CN117186151A - Near-infrared zwitterionic cyanine dye and preparation method and application thereof - Google Patents
Near-infrared zwitterionic cyanine dye and preparation method and application thereof Download PDFInfo
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- CN117186151A CN117186151A CN202311069021.4A CN202311069021A CN117186151A CN 117186151 A CN117186151 A CN 117186151A CN 202311069021 A CN202311069021 A CN 202311069021A CN 117186151 A CN117186151 A CN 117186151A
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- zwitterionic
- cyanine dye
- near infrared
- condensation reaction
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
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Landscapes
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Abstract
The invention belongs to the technical field of biomedicine, and particularly relates to a near-infrared zwitterionic cyanine dye, and a preparation method and application thereof. The near infrared zwitterion takes the derivative of the cyanine dye structure as a fluorophore, and the amphoteric group is modified on the benzene ring, so that the compound has extremely high water solubility, becomes a novel small molecular fluorescent probe capable of being cleared by the kidney, has better biocompatibility and optical stability, can be used as a fluorescent probe, and can be used for more accurately carrying out early diagnosis on the kidney diseases, navigation treatment in operation, functional evaluation on tissue organs and the like.
Description
Technical Field
The invention belongs to the technical field of biomedicine. More particularly, to near infrared zwitterionic cyanine dyes, methods of making and uses thereof.
Background
The urinary system is composed of kidneys, ureters, bladder, and urethra, and is an important excretion pathway for human metabolites. During excretion, abnormal metabolic waste in vivo, foreign microorganisms, drugs, etc. are liable to cause infection and damage of surrounding tissues, cells, and further cause a series of diseases. The current clinical diagnosis of urinary system diseases often depends on traditional imaging means, however, the methods have the defects of high ionization radiation, low sensitivity, high cost and the like, and are difficult to diagnose early and perform intervention. Compared with the traditional imaging technology, the optical imaging/detection technology has the advantages of high sensitivity, strong specificity, high safety, convenience, easiness in popularization and the like. Therefore, the non-invasive, non-ionizing radiation, high-specificity and high-sensitivity fluorescent imaging technology for detecting the urinary system diseases has excellent application prospect.
Fluorescence imaging has evolved rapidly over the last decade. This technique allows for real-time detection of specific targets, such as malignant cells, nerves, blood vessels, and lymph nodes, during surgery. When the fluorescent substance has specific properties such as hydrophilicity, the fluorescent substance can be selectively accumulated in organs rich in water such as kidneys, ureters, bladders and the like, and according to the characteristics, the organ imaging can be performed by utilizing a fluorescence imaging means, so that whether lesions exist in the organs or not can be judged. Meanwhile, the hydrophilic substances can be metabolized by kidneys and discharged out of the body very quickly, and have higher biocompatibility. However, a fundamental problem of fluorescence imaging is that conventional fluorescent substances are mostly electronegative sulfonates, carboxylates, etc. to protect the central hydrophobic resonance structure and to increase solubility, and thus show nonspecific uptake in tissues and organs after intravenous injection, which results in higher background fluorescence signals, thus decreasing signal-to-noise ratio (Reinhart MB, huntington CR, blair LJ, henifod BT, augenstein va. Indocyanine Green: historical Context, current Applications, and Future constituency. Surg innov.2016;23 (2): 166-175.). There are few cyanine dyes currently developed for use in the urinary system, and only indocyanine green and methylene blue are currently available as clinical dyes approved by the FDA. Indocyanine green is mainly metabolized by liver and gall, has poor hydrophilicity, almost has no urinary system enrichment, and methylene blue has certain hydrophilicity and can be used for fluorescent imaging of the urinary system, but has low kidney clearance rate and still has defects in kidney disease examination. Therefore, developing single-molecule, label-free, ampholytic, neutral, highly hydrophilic and highly efficient transrenal clearance fluorescent dyes has important significance for diagnosis and treatment of urinary system diseases, and particularly applying the fluorescent dyes to evaluation of renal function and ureter imaging can provide new methods and strategies for clinicians.
The current fluorescent probes for kidney disease detection mainly comprise inorganic nano probes and organic molecular probes. The metabolism of the inorganic nano-probe is limited by the glomerular basement membrane pore size, has strict selectivity on the nano-probe size, and only inorganic nano-particles with the hydration diameter smaller than 6nm and low protein binding rate can be effectively discharged through the kidney. Second, the inorganic nanomaterials have a slow metabolic rate and can be trapped and accumulated by the endothelial reticulation system of the liver during in vivo circulation, resulting in long-term, potentially biotoxic effects. In addition, the preparation scale of the inorganic nano-probe is limited, the price is high, and the reproducibility and quantification of the synthetic production are difficult. In contrast, the organic molecular probe has the advantages of high metabolism speed, high biocompatibility, modifiable structure and the like, and has wide application in the biomedical field including cell imaging, tumor diagnosis and treatment, navigation in clinical operation and the like.
Disclosure of Invention
The invention aims to overcome the defects of poor specificity and low signal-to-noise ratio of the existing single-charge fluorescent probe fluorescent imaging result and provide the near-infrared zwitterionic cyanine dye which has strong charges (sulfonate and quaternary ammonium salt) and is balanced in charge on the molecular surface, so that the near-infrared zwitterionic cyanine dye shows extremely low non-specific binding and tissue uptake in vivo after intravenous injection, and has good specificity of the fluorescent imaging result and high noise-to-signal ratio.
It is therefore another object of the present invention to provide the use of near infrared zwitterionic cyanine dyes as fluorescent probes.
The invention also aims to provide a preparation method of the near infrared zwitterionic cyanine dye.
The above object of the present invention is achieved by the following technical solutions:
the invention provides a near infrared zwitterionic cyanine dye which is characterized by having a structure shown in any one of formulas (I) to (IV):
wherein X is N, O, S; n is an integer of 0 to 20.
Preferably, n is an integer of 1 to 20.
After intravenous injection, the near infrared zwitterionic cyanine dye provided by the invention can be rapidly metabolized by kidneys without being nonspecifically absorbed by other tissues or organs, dynamic monitoring of the lesion parts of the urinary system and visual identification of lesion areas are realized through fluorescent imaging real-time monitoring, the near infrared zwitterionic cyanine dye has important significance for diagnosing kidney injury, ureteral obstruction and the like, and meanwhile, more accurate guidance can be provided for accurate treatment of ureteral operation by means of real-time fluorescent imaging equipment, so that the operation curative effect and the prognosis of patients are improved, and a novel auxiliary method is hopeful to be provided for disease diagnosis and treatment of human beings.
Further, the near infrared zwitterionic cyanine dye has any one of the following structures:
preferably, it has the structure as follows:
further, the preparation method of the near infrared zwitterionic cyanine dye comprises the following steps:
s1, performing condensation reaction on the compound 5 and the compound (1) to obtain a near infrared zwitterionic cyanine dye formula A compound;
or S2, carrying out condensation reaction on the compound 5 and the compound (2) to obtain the near infrared zwitterionic cyanine dye formula B compound;
or S3, performing condensation reaction on the compound 5 and the compound (3) to obtain the near infrared zwitterionic cyanine dye type C compound;
or S4, performing condensation reaction on the compound 5 and the compound (4) to obtain a near infrared zwitterionic cyanine dye formula D compound;
or S5, carrying out condensation reaction on the compound 5 and the compound (5) to obtain the near infrared zwitterionic cyanine dye compound;
or S6, carrying out condensation reaction on the compound 5 and the compound (6) to obtain the near infrared zwitterionic cyanine dye formula F compound;
or S7, carrying out condensation reaction on the compound 5 and the compound (7) to obtain the near infrared zwitterionic cyanine dye formula G compound;
or S8, carrying out condensation reaction on the compound 5 and the compound (8) to obtain the near infrared zwitterionic cyanine dye type H compound;
wherein the structure of the related compound is as follows:
wherein n is an integer of 1 to 20.
Preferably, in the steps S1 to S8, the reaction temperature of the condensation reaction is 45-100 ℃ and the time is 12-24 hours.
Preferably, in the steps S1 to S8, the solvent selected for the condensation reaction is one or more of absolute ethanol, absolute methanol, N-dimethylformamide or acetic anhydride, and the activator selected for the condensation reaction is one or more of potassium carbonate, cesium carbonate, sodium acetate, potassium acetate or triethylamine.
Further, the compound 5 is prepared by the following steps:
s9, performing condensation reaction on the compound 1 and the compound 20 (preferably, performing condensation reaction at 80-110 ℃ in the presence of acetic acid) to obtain a compound 2 for later use;
s10, carrying out substitution reaction on the compound 2 and the compound 30 (preferably, the solvent is one of toluene or o-dichlorobenzene, preferably, the reaction temperature is 110-130 ℃, and the reaction time is 48-72 h), so as to obtain a compound 4 for later use;
s11, carrying out substitution reaction on the compound 4 and the compound 3 (preferably, carrying out substitution reaction at 80 ℃ in the presence of sodium acetate, and preferably, carrying out substitution reaction on one or more of absolute ethyl alcohol, absolute methyl alcohol, N-dimethylformamide or acetic anhydride as a solvent) to obtain a compound 5;
wherein the structure of the compound is as follows:
further, compound 7 or compound 9 is prepared by the steps of:
s12, carrying out substitution reaction on the compound 6 and the compound 21 to obtain a compound 7 or a compound 9; preferably, the reaction time of the substitution reaction in the step S12 is 6-24 hours; more preferably, the reaction time is 6-8 h to obtain the compound 7, and the reaction time is 12-24h to obtain the compound 9;
wherein the structure of the compound is as follows:
further, compound 14 or compound 17 was prepared by the following steps:
s13, carrying out substitution reaction on the compound 11 and the compound 21 to obtain a compound 14 or a compound 17; preferably, the reaction time of the substitution reaction in the step S13 is 6-24 hours; more preferably, the reaction time is 6 to 8 hours to obtain the compound 14, and the reaction time is 12 to 24 hours to obtain the compound 17;
wherein the structure of the compound is as follows:
still further, compound 15 or compound 18 is prepared by the steps of:
s14, carrying out substitution reaction on the compound 12 and the compound 21 to obtain a compound 15 or a compound 18; preferably, the reaction time of the substitution reaction in the step S14 is 6-24 hours; more preferably, the reaction time is 6 to 8 hours to obtain a compound 15, and the reaction time is 12 to 24 hours to obtain a compound 18;
wherein the structure of the compound is as follows:
further, compound 16 or compound 19 was prepared by the following steps:
s15, carrying out substitution reaction on the compound 13 and the compound 21 to obtain a compound 16 or a compound 19; preferably, the reaction time of the substitution reaction in the step S15 is 6-24 hours; more preferably, the reaction time is 6 to 8 hours to obtain the compound 16, and the reaction time is 12 to 24 hours to obtain the compound 19;
wherein the structure of the compound is as follows:
preferably, in the steps S12 to S15, the substitution reaction is carried out in the presence of alkali, the reaction temperature is 0-25 ℃, and the solvent is acetonitrile; more preferably, the base is quinoline or pyridine.
Further, the compound 7 undergoes a reduction reaction to obtain a compound 8; the compound 9 undergoes a reduction reaction to obtain a compound 10; preferably, the reduction reaction is carried out in the presence of stannous chloride, the solvent is one or more of absolute methanol, absolute ethanol or absolute acetonitrile, and the reaction temperature is 25-40 ℃;
wherein the structure of the compound is as follows:
meanwhile, the invention also claims the application of the near infrared zwitterionic cyanine dye and pharmaceutically acceptable salts, solvates, enantiomers, diastereomers and tautomers thereof in preparing fluorescent probes.
Preferably, the fluorescent probe is a renal clearance type fluorescent probe.
Preferably, the pharmaceutically acceptable salt is at least one of hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, glycolate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, para-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, ortho-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, oxybenzoate, methoxybenzoate, mandelate, tanninate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, propionate laurate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, sulfanilate, para-toluenesulfonate (tosylate), or naphthalene-2-sulfonate.
The invention has the following beneficial effects:
the research provides a kind of chemical balance, electric neutrality and multi-ion near-infrared cyanine dye (called amphoteric cyanine dye for short), which takes the derivative of the cyanine dye structure as a fluorophore, and modifies hydrophilic groups on benzene rings, so that the dye has high specificity and sensitivity, better biocompatibility and optical stability, can be rapidly metabolized by kidneys without being nonspecifically absorbed by other tissues or organs as a fluorescent probe, has higher renal clearance rate, can more accurately perform early diagnosis on diseases, navigation treatment in operation, evaluation of tissue organ functions and the like, can play an important role in future medical optical examination, and has excellent application prospect.
Drawings
The ultraviolet absorption spectrum and the fluorescence emission spectrum of the near infrared zwitterionic cyanine dye compounds 22 and 26 of examples 3 and 4 of fig. 1.
Fig. 2 is a statistical plot of recovery of dye in urine within 24 hours after injection of near infrared zwitterionic cyanine dye compound 22 of example 3.
FIG. 3 is a statistical plot of the in vitro plasma protein binding rate of near infrared zwitterionic cyanine dye compound 22 of example 3.
Fig. 4 is a graph of plasma half-life measured at various time points after injection of near infrared zwitterionic cyanine dye compound 22 of example 3 in a rat model of acute kidney injury.
Fig. 5 is a graph showing plasma half-life of near infrared zwitterionic cyanine dye compound 22 measured at different time points after administration of an anionic blocker and a cationic blocker in a rat model of acute kidney injury of example 3.
FIG. 6 is an organ imaging of near infrared zwitterionic cyanine dye compound 22 of example 3 in normal rats; wherein He represents heart, li represents liver, sp represents spleen, lu represents lung, ki represents kidney, bl represents bladder, sk represents skin, mu represents muscle, in represents small intestine.
FIG. 7 is an organ imaging of near infrared zwitterionic cyanine dye compound 22 of example 3 in a rat model of acute kidney injury; wherein He represents heart, li represents liver, sp represents spleen, lu represents lung, ki represents kidney, bl represents bladder, sk represents skin, mu represents muscle, in represents small intestine.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
Example 1 precursor Compound 8 of near-infrared zwitterionic cyanine dye Compound
The embodiment provides a precursor of a near infrared zwitterionic cyanine dye compound, and the synthetic route is as follows:
the method specifically comprises the following steps:
1. a100 mL round bottom flask was taken and added with compound 6 (1 g,4 mmol), compound 21 (1.2 g,5 mmol), acetonitrile (30 mL), quinoline (470 μl,4 mmol) followed by stirring at 0deg.C for 6h. The reaction was completed. Adding 2ml of methanol, 300 μl of triethylamine, stirring at normal temperature for 1h, spin-drying, separating and analyzing by high performance liquid chromatography, collecting target compound, and spin-drying to obtain compound 7 (100 mg, yield 39%). 1 H NMR(400MHz,DMSO):δ8.15-8.18(d,J＝12,2H),7.38-7.40(d,J＝8,2H),4.30-4.20(m,2H),3.63-3.52(m,2H),3.15-3.05(m,9H).LRMS(ESI)m/z:[M+H]+Calcd for C11H18N2O6P+305.09，Found 306.01
2. A50 mL round bottom flask was taken and added with compound 7 (60 mg,0.02 mmol), stannous chloride (160 mg,0.85 mmol), methanol (1 mL) and then the reaction was carried out in order with an oil bath at 40℃for 24h. After the reaction, saturated sodium bicarbonate solution was added, the precipitate was removed by centrifugation, the supernatant was collected, and the mixture was dried by spin-drying and separated by high performance liquid chromatography to give Compound 8 (44 mg, yield 80%) as a white solid. 1 H NMR(400MHz,DMSO):δ6.86-6.83(d,J＝12,2H),6.46-6.44(d,J＝8,2H),5.14(s,2H),4.40-4.70(m,2H)3.75-3.63(m,2H),3.22-3.10(m,9H),LRMS(ESI)m/z:[M+H]+Calcd for C11H20N2O4P+275.12，Found 275.79
Example 2 precursor Compound 10 of near-infrared zwitterionic cyanine dye Compound
The embodiment provides a precursor of a near infrared zwitterionic cyanine dye compound, and the synthetic route is as follows:
the method specifically comprises the following steps:
1. a100 mL round bottom flask was taken and added with compound 6 (1 g,4 mmol), compound 21 (1.2 g,5 mmol), acetonitrile (30 mL), quinoline (470 μl,4 mmol) followed by stirring at 0deg.C for 24h. The reaction was completed. Adding 2ml of methanol, 300 μl of triethylamine, stirring at normal temperature for 1h, spin-drying, separating and analyzing by high performance liquid chromatography, collecting the target compound, and spin-drying to obtain compound 9 (100 mg, yield 39%). 1 H NMR(400MHz,DMSO):δ8.36-8.34(d,J＝8,2H),7.59-7.57(d,J＝8,2H),4.80-4.70(m,4H),3.80-3.70(m,4H),3.20-3.10(m,18H),LRMS(ESI)m/z:[M+H]+Calcd for C16H30N3O6P2+391.19，Found 392.08.
2. A50 mL round bottom flask was taken and added with Compound 9 (60 mg,0.02 mmol), stannous chloride (160 mg,0.85 mmol), methanol (1 mL) and then the temperature was raised to 40℃in an oil bath to react for 24h. After the reaction, saturated sodium bicarbonate solution was added, the precipitate was removed by centrifugation, the supernatant was collected, and the mixture was dried by spin-drying and separated by high performance liquid chromatography to give compound 10 (44 mg, yield 80%) as a white solid. 1 H NMR(400MHz,DMSO):δ6.95-6.93(d,J＝8,2H),6.56-6.54(d,J＝8,2H),5.14(s,2H),4.70-4.60(m,4H)3.83-3.75(m,4H),3.22-3.10(m,18H),LRMS(ESI)m/z:[M+H]+Calcd for C16H32N3O4P2+361.21，Found 362.16.
Example 3 near infrared zwitterionic cyanine dye Compound 22
The embodiment provides a near infrared zwitterionic cyanine dye compound, the synthetic route is as follows:
the method specifically comprises the following steps:
1. a100 mL two-necked round bottom flask was taken, acetic acid (30 mL), sodium acetate 3.2g, compound 1 (3.76 g,20 mmol) and Compound 20 (3.2 mL,30 mmol) were sequentially added under argon atmosphere and stirred overnight at 110deg.C. Directly loading the sample column for chromatography without treatment after the reaction is finished, and using dichloromethane: methanol=15:1 eluting the target product. The yellow liquid was collected, dried by spin-drying to give compound 2 (3.8 g, 80%) as a pink solid. 1 H NMR(400MHz,DMSO-d 6 ):δ7.63(s,1H),7.55(d,J＝7.9Hz,1H),7.34(d,J＝7.9Hz,1H),2.21(s,3H),1.25(s,6H).LRMS(ESI)m/z:[M+H] + Calcd for C 11 H 14 NO 3 S240.07；Found 240.19.。
2. A100 mL two-necked round bottom flask was taken and charged with compound 2 (2 g,8.36 mmol), compound 30 (4.5 g,25 mmol), toluene (10 mL) and stirred at 110℃for 48h under argon atmosphere. After the reaction is finished, the mixture is dried by spinning, dichloromethane is extracted for three times, ethyl acetate is extracted for three times, the plate is spotted until no raw material is present, and the mixture is dried by anhydrous sodium sulfate and then dried by spinning. Thus, pink solid compound 4 was obtained. LRMS (ESI) M/z: [ M+H ] +Calcd for C17H28N2O3S2+340.18,Found 341.16.
3. A100 mL round bottom flask was taken and charged with compound 4 (3 g,8 mmol), acetic anhydride (30 mL), compound 3 (0.3 g,2 mmol), anhydrous sodium acetate (2.5 g,30 mmol) in sequence, and the oil bath was heated to 80℃and reacted overnight. Directly loading the sample column for chromatography without treatment after the reaction is finished, and using dichloromethane: methanol=15:1 eluting the target product. Spin-drying to obtain golden green solid compound 5 (0.4 g, yield 30%).
4. A10 mL round bottom flask was taken, and after adding compound 5 (15 mg,0.02 mmol), compound 8 (20 mg, 0.07 mmol) obtained in example 1, water (2 mL) and sodium carbonate (4 mg,0.04 mmol) in this order, the oil bath was heated to 60℃and reacted for 24 hours. After the reaction, the blue target compound 22 was collected by high performance liquid chromatography. (6 mg, 30%) 1 H NMR(500MHz,DMSO):δ9.29(s,1H),7.97-7.94(d,J＝30Hz,2H),7.60(s,2H),7.58-7.56(d,J＝10Hz,2H),7.28-7.27(d,J＝10Hz,2H),7.13-7.11(d,J＝10Hz,2H),7.05-7.04(d,J＝5Hz,2H),6.06-6.04(d,J＝10Hz,2H),4.39(s,2H),4.11(s,4H),3.65(m,4H),3.18-3.05(m,9H),3.10-3.04(m,18H),2.64(m,4H),2.09(m,4H),1.86(m,2H),1.61(m,2H),1.35(m,12H),1.23(s,2H).LRMS(ESI)m/z:[M+H]+Calcd for C53H79N6O10PS24+1054.50；Found 1055.07.
Example 4 near infrared zwitterionic cyanine dye Compound 26
The embodiment provides a near infrared zwitterionic cyanine dye compound, the synthetic route is as follows:
the method specifically comprises the following steps:
1. a100 mL two-necked round bottom flask was taken, acetic acid (30 mL), sodium acetate 3.2g, compound 1 (3.76 g,20 mmol) and Compound 20 (3.2 mL,30 mmol) were sequentially added under argon atmosphere and stirred overnight at 110deg.C. Directly loading the sample column for chromatography without treatment after the reaction is finished, and using dichloromethane: methanol=15:1 eluting the target product. The yellow liquid was collected, dried by spin-drying to give compound 2 (3.8 g, 80%) as a pink solid. 1 H NMR(400MHz,DMSO-d 6 ):δ7.63(s,1H),7.55(d,J＝7.9Hz,1H),7.34(d,J＝7.9Hz,1H),2.21(s,3H),1.25(s,6H).LRMS(ESI)m/z:[M+H] + Calcd for C 11 H 14 NO 3 S240.07；Found 240.19.。
2. A100 mL two-necked round bottom flask was taken and charged with compound 2 (2 g,8.36 mmol), compound 30 (4.5 g,25 mmol), toluene (10 mL) and stirred at 110℃for 48h under argon atmosphere. After the reaction is finished, the mixture is dried by spinning, dichloromethane is extracted for three times, ethyl acetate is extracted for three times, the plate is spotted until no raw material is present, and the mixture is dried by anhydrous sodium sulfate and then dried by spinning. Thus, pink solid compound 4 was obtained. LRMS (ESI) M/z: [ M+H ] +Calcd for C17H28N2O3S2+340.18,Found 341.16.
3. A100 mL round bottom flask was taken and charged with compound 4 (3 g,8 mmol), acetic anhydride (30 mL), compound 3 (0.3 g,2 mmol), anhydrous sodium acetate (2.5 g,30 mmol), and oil bathHeat to 80 ℃, and react overnight. Directly loading the sample column for chromatography without treatment after the reaction is finished, and using dichloromethane: methanol=15:1 eluting the target product. Spin-drying to obtain golden green solid compound 5 (0.4 g, 30%). LRMS (ESI) M/z: [ M+H ]] + Calcd for C42H60ClN4O6S23+815.36，Found 815.98.
4. A10 mL round bottom flask was taken, and after adding compound 5 (15 mg,0.02 mmol), compound 10 obtained in example 2 (20 mg, 0.07 mmol), water (2 mL), and sodium carbonate (4 mg,0.04 mmol) in this order, the oil bath was heated to 60℃and reacted for 24 hours. After the completion of the reaction, the blue target compound 26 (6.3 mg, 30%) was collected by high performance liquid chromatography. LRMS (ESI) M/z: [ M+H ]] + Calcd for C58H91N7O10PS25+1140.60，Found 1141.40.
Experimental example 1 Spectrum test
PBS solutions of 0.05mg/mL of normally-bright fluorescent probe compounds 22 and 26 were prepared. The absorption spectrum of each sample at 400 to 900nm was measured by an ultraviolet spectrometer, and the fluorescence spectrum (excitation wavelength: 700 nm) of each sample was measured by a fluorescence spectrometer. As shown in FIG. 1, the fluorescence groups of the probes are of a cyanine structure, so that the maximum absorption and the maximum emission wavelength of the spectrum have no obvious difference.
Experimental example 2 Kidney clearance efficiency test
A PBS solution of 0.05mg/mL of normally-bright fluorescent probe compound 22 was prepared. 9 SD rats were randomly divided into A, B, C groups of 3, 150. Mu.L of the probe solution for tail vein injection. Mice were placed individually in clean metabolic cages after injection, urine was collected over 24h and volume was recorded. And (3) preparing a standard curve of probe concentration-ultraviolet absorption intensity by using an ultraviolet absorption spectrum, and calculating the recovery rate of the probe in the urine of the mice.
The test results are shown in fig. 2. The urine recovery rate of the probe is high and is 96%, 99% and 98%, and the zwitterionic fluorescent probe provided by the invention has good kidney clearance efficiency and can realize detection of urinary system diseases.
Experimental example 3 plasma protein binding Rate (PBB) test
A PBS solution of 0.05mg/mL of normally-bright fluorescent probe compound 22 was prepared. Taking 0.5mL fluorescent probe and 0.5mL FBS (fetal bovine serum) to incubate for 24 hours at 37 ℃ and then ultracentrifugating, analyzing by a fluorescent imaging system to obtain the fluorescent signal intensity of the lower layer (PBS layer) of the ultrafiltration tube filter membrane, and carrying the fluorescent signal intensity into the following formula to obtain the plasma protein binding rate.
As shown in FIG. 3, it can be seen from the graph that after the probes were incubated with FBS (fetal bovine serum) and ultracentrifuged, almost all of the probes on the upper layer (FBS layer) of the ultrafiltration tube membrane were filtered down to the lower layer (PBS solution layer), and the fluorescence signal on the upper layer of the membrane of the experimental group was similar to that of the blank group without the probes, indicating that the probes did not substantially interact with serum albumin and the like in fetal bovine serum, and the binding rate of the plasma protein of the probes was low, about 9.7%, as calculated according to the PPB test formula. The probes were shown to bind little to plasma proteins, metabolized in prototype form, and were responsible for their extremely high urine recovery.
Experimental example 4 plasma half-life test of Acute Kidney Injury (AKI) mice
The 18 SD rats were randomly divided into 6 groups, namely a blank control group (control group), an N-acetylcysteine (NAC) control group and a model group (24 h group, 36h group, 48h group and 72h group), and three groups each. (1) control group: injecting 1mL of physiological saline into the abdominal cavity; (2) AKI model group: injecting 10mg/kg cisplatin solution into abdominal cavity; (3) NAC group: NAC solution at a dose of 400mg/kg was injected caudally and intraperitoneally after 30min with 10mg/kg cisplatin solution.
Plasma half-life test: a PBS solution of 0.05mg/mL of normally-bright fluorescent probe compound 22 was prepared. 18 SD rats of the acute kidney injury model are randomly divided into 6 groups of Control, 24h, 36h, 48h, 72h and NAC, 3 of which are respectively injected with 150 mu L of probe solution for tail vein injection. And blood is collected from tail veins every 10min after injection, plasma is taken, the concentration of the fluorescent probe is measured according to peak area by HPLC, and a plasma half-life curve graph is drawn, as shown in figure 4, the fluorescent probe developed by the invention can be used for detecting the obvious change of kidney metabolism after about 36h of kidney injury, and the experimental result shows that the near infrared zwitterionic cyanine dye has the diagnosis effect of kidney function injury.
Experimental example 5 Probe metabolic pathway exploration
A PBS solution of 0.05mg/mL of normally-bright fluorescent probe compound 22 was prepared. 9 SD rats were randomly allocated to Control group, cation transporter inhibitor (cetiridine) group, and anion cargo inhibitor (probe) group, each group having 3 animals. (1) control group: injecting 1mL of physiological saline into the abdominal cavity; (2) group of cation transporter inhibitors (cetiridine): injecting 50mg/kg of cetiridine solution into the abdominal cavity; (3) anionic shipment inhibitors (probenecid) group: a50 mg/kg dose of probenecid solution was injected caudally.
150. Mu.L of probe solution was injected into the tail vein. And blood was collected from tail vein every 10min after injection, plasma was taken, fluorescent probe concentration was measured by HPLC according to peak area, and plasma half life graph was drawn as shown in fig. 5. According to the metabolism curve, the metabolism characteristics of the probe after the cation transporter and the anion transporter inhibitor are injected are not significantly different from those of a blank control group, the metabolism curve is similar, and experimental results show that the near infrared zwitterionic cyanine dye is not metabolized through a cation transporter or anion transporter pathway.
Experimental example 6 tissue distribution study of Probe
A PBS solution of 0.05mg/mL of normally-bright fluorescent probe compound 22 was prepared. Healthy SD rats were taken and randomly divided into four groups (1 h group, 2h group, 24h group, 72h group) and 150. Mu.L of the probe solution was injected into the tail vein. Rats were sacrificed 1h,2h,24h and 72h after injection, and major organs (heart He, liver Li, spleen Sp, lung Lu, kidney Ki, bladder Bl, small intestine In, skin Sk, muscle Mu) were collected and subjected to fluorescence imaging. The test results are shown in fig. 6, which show that the probe is mainly metabolized by the kidney, and is rapidly enriched in the kidney 1h after the probe is injected, other organs do not see obvious fluorescent signals, and the nonspecific uptake of the probe by other tissues and organs is extremely low, so that the probe can be used for detecting urinary system diseases.
Experimental example 6 Acute Kidney Injury (AKI) mouse organ imaging
The 18 SD rats were randomly divided into 6 groups, namely a blank control group (control group), a NAC control group and a model group (24 h group, 36h group, 48h group and 72h group), three in each group. (1) control group: injecting 1mL of physiological saline into the abdominal cavity; (2) AKI model group: injecting 10mg/kg cisplatin solution into abdominal cavity, and performing imaging examination at 24h, 36h, 48h, 72h after injection; (3) NAC group: NAC solution at a dose of 400mg/kg was injected into the tail vein, 10mg/kg of cisplatin solution was injected intraperitoneally after 30min, and imaging was performed at 48h after cisplatin injection. Finally, the mice were euthanized and the organs (heart He, liver Li, spleen Sp, lung Lu, kidney Ki, bladder Bl, small intestine In, skin Sk, muscle Mu) were imaged. As shown in FIG. 7, the probe compound 22 showed low fluorescence signal intensity after injection into the body, because the kidneys were normal and non-diseased in the control group. Along with the extension of time after cisplatin injection, cisplatin gradually damages kidney tissues, and induces acute kidney injury, so that the glomerular filtration rate of the kidney is reduced, the probe cannot be metabolized out of the body in time, enrichment phenomenon occurs in the kidney, and the fluorescence signal intensity of the kidney is increased along with the time. NAC is N-acetylcysteine, has the capacity of resisting oxidative damage, and can delay acute kidney injury induced by cisplatin to a certain extent, so that the kidney fluorescence signal intensity of NAC rats is similar to that of normal rats, and no obvious lesion exists in the kidney. The test result shows that the near infrared zwitterionic cyanine dye compound 22 can be used for diagnosing kidney injury and evaluating the therapeutic effect of the kidney injury-resisting medicaments, and has good application prospect.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. The near infrared zwitterionic cyanine dye is characterized by having a structure shown in any one of formulas (I) to (IV):
wherein X is NH, O or S; n is an integer of 0 to 20.
2. The near infrared zwitterionic cyanine dye of claim 1, wherein n is an integer from 1 to 20.
3. The near infrared zwitterionic cyanine dye of claim 2, having any of the following structures:
4. a process for the preparation of a near infrared zwitterionic cyanine dye of claim 3, comprising the steps of:
s1, performing condensation reaction on the compound 5 and the compound (1) to obtain a near infrared zwitterionic cyanine dye formula A compound;
or S2, carrying out condensation reaction on the compound 5 and the compound (2) to obtain the near infrared zwitterionic cyanine dye formula B compound;
or S3, performing condensation reaction on the compound 5 and the compound (3) to obtain the near infrared zwitterionic cyanine dye type C compound;
or S4, performing condensation reaction on the compound 5 and the compound (4) to obtain a near infrared zwitterionic cyanine dye formula D compound;
or S5, carrying out condensation reaction on the compound 5 and the compound (5) to obtain the near infrared zwitterionic cyanine dye compound;
or S6, carrying out condensation reaction on the compound 5 and the compound (6) to obtain the near infrared zwitterionic cyanine dye formula F compound;
or S7, carrying out condensation reaction on the compound 5 and the compound (7) to obtain the near infrared zwitterionic cyanine dye formula G compound;
or S8, carrying out condensation reaction on the compound 5 and the compound (8) to obtain the near infrared zwitterionic cyanine dye type H compound;
wherein the structure of the related compound is as follows:
wherein n is an integer of 1 to 20.
5. The process according to claim 4, wherein in the steps S1 to S8, the reaction temperature of the condensation reaction is 45 to 100℃and the time is 12 to 24 hours.
6. The process according to claim 4, wherein in the steps S1 to S8, the condensation reaction is carried out in the presence of an organic solvent selected from one or more of absolute ethanol, absolute methanol, N-dimethylformamide and acetic anhydride.
7. The process according to claim 4, wherein in the steps S1 to S8, the condensation reaction is carried out in the presence of an activator selected from one or more of potassium carbonate, cesium carbonate, sodium acetate, potassium acetate and triethylamine.
8. Use of a near infrared zwitterionic cyanine dye according to any of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, tautomer thereof, for the preparation of a fluorescent probe.
9. The use according to claim 8, wherein the fluorescent probe is a renal clearance type fluorescent probe.
10. A fluorescent probe comprising the near infrared zwitterionic cyanine dye of any of claims 1 to 3 and/or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, tautomer thereof.
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