) phenylboronic acid, Aliquat 336, potassium carbonate and tetrakis (triphenylphosphine) palladium added was 1 mmol: 2.1 mmol: 10 mg: 5 mmol: 0.05 mmol.
Example 4:
most of them were the same as in example 1 except that the amounts of pinacol ester of 4- (diphenylamino) phenylboronic acid, Aliquat 336, potassium carbonate and tetrakis (triphenylphosphine) palladium were adjusted so that the ratio of the amounts of N, N '- (2' -ethyl) hexyl-2, 6-dibromo-1, 4,5, 8-naphthalenetetracarboxylic acid diimine added to pinacol ester of 4- (diphenylamino) phenylboronic acid, Aliquat 336, potassium carbonate and tetrakis (triphenylphosphine) palladium added was 1 mmol: 2.5 mmol: 50 mg: 10 mmol: 1 mmol.
Example 5:
compared with example 1, the catalyst is mostly the same except that the temperature of the catalytic reaction in step 3) is 90 ℃ and the time is 36 h.
Example 6:
compared with example 1, the catalyst is mostly the same except that the temperature of the catalytic reaction in step 3) is 130 ℃ and the time is 12 h.
Example 7:
compared with the example 2, the method is mostly the same, except that the mass ratio of the added near-infrared two-zone dye to the amphiphilic lipid molecules is 1: 4.
Example 8:
compared with the example 2, the method is mostly the same, except that the mass ratio of the added near-infrared two-zone dye to the amphiphilic lipid molecules is 1: 8.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A near-infrared two-region dye based on a naphthalene diimide derivative is characterized in that the chemical structural formula is as follows:
wherein R is1Is alkyl of 1-20 carbon atoms, R2Is one of the following groups:
2. the method for preparing the near-infrared two-region dye based on the naphthalene diimide derivative according to claim 1, wherein the naphthalene diimide is used as an acceptor structural unit to perform a coupling reaction with a donor unit to obtain a target product,
the chemical structural formula of the naphthalimide is
The chemical structural formula of the donor unit is
X is Br, Cl or I.
3. The method for preparing the near-infrared two-region dye based on the naphthalene diimide derivative according to claim 2, comprising the steps of:
(1) dissolving naphthalene diimide as an acceptor structure unit and a donor unit in a mixed solution of toluene and water, and adding a phase transfer catalyst Aliquat 336, potassium carbonate and a catalyst tetrakis (triphenylphosphine) palladium for catalytic reaction under the protection of inert gas;
(2) and after the reaction is finished, cooling, extracting by adopting dichloromethane, and performing column chromatography to obtain the target product.
4. The method for preparing the near-infrared two-region dye based on the naphthalene diimide derivative as claimed in claim 3, wherein in the step (1), the ratio of the addition amounts of the naphthalene diimide as the acceptor structural unit, the donor unit, Aliquat 336, potassium carbonate and tetrakis (triphenylphosphine) palladium is 1 mmol: (2.1-2.5) mmol: (10-50) mg: (5-10) mmol: (0.05-1) mmol.
5. The method for preparing the near-infrared two-region dye based on the naphthalene diimide derivative according to claim 3, wherein the temperature of the catalytic reaction in the step (1) is 90-130 ℃ and the time is 12-36 hours.
6. The use of a near-infrared two-region dye based on a naphthalene diimide derivative according to claim 1, for the preparation of a contrast agent.
7. The application of the near-infrared two-region dye based on the naphthalene diimide derivative as claimed in claim 6, wherein the preparation process of the contrast agent is specifically as follows:
s01: dissolving the near-infrared second-zone dye in dichloromethane to obtain a dichloromethane solution of the near-infrared second-zone dye;
s02: dissolving the amphiphilic lipid molecules in water to obtain an aqueous solution of the amphiphilic lipid molecules;
s03: mixing a dichloromethane solution of the near-infrared two-region dye and an aqueous solution of amphiphilic lipid molecules, stirring overnight at room temperature, and evaporating to remove excessive dichloromethane to obtain the target product contrast agent.
8. The use of the naphthalene diimide derivative-based near-infrared two-region dye according to claim 7, wherein in step S01, the concentration of the near-infrared two-region dye in dichloromethane is 0.5-2 mg/mL;
in step S02, the concentration of the aqueous solution of the amphiphilic lipid molecules is 2-8 mg/mL;
in the step S03, the mass ratio of the added near-infrared two-region dye to the amphiphilic lipid molecules is 1: 4-8.
9. The use of the naphthalene diimide derivative-based near-infrared two-region dye according to claim 7, wherein the amphiphilic lipid molecule is DSPE-PEG 5000.
10. The use of the naphthalene diimide derivative-based near-infrared two-region dye according to claim 6, wherein the contrast agent is used for preparing a tumor disease diagnosis and treatment drug.
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