CN111875587A - 5-fluorocytosine derivative, preparation method thereof and application thereof in 5-fluorocytosine immunodetection reagent - Google Patents
5-fluorocytosine derivative, preparation method thereof and application thereof in 5-fluorocytosine immunodetection reagent Download PDFInfo
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- CN111875587A CN111875587A CN202010717261.0A CN202010717261A CN111875587A CN 111875587 A CN111875587 A CN 111875587A CN 202010717261 A CN202010717261 A CN 202010717261A CN 111875587 A CN111875587 A CN 111875587A
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- Prior art keywords
- fluorocytosine
- solution
- derivative
- buffer solution
- dissolving
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- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 56
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Abstract
The invention obtains a brand-new 5-fluorocytosine derivative, and uses the 5-fluorocytosine derivative to prepare the 5-fluorocytosine artificial antigen with high immunogenicity, so as to immunize experimental animals to obtain the anti-5-fluorocytosine specific antibody with high titer; meanwhile, 5-fluorocytosine enzyme-labeled conjugate is prepared by using the 5-fluorocytosine derivative. The 5-fluorocytosine immunodetection reagent containing the anti-5-fluorocytosine specific antibody and the 5-fluorocytosine enzyme-labeled conjugate can realize the automatic determination of the content of 5-fluorocytosine on a full-automatic biochemical analyzer, can determine the content of 5-fluorocytosine in a biological sample in a high-throughput, rapid and accurate manner, has the advantages of simple and convenient operation, high sensitivity, strong specificity, accurate result and the like, effectively reduces the detection cost of 5-fluorocytosine, and is favorable for wide clinical popularization and application.
Description
Technical Field
The invention belongs to the field of biomedical inspection, and particularly relates to a 5-fluorocytosine derivative, a preparation method thereof and application thereof in a 5-fluorocytosine immunodetection reagent.
Background
5-fluorocytosine (5-FC) is an antifungal drug, has an antibacterial effect at low concentration and has a bactericidal effect at high concentration. The action mechanism is that the medicine enters cells through an osmotic enzyme system of the fungal cells, is converted into 5-fluorouracil under the action of cytosine deaminase of the fungal cells, replaces uracil to enter ribonucleic acid chains of the fungi, and accordingly blocks normal synthesis of the nucleic acid, and leads to apoptosis of the fungal cells. 5-fluorocytosine is mainly used for treating fungal infectious diseases caused by cryptococcus and candida, such as fungal septicemia, endocarditis, meningitis, pulmonary and genitourinary tract infections and the like. In addition, 5-fluorocytosine has antibacterial effect on Blastomyces, Mycobacteria, certain Coccomydia, and Aspergillus. The medicine is absorbed rapidly and completely, and is mainly distributed in organs such as liver, kidney, heart, lung, etc., and body fluid of joint cavity, abdominal cavity, etc., and can enter into cerebrospinal fluid, wherein the concentration of the medicine in cerebrospinal fluid can reach 5-10 times of that in blood. 5-fluorocytosine is only combined with protein by 2-4% in vivo, the half-life period is 2.5-6 h, the half-life period of people with renal insufficiency can be obviously prolonged, and about 90% of the medicine is filtered by glomeruli in an original shape and is discharged out of the body through urine. The 5-fluorocytosine and amphotericin B have synergistic effect, but can reduce the excretion amount of the product from the kidney, increase the blood concentration and promote the toxic reaction of the kidney and the blood system; the bone marrow inhibitor can also increase the toxicity of the product in blood system. The adverse reactions caused by using 5-fluorocytosine are more, and mainly comprise the following components: gastrointestinal symptoms (nausea, diarrhea), liver damage (elevated transaminase and alkaline phosphatase, and also liver enlargement and even liver necrosis), bone marrow suppression, leukopenia, anemia, thrombocytopenia, kidney damage, headache, dizziness, visual deterioration, hallucinations, hearing loss, dyskinesia, decreased serum kalium calcium phosphorus, anaphylaxis (such as skin rash), fatal granulocytopenia and aplastic anemia are also reported. Therefore, patients treated with 5-fluorocytosine need to regularly monitor their blood levels and adjust the therapeutic dose in time to achieve optimal therapeutic efficacy and reduce toxic side effects.
At present, the laboratory method for detecting 5-fluorocytosine mainly comprises high performance liquid chromatography, liquid chromatography-tandem mass spectrometry, capillary electrophoresis and the like. The methods have the disadvantages that the methods cannot be avoided, for example, the defects of complicated operation, low efficiency, long measuring period and high analysis cost of the high performance liquid chromatography and the liquid chromatography-tandem mass spectrometry limit the wide application of the methods in the clinical large-scale drug concentration monitoring, and the capillary electrophoresis method is more applied to scientific research laboratories and is difficult to realize the requirement of clinical accurate quantification. At present, 5-fluorocytosine detection reagents with good stability, high sensitivity and strong specificity, in particular high-throughput automatic detection reagents with good quality, are lacked in the market. Therefore, the research and development of a 5-fluorocytosine detection reagent which has the advantages of clinical requirement meeting quality, strong practicability and high cost performance and can be applied to a full-automatic biochemical analyzer becomes a hotspot in the therapeutic drug monitoring industry at home and abroad. The invention can realize high-flux and rapid detection of 5-fluorocytosine on a full-automatic biochemical analyzer, has the advantages of simple and convenient operation, high sensitivity, strong specificity, accurate result and the like, and can effectively meet the increasing clinical detection requirement in China.
Disclosure of Invention
The technical scheme adopted by the invention for solving the technical problems is as follows:
a5-fluorocytosine derivative is provided, and the structural formula of the derivative is shown as the following formula (I):
the compound is shown in a formula (I),
wherein R1 is a linking group
Wherein n is any integer between 1 and 10; preferably, the linking group is
。
Secondly, a preparation method of the 5-fluorocytosine derivative in the technical scheme I is provided, wherein the structural formula of the 5-fluorocytosine derivative is shown as a formula (II):
the compound of the formula (II),
the preparation method comprises the following steps:
(1) synthesis of Compound 3: compound 1 and compound 2 in the presence of K2CO3Is heated and refluxed in acetonitrile for 20 hours to prepare a reaction mixture. The reaction mixture was diluted with ethyl acetate, washed with purified water and brine, dried over sodium sulfate and evaporated to give compound 3.
(2) Synthesis of 5-fluorocytosine acid derivatives: dissolving compound 3 in methanol to obtain reaction solution, and adding LiOH2And O, then stirring at room temperature for reaction overnight, evaporating and drying the reacted solution under reduced pressure, and purifying the obtained residue by silica gel chromatography to obtain the 5-fluorocytosine acid derivative.
(3) Synthesis of 5-fluorocytosine maleimide derivative: dissolving the 5-fluorocytosine acid derivative in dimethylformamide, and then adding N, N-diisopropylethylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and the compound 4 to prepare a reaction mixture solution. The reaction mixture solution was stirred at room temperature overnight, and after completion of the reaction, purified water was added to the reaction mixture solution, followed by filtration. And purifying the filter cake obtained by filtering by using a flash column chromatography to obtain the 5-fluorocytosine maleimide derivative.
Preferably, the specific preparation steps of the 5-fluorocytosine derivative are as follows:
(1) synthesis of Compound 3: 2.6 g of Compound 1 (0.02mmol) and 3.6 g of Compound 2 (0.02mmol) were mixed in a solution containing 2.8 g K2CO3A reaction mixture was prepared by heating and refluxing (0.02mmol) in 25 ml of Acetonitrile (ACN) for 20 hours under cyclic conditions. The reaction mixture was diluted with ethyl acetate, washed with purified water and brine, dried over sodium sulfate and evaporated to give compound 3.
(2) Synthesis of 5-fluorocytosine acid derivatives: 2.3 g of Compound 3 (0.01 mmol) was dissolved in 20 ml of methanol (MeOH) to prepare a reaction solution, and 0.8 g of LiOH. H was added to the reaction solution at room temperature2O (0.02mmol), followed by stirring at room temperature overnight, drying the reacted solution by evaporation under reduced pressure, and purifying the obtained residue by silica gel chromatography to obtain a 5-fluorocytosine acid derivative.
(3) Synthesis of 5-fluorocytosine maleimide derivative: 0.65 g of 5-fluorocytosine acid derivative (3mmol) was dissolved in 5 ml of Dimethylformamide (DMF), and then 1.5 ml of N, N-Diisopropylethylamine (DIEA) (9mmol), 1.4 g of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (3mmol) and 0.45 g of compound 4(3 mmol) were added to prepare a reaction mixture solution. The reaction mixture solution was stirred at room temperature overnight, and after completion of the reaction, purified water (50 mL) was added to the reaction mixture solution, followed by filtration. And purifying the filter cake obtained by filtering by using a Flash Column Chromatography (FCC) method to obtain the 5-fluorocytosine maleimide derivative.
Thirdly, providing a 5-fluorocytosine artificial antigen which is formed by connecting a 5-fluorocytosine derivative and a carrier according to the technical scheme I, wherein the structural formula is shown as a formula (III):
a compound of the formula (III),
wherein R2 is a linking group
Wherein n is any integer between 1 and 10; preferably, the linking group is
(ii) a The carrier is one of serum albumin, immunoglobulin, fibrinogen, ovalbumin, thyroglobulin, hemocyanin and polylysine, preferably serum protein, and more preferably bovine serum albumin.
Fourthly, an anti-5-fluorocytosine specific antibody is provided, which is obtained by separating and purifying the 5-fluorocytosine artificial antigen immune experimental animal in the technical scheme III.
The anti-5-fluorocytosine specific antibody is a polyclonal antibody obtained by enhancing immunity of the 5-fluorocytosine artificial antigen to an experimental animal in the third technical scheme, or is a monoclonal antibody obtained by immunizing the experimental animal with the 5-fluorocytosine artificial antigen in the third technical scheme and then hybridizing somatic cells; the host animal is one of rabbit, goat, sheep, rat, mouse, guinea pig or horse.
Fifthly, the 5-fluorocytosine immunodetection reagent is provided, and consists of the following components:
reagent R1: comprises the anti-5-fluorocytosine specific antibody and an R1 buffer solution, wherein the R1 buffer solution consists of bovine serum albumin, glucose-6-phosphate, oxidized nicotinamide adenine dinucleotide and a Tris buffer solution;
reagent R2: the enzyme-labeled conjugate of 5-fluorocytosine and R2 buffer solution are included, the enzyme-labeled conjugate of 5-fluorocytosine is formed by connecting a 5-fluorocytosine derivative and glucose-6-phosphate dehydrogenase in the technical scheme I, and the R2 buffer solution is composed of bovine serum albumin and Tris buffer solution.
Calibration solution: consists of 5-fluorocytosine pure powder, Tris-HCl buffer solution, sodium chloride, bovine serum albumin, ethylene diamine tetraacetic acid and sodium azide.
Sixthly, a preparation method of the 5-fluorocytosine immunodetection reagent provided by the technical scheme five is provided, which comprises the following specific steps:
(1) sequentially adding bovine serum albumin, glucose-6-phosphate and oxidized nicotinamide adenine dinucleotide into a Tris buffer solution, stirring and dissolving to prepare an R1 buffer solution, adding the anti-5-fluorocytosine specific antibody in the technical scheme IV into the R1 buffer solution according to the volume ratio of 1: 100-1: 10000, uniformly mixing, and adjusting the pH value to 6.0-9.0 by using hydrochloric acid to prepare an R1 reagent;
(2) adding bovine serum albumin into a Tris buffer solution, stirring and dissolving to prepare an R2 buffer solution, adding the 5-fluorocytosine enzyme-labeled conjugate in the technical scheme V into the R2 buffer solution according to the volume ratio of 1: 100-1: 10000, uniformly mixing, and adjusting the pH value to 6.0-9.0 by using hydrochloric acid to prepare an R2 reagent;
(3) respectively adding 5-fluorocytosine pure powder into 6 parts of Tris-HCl buffer solution, stirring and dissolving until the final concentrations are respectively 0.0 mu g/mL, 4.0-6.0 mu g/mL, 8.0-12.0 mu g/mL, 16.0-24.0 mu g/mL, 32.0-48.0 mu g/mL and 64.0-96.0 mu g/mL, then respectively adding sodium chloride, bovine serum albumin, ethylenediamine tetraacetic acid and sodium azide into each solution, and uniformly stirring to obtain the 5-fluorocytosine calibration solution.
Preferably, the specific preparation steps of the 5-fluorocytosine immunodetection reagent are as follows:
(1) sequentially adding 0.25% bovine serum albumin, 50mmol/L glucose-6-phosphate and 50mmol/L oxidized nicotinamide adenine dinucleotide into 50mmol/L Tris buffer solution, stirring and dissolving to prepare R1 buffer solution, adding the anti-5-fluorocytosine specific antibody in the technical scheme IV into the R1 buffer solution according to the volume ratio of 1: 500-1: 5000, uniformly mixing, and adjusting the pH value to 8.0 by using 6mol/L hydrochloric acid to prepare an R1 reagent;
(2) adding 0.25% bovine serum albumin into 100mmol/L Tris buffer solution, stirring and dissolving to prepare R2 buffer solution, adding the 5-fluorocytosine enzyme-labeled conjugate in the technical scheme V into the R2 buffer solution according to the volume ratio of 1: 1000-1: 8000, uniformly mixing, and adjusting the pH to 7.6 by using 6mol/L hydrochloric acid to prepare an R2 reagent;
(3) respectively adding 5-fluorocytosine pure powder into 6 parts of Tris-HCl buffer solution with the concentration of 50mmol/L and the pH =7.2, stirring and dissolving until the final concentration is 0.0 mu g/mL, 5.0 mu g/mL, 10.0 mu g/mL, 20.0 mu g/mL, 40.0 mu g/mL and 80.0 mu g/mL, respectively, then respectively adding sodium chloride with the mass fraction of 0.5%, bovine serum albumin with the mass fraction of 1.0%, ethylene diamine tetraacetic acid with the mass fraction of 0.75% and sodium azide with the mass fraction of 0.05% into each solution, and uniformly stirring to prepare the 5-fluorocytosine calibration solution.
Wherein the preparation of the anti-5-fluorocytosine specific antibody comprises the following steps:
a. dissolving potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride and magnesium chloride in deionized water to obtain buffer solution A;
b. dissolving bovine serum albumin in the buffer solution A to prepare a carrier protein solution;
c. dissolving the 5-fluorocytosine derivative shown in the structural formula (I) in the buffer solution A to prepare a 5-fluorocytosine derivative solution;
d. when the 5-fluorocytosine derivative solution just becomes clear, the 5-fluorocytosine derivative solution is added dropwise into the carrier protein solution, and then the mixed solution is stirred for 12 hours;
e. the mixed solution after reaction is used as dialysate by taking the buffer solution A as the dialysateDialyzing to obtain 5-fluorocytosine immunogen solution, and adding NaN into the 5-fluorocytosine immunogen solution3Storing at-20 deg.C;
f. diluting the 5-fluorocytosine immunogen solution into a 5-fluorocytosine artificial antigen solution by using a potassium phosphate buffer solution, mixing the 5-fluorocytosine artificial antigen solution with an equivalent amount of Freund's complete adjuvant, and injecting the experimental animal; after 21 days, mixing the same 5-fluorocytosine artificial antigen solution with the same amount of Freund incomplete adjuvant, and injecting the mixture once to the experimental animal; injecting the mixture once every 21 days by the same method, collecting blood from the experimental animal after 4 months from the initial injection of the experimental animal, and separating and purifying to obtain the polyclonal antibody.
Preferably, the preparation of said anti-5-fluorocytosine specific antibody comprises the following specific steps:
a. weighing 8 g of potassium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 2.5 g of sodium chloride and 3.5 g of magnesium chloride, dissolving the components in 500mL of deionized water together, and adjusting the pH value to 8.2 to prepare a buffer solution A;
b. weighing 100 mg of bovine serum albumin, and dissolving the bovine serum albumin in 100 mL of the buffer solution A at 4 ℃ to prepare a carrier protein solution;
c. weighing 10 mg of the 5-fluorocytosine derivative shown in the structural formula (II) and dissolving the 5-fluorocytosine derivative into 10mL of the buffer solution A at 4 ℃ to prepare a 5-fluorocytosine derivative solution;
d. when the 5-fluorocytosine derivative solution is just clear, dropwise adding the 5-fluorocytosine derivative solution into the carrier protein solution, and then stirring the mixed solution at-8 ℃ for 12 hours;
e. dialyzing the reacted mixed solution by taking 300mL of the buffer solution A as dialysate, wherein the solution obtained after dialysis is the 5-fluorocytosine immunogen solution, and adding NaN with the mass fraction of 0.1% into the 5-fluorocytosine immunogen solution3Storing at-20 deg.C;
f. diluting the 5-fluorocytosine immunogen into a 5-fluorocytosine artificial antigen solution with the concentration of 1.0mg/mL by using a potassium phosphate buffer solution (10 mmol/L, pH 7.4), mixing the 5-fluorocytosine artificial antigen solution with an equivalent amount of Freund's complete adjuvant, and injecting the mixture into a rabbit, wherein the injection amount is 10 mL/mouse; after 21 days, the same 5-fluorocytosine artificial antigen solution is mixed with the same amount of Freund incomplete adjuvant, and the injection is injected once to the rabbit, wherein the injection amount is 8 mL/rabbit; injecting every 21 days by the same method, collecting blood from the rabbit after 4 months, separating and purifying to obtain polyclonal antibody.
Wherein the preparation of the 5-fluorocytosine enzyme-labeled conjugate comprises the following steps:
a. dissolving potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride and magnesium chloride in deionized water to obtain buffer solution B;
b. dissolving glucose-6-phosphate dehydrogenase in the buffer solution B to obtain glucose-6-phosphate dehydrogenase solution;
c. dissolving the 5-fluorocytosine derivative shown in the structural formula (I) in the buffer solution B to prepare a 5-fluorocytosine derivative solution;
d. when the 5-fluorocytosine derivative solution just becomes clear, the 5-fluorocytosine derivative solution is added dropwise into the glucose-6-phosphate dehydrogenase solution, and then the mixed solution is stirred for 12 hours;
e. dialyzing the reacted mixed solution by using the buffer solution B as dialysate to obtain a solution, namely a 5-fluorocytosine enzyme-labeled conjugate solution, and adding BSA and NaN into the 5-fluorocytosine enzyme-labeled conjugate solution3And stored at 4 ℃.
Preferably, the preparation of the 5-fluorocytosine enzyme-labeled conjugate comprises the following specific steps:
a. weighing 1.8 g of monopotassium phosphate, 2.5 g of disodium hydrogen phosphate, 1.5 g of sodium chloride and 1.5 g of magnesium chloride, dissolving the components in 500mL of deionized water, and adjusting the pH value to 8.2 to prepare a buffer solution B;
b. weighing 100 mg of glucose-6-phosphate dehydrogenase, and dissolving the glucose-6-phosphate dehydrogenase in 100 mL of the buffer solution B at the temperature of 4 ℃ to prepare a glucose-6-phosphate dehydrogenase solution;
c. weighing 10 mg of the 5-fluorocytosine derivative represented by the structural formula (II) above, and dissolving the 5-fluorocytosine derivative in 10mL of the buffer solution B at 4 ℃ to prepare a 5-fluorocytosine derivative solution;
d. when the 5-fluorocytosine derivative solution is just clear, the 5-fluorocytosine derivative solution is dropwise added into the glucose-6-phosphate dehydrogenase solution, and then the mixed solution is stirred at-8 ℃ for 12 hours;
e. dialyzing the reacted mixed solution by using 300mL of the buffer solution B as dialysate to obtain a solution, namely a 5-fluorocytosine enzyme-labeled conjugate solution, and adding BSA with the mass fraction of 0.5% and NaN with the mass fraction of 0.1% into the 5-fluorocytosine enzyme-labeled conjugate solution3And stored at 4 ℃.
Seventhly, the application of the 5-fluorocytosine immunoassay reagent is provided, the immunoassay reagent is used for measuring the content of 5-fluorocytosine or 5-fluorocytosine in a biological sample, the biological sample is a liquid physiological sample of a human body or an animal, and the liquid physiological sample is serum, plasma, whole blood, urine, saliva, lymph fluid, interstitial fluid, cerebrospinal fluid, amniotic fluid or tear fluid.
The invention provides a novel 5-fluorocytosine derivative and a preparation method thereof, and an anti-5-fluorocytosine specific antibody developed by using the novel 5-fluorocytosine derivative can be used for preparing a 5-fluorocytosine immunoassay reagent with high sensitivity, strong specificity and good detection effect. The invention also provides a preparation method and a corresponding using method of the 5-fluorocytosine immunoassay reagent. The 5-fluorocytosine immunodetection reagent provided by the invention is convenient to use, rapid in detection, accurate in result, high in sensitivity and strong in specificity, and can be used for quantitatively detecting the content of 5-fluorocytosine in human serum, plasma and other samples. The defects of complex operation, low automation degree and the like of the 5-fluorocytosine detection method in the prior art are overcome, and clinical individualized and reasonable administration can be effectively guided.
Drawings
FIG. 1 is a graph showing the reaction standard of 5-fluorocytosine sample detection using a 5-fluorocytosine immunoassay reagent.
Detailed Description
The present invention will be further described with reference to the accompanying drawings, which are simplified schematic drawings illustrating only the basic structure of the present invention and showing only the constitution related to the present invention, and detailed embodiments. Unless otherwise specified, reagents, instruments, equipment, consumables used in the following examples are all available from a regular distributor.
Example 1: preparation of 5-fluorocytosine derivatives
The structural formula of the 5-fluorocytosine derivative is shown as the formula (II):
the compound of the formula (II),
the specific preparation steps of the 5-fluorocytosine derivative are as follows:
(1) synthesis of Compound 3: 2.6 g of Compound 1 (0.02mmol) and 3.6 g of Compound 2 (0.02mmol) were mixed in a solution containing 2.8 g K2CO3A reaction mixture was prepared by heating and refluxing (0.02mmol) in 25 ml of Acetonitrile (ACN) for 20 hours under cyclic conditions. The reaction mixture was diluted with ethyl acetate, washed with purified water and brine, then dried over sodium sulfate and evaporated to give 2.5 g of compound 3 as a white foam.
(2) Synthesis of 5-fluorocytosine acid derivatives: 2.3 g of Compound 3 (0.01 mmol) was dissolved in 20 ml of methanol (MeOH) to prepare a reaction solution, and 0.8 g of LiOH. H was added to the reaction solution at room temperature2O (0.02mmol), followed by stirring at room temperature overnight, the reacted solution was dried by evaporation under reduced pressure, and the obtained residue was purified by silica gel chromatography to give 2.1 g of 5-fluorocytosine acid derivative.
(3) Synthesis of 5-fluorocytosine maleimide derivative: 0.65 g of 5-fluorocytosine acid derivative (3mmol) was dissolved in 5 ml of Dimethylformamide (DMF), and then 1.5 ml of N, N-Diisopropylethylamine (DIEA) (9mmol), 1.4 g of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (3mmol) and 0.45 g of compound 4(3 mmol) were added to prepare a reaction mixture solution. The reaction mixture solution was stirred at room temperature overnight, and after completion of the reaction, purified water (50 mL) was added to the reaction mixture solution, followed by filtration. The filter cake obtained by the filtration was purified by Flash Column Chromatography (FCC) to obtain 0.6 g of 5-fluorocytosine maleimide derivative as a white solid.
By passing1The structural identification of the 5-fluorocytosine maleimide derivative obtained in the above preparation step as a white solid was carried out by H NMR (Varian mercury plus 400 MHz) spectral scanning analysis (TMS as an internal standard) and LC-MS (Agilent 1200A), and the results showed that: the 5-fluorocytosine maleimide derivative is a 5-fluorocytosine derivative with a structural formula shown as a formula (II).
The formula (II).
Example 2: preparation of 5-fluorocytosine immunoassay reagent
The specific preparation steps of the 5-fluorocytosine immunodetection reagent are as follows:
(1) sequentially adding 0.25% bovine serum albumin, 50mmol/L glucose-6-phosphate and 50mmol/L oxidized nicotinamide adenine dinucleotide into 50mmol/L Tris buffer solution, stirring and dissolving to prepare R1 buffer solution, adding an anti-5-fluorocytosine specific antibody into the R1 buffer solution according to the volume ratio of 1: 1500, uniformly mixing, and adjusting the pH value to 8.0 by using 6mol/L hydrochloric acid to prepare an R1 reagent;
(2) adding 0.25% bovine serum albumin into 100mmol/L Tris buffer solution, stirring and dissolving to prepare R2 buffer solution, adding the 5-fluorocytosine enzyme-labeled conjugate into the R2 buffer solution according to the volume ratio of 1: 3000, uniformly mixing, and adjusting the pH to 7.6 by using 6mol/L hydrochloric acid to prepare an R2 reagent;
(3) respectively adding 5-fluorocytosine pure powder into 6 parts of Tris-HCl buffer solution with the concentration of 50mmol/L and the pH =7.2, stirring and dissolving until the final concentration is 0.0 mu g/mL, 5.0 mu g/mL, 10.0 mu g/mL, 20.0 mu g/mL, 40.0 mu g/mL and 80.0 mu g/mL, respectively, then respectively adding sodium chloride with the mass fraction of 0.5%, bovine serum albumin with the mass fraction of 1.0%, ethylene diamine tetraacetic acid with the mass fraction of 0.75% and sodium azide with the mass fraction of 0.05% into each solution, and uniformly stirring to prepare the 5-fluorocytosine calibration solution.
Wherein, the preparation of the anti-5-fluorocytosine specific antibody in the step (1) comprises the following specific steps:
a. weighing 8 g of potassium dihydrogen phosphate, 12 g of disodium hydrogen phosphate, 2.5 g of sodium chloride and 3.5 g of magnesium chloride, dissolving the components in 500mL of deionized water together, and adjusting the pH value to 8.2 to prepare a buffer solution A;
b. weighing 100 mg of bovine serum albumin, and dissolving the bovine serum albumin in 100 mL of the buffer solution A at 4 ℃ to prepare a carrier protein solution;
c. weighing 10 mg of the 5-fluorocytosine derivative shown in the structural formula (II) and dissolving the 5-fluorocytosine derivative into 10mL of the buffer solution A at 4 ℃ to prepare a 5-fluorocytosine derivative solution;
d. when the 5-fluorocytosine derivative solution is just clear, dropwise adding the 5-fluorocytosine derivative solution into the carrier protein solution, and then stirring the mixed solution at-8 ℃ for 12 hours;
e. dialyzing the reacted mixed solution by taking 300mL of the buffer solution A as dialysate, wherein the solution obtained after dialysis is the 5-fluorocytosine immunogen solution, and adding NaN with the mass fraction of 0.1% into the 5-fluorocytosine immunogen solution3Storing at-20 deg.C;
f. diluting the 5-fluorocytosine immunogen into a 5-fluorocytosine artificial antigen solution with the concentration of 1.0mg/mL by using a potassium phosphate buffer solution (10 mmol/L, pH 7.4), mixing the 5-fluorocytosine artificial antigen solution with an equivalent amount of Freund's complete adjuvant, and injecting the mixture into a rabbit, wherein the injection amount is 10 mL/mouse; after 21 days, the same 5-fluorocytosine artificial antigen solution is mixed with the same amount of Freund incomplete adjuvant, and the injection is injected once to the rabbit, wherein the injection amount is 8 mL/rabbit; injecting every 21 days by the same method, collecting blood from the rabbit after 4 months, separating and purifying to obtain polyclonal antibody.
Wherein, the preparation of the 5-fluorocytosine enzyme-labeled conjugate in the step (2) comprises the following specific steps:
a. weighing 1.8 g of monopotassium phosphate, 2.5 g of disodium hydrogen phosphate, 1.5 g of sodium chloride and 1.5 g of magnesium chloride, dissolving the components in 500mL of deionized water, and adjusting the pH value to 8.2 to prepare a buffer solution B;
b. weighing 100 mg of glucose-6-phosphate dehydrogenase, and dissolving the glucose-6-phosphate dehydrogenase in 100 mL of the buffer solution B at the temperature of 4 ℃ to prepare a glucose-6-phosphate dehydrogenase solution;
c. weighing 10 mg of the 5-fluorocytosine derivative represented by the structural formula (II) above, and dissolving the 5-fluorocytosine derivative in 10mL of the buffer solution B at 4 ℃ to prepare a 5-fluorocytosine derivative solution;
d. when the 5-fluorocytosine derivative solution is just clear, the 5-fluorocytosine derivative solution is dropwise added into the glucose-6-phosphate dehydrogenase solution, and then the mixed solution is stirred at-8 ℃ for 12 hours;
e. dialyzing the reacted mixed solution by using 300mL of the buffer solution B as dialysate to obtain a solution, namely a 5-fluorocytosine enzyme-labeled conjugate solution, and adding BSA with the mass fraction of 0.5% and NaN with the mass fraction of 0.1% into the 5-fluorocytosine enzyme-labeled conjugate solution3And stored at 4 ℃.
Example 3: 5-fluorocytosine sample detection by using 5-fluorocytosine immunoassay reagent
1. Making a standard curve:
(1) reaction parameters of the michigan BS480 fully-automatic biochemical analyzer were set (table 1).
(2) The operation steps are as follows: the reagent R1 was added first, the calibration solution was added, and finally the reagent R2 was added. After reagent R2 is added, OD340nm light absorption values at different time points are measured, reaction rates at different concentrations of calibration solution are calculated, the volume ratio of R1 reagent to R2 reagent needs to be adjusted continuously in the actual operation process, the light measurement point is adjusted at the same time, and finally the optimal reaction standard curve chart is obtained, as shown in figure 1.
TABLE 1 Merrill BS480 fully automatic biochemical analyzer for detecting 5-fluorocytosine reaction parameters
2. Sample detection: the standard curve obtained by using the 5-fluorocytosine immunoassay reagent is used for repeatedly measuring low, medium and high concentration quality control samples for 10 times, wherein the quality control samples are as follows: 5-fluorocytosine standards were dissolved in blank artificial plasma to concentrations of 15.00, 30.00, 60.00 ng/mL, respectively. The results and data analysis are shown in Table 2.
TABLE 25 Fluocytidyl sample measurements and evaluation of precision and recovery
| Blood sample | Is low in | In | Height of |
| Sample concentration (ng/mL) | 15.00 | 30.00 | 60.00 |
| 1 | 14.62 | 31.46 | 58.96 |
| 2 | 15.62 | 28.92 | 59.62 |
| 3 | 16.34 | 29.57 | 59.32 |
| 4 | 14.88 | 29.64 | 57.96 |
| 5 | 15.32 | 29.84 | 59.82 |
| 6 | 16.22 | 27.59 | 62.31 |
| 7 | 14.92 | 31.15 | 61.47 |
| 8 | 14.77 | 30.55 | 61.33 |
| 9 | 15.16 | 30.95 | 60.57 |
| 10 | 15.82 | 30.67 | 58.74 |
| Mean value (ng/mL) | 15.37 | 30.03 | 60.01 |
| Standard Deviation (SD) | 0.609 | 1.174 | 1.377 |
| Precision (CV%) | 3.96 | 3.91 | 2.29 |
| Recovery (%) | 102.46 | 100.10 | 100.02 |
And (3) detection results: the 5-fluorocytosine immunoassay reagent can accurately determine the content of 5-fluorocytosine, and the recovery rate is 95-105%; the coefficient of variation CV was less than 5%.
Example 4: common drug interference test
Selecting 62 common medicines as interferents to carry out interference tests, preparing pure powder of the 62 common medicines into a solution with the concentration of 100.0ng/mL as an interferent sample to be detected, and detecting by using the 5-fluorocytosine immunoassay reagent prepared in the example 2: the sample of the interferent to be detected is contacted and reacted with the R1 reagent prepared in the embodiment 2, and then the R2 reagent is added; and detecting the OD340 light absorption value of the mixed solution, and obtaining the concentration of the corresponding substance according to the standard curve of the figure 1. The names of the 62 common medicines and the detection results are shown in Table 3.
TABLE 3 common drug interference test results
| ID# | Name of Compound | Actual detection value (ng/mL) | ID# | Name of Compound | Actual detection value (ng/mL) |
| 1 | Aspirin | 0.00 | 2 | Phenylpropanolamine | 0.00 |
| 3 | Beta-phenylethylamine | 0.00 | 4 | Procaine amides | 0.00 |
| 5 | Amphetamines | 0.00 | 6 | Procaine | 0.00 |
| 7 | Ampicillin | 0.00 | 8 | Quinidine (I) | 0.00 |
| 9 | Methotrexate tall and erect | 0.00 | 10 | Zuomei acid | 0.00 |
| 11 | Chlorpromazine | 0.00 | 12 | Phenylephrine | 0.00 |
| 13 | Loratadine acid | 0.00 | 14 | Cinnamyl Aikening | 0.00 |
| 15 | Dimethylphenoxy heptanoic acid | 0.00 | 16 | Ecgonine | 0.00 |
| 17 | Fenoprofen | 0.00 | 18 | Dixiyang | 0.00 |
| 19 | Methylamphetamine | 0.00 | 20 | Cotinine | 0.00 |
| 21 | Gentisic acid | 0.00 | 22 | Atenolol | 0.00 |
| 23 | Gemfibrozil | 0.00 | 24 | Xinde' an medicine | 0.00 |
| 25 | Hydrocodone | 0.00 | 26 | Phenylethylpiperidinone | 0.00 |
| 27 | Ibuprofen | 0.00 | 28 | Phenylbutyrophenones | 0.00 |
| 29 | Imipramine | 0.00 | 30 | Lysergic acid diethylamide | 0.00 |
| 31 | Diamino diphenyl sulfone | 0.00 | 32 | Cannabinol | 0.00 |
| 33 | Naproxen | 0.00 | 34 | Loperamide | 0.00 |
| 35 | Hydrochlorothiazide | 0.00 | 36 | Yikeshuling | 0.00 |
| 37 | Pertipidine | 0.00 | 38 | Phenylalanine (phenylalanine) | 0.00 |
| 39 | Allyl oxymorphone | 0.00 | 40 | Fluoxetine hydrochloride | 0.00 |
| 41 | Ephedrine | 0.00 | 42 | Salbutamol | 0.00 |
| 43 | Nicotinamide | 0.00 | 44 | Penicillin | 0.00 |
| 45 | Methylamirfurthion | 0.00 | 46 | Methyldiethanolamine | 0.00 |
| 47 | Pregabal | 0.00 | 48 | Dimethylene dioxyamphetamine | 0.00 |
| 49 | Methylenedioxyamphetamine | 0.00 | 50 | Doxylamine succinate | 0.00 |
| 51 | Tetrahydrocannabinol | 0.00 | 52 | Nalbuphine | 0.00 |
| 53 | Nystatin | 0.00 | 54 | Normorphine | 0.00 |
| 55 | Acetylmorphine | 0.00 | 56 | Oxycodone | 0.00 |
| 57 | Benzphetamine | 0.00 | 58 | Ketamin | 0.00 |
| 59 | Promethazine | 0.00 | 60 | Diphenhydramine | 0.00 |
| 61 | Aspartame | 0.00 | 62 | Phenylbutylamine | 0.00 |
The measurement results show that: the 62 common medicines are detected by the 5-fluorocytosine immunoassay reagent prepared in the example 2, and the actual detection values are all 0.00 ng/mL. Therefore, the anti-5-fluorocytosine specific antibody has stronger antigen recognition specificity and has no cross reaction with 62 common medicines.
Example 5: validation of the Properties of reagents prepared using 5-fluorocytosine derivatives of different linking groups
To illustrate that 5-fluorocytosine derivatives using other different linking groups according to the present invention can be used for preparing 5-fluorocytosine immunoassay reagents and all have performance advantages, 5-fluorocytosine derivatives using various different linking groups were used to prepare corresponding 5-fluorocytosine immunoassay reagents according to the method described in example 2, and the prepared 5-fluorocytosine immunoassay reagents were subjected to the experiments according to the methods described in examples 3 to 5, and the results of the structure of the linking group and the performance verification of the reagents of the 5-fluorocytosine derivatives used in each experimental protocol are shown in table 4:
TABLE 4 validation of the Properties of reagents prepared using 5-fluorocytosine derivatives of different linking groups
The experimental results show that: the invention uses other 5-fluorocytosine derivatives with different connecting groups to prepare 5-fluorocytosine immunoassay reagents, and has excellent performance.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present invention or directly or indirectly applied to other related technical fields are included in the scope of the present invention.
Claims (10)
1.5-fluorocytosine derivatives characterized in that they have the formula (i):
the compound is shown in a formula (I),
wherein R1 is a linking group
Wherein n is any integer between 1 and 10; preferably, the linking group is
。
2. A process for the preparation of a 5-fluorocytosine derivative according to claim 1, wherein the 5-fluorocytosine derivative has a structural formula represented by formula (ii):
the compound of the formula (II),
the preparation method comprises the following steps:
(1) synthesis of Compound 3: compound 1 and compound 2 in the presence of K2CO3Heating and refluxing the mixture in acetonitrile for 20 hours in a circulating manner to prepare a reaction mixture, diluting the reaction mixture by using ethyl acetate, washing the reaction mixture by using purified water and concentrated brine, drying the reaction mixture by using sodium sulfate, and finally evaporating the reaction mixture to obtain a compound 3;
(2) synthesis of 5-fluorocytosine acid derivatives: dissolving compound 3 in methanol to obtain reaction solution, and adding LiOH2O, stirring at room temperature for reacting overnight, evaporating and drying the reacted solution under reduced pressure, and purifying the obtained residue by silica gel chromatography to obtain a 5-fluorocytosine acid derivative;
(3) synthesis of 5-fluorocytosine maleimide derivative: dissolving a 5-fluorocytosine acid derivative in dimethylformamide, adding N, N-diisopropylethylamine, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and a compound 4 to prepare a reaction mixture solution, stirring the reaction mixture solution at room temperature overnight, adding purified water into the reaction mixture solution after the reaction is finished, filtering, and purifying a filter cake obtained by filtering by using a rapid column chromatography to obtain the 5-fluorocytosine maleimide derivative.
A5-fluorocytosine artificial antigen, which is formed by linking the 5-fluorocytosine derivative according to claim 1 to a carrier and has a structural formula represented by the formula (III):
a compound of the formula (III),
wherein R2 is a linking group
Wherein n is any integer between 1 and 10; preferably, the linking group is
(ii) a The carrier is one of serum albumin, immunoglobulin, fibrinogen, ovalbumin, thyroglobulin, hemocyanin and polylysine, preferably serum protein, and more preferably bovine serum albumin.
4. An antibody specific to 5-fluorocytosine, which is obtained by immunizing an animal to be tested with the 5-fluorocytosine artificial antigen according to claim 3 and then isolating and purifying the antibody.
5. The anti-5-fluorocytosine specific antibody according to claim 4, characterized in that: the antibody is a polyclonal antibody obtained by boosting immunization of an experimental animal with the 5-fluorocytosine artificial antigen described in claim 3, or a monoclonal antibody obtained by somatic hybridization after immunization of an experimental animal with the 5-fluorocytosine artificial antigen described in claim 3; the host animal is one of rabbit, goat, sheep, rat, mouse, guinea pig or horse.
6. The 5-fluorocytosine immunodetection reagent is characterized by comprising the following components:
reagent R1: comprising the anti-5-fluorocytosine specific antibody of any one of claims 4 to 5 and an R1 buffer, the R1 buffer consisting of bovine serum albumin, glucose-6-phosphate, oxidized nicotinamide adenine dinucleotide and Tris buffer;
reagent R2: the enzyme-labeled conjugate of 5-fluorocytosine and R2 buffer solution are contained, the enzyme-labeled conjugate of 5-fluorocytosine is formed by connecting the 5-fluorocytosine derivative of claim 1 and glucose-6-phosphate dehydrogenase, and the R2 buffer solution is composed of bovine serum albumin and Tris buffer solution;
calibration solution: consists of 5-fluorocytosine pure powder, Tris-HCl buffer solution, sodium chloride, bovine serum albumin, ethylene diamine tetraacetic acid and sodium azide.
7. A method for preparing the 5-fluorocytosine immunodetection reagent according to claim 6, which comprises the following steps:
(1) sequentially adding bovine serum albumin, glucose-6-phosphate and oxidized nicotinamide adenine dinucleotide into a Tris buffer solution, stirring and dissolving to prepare an R1 buffer solution, adding the anti-5-fluorocytosine specific antibody of any one of claims 4 to 5 into the R1 buffer solution according to the volume ratio of 1: 100-1: 10000, uniformly mixing, and adjusting the pH to 6.0-9.0 by using hydrochloric acid to prepare an R1 reagent;
(2) adding bovine serum albumin into a Tris buffer solution, stirring and dissolving to prepare an R2 buffer solution, adding the 5-fluorocytosine enzyme-labeled conjugate in the volume ratio of 1: 100-1: 10000 to the R2 buffer solution, uniformly mixing, and adjusting the pH to 6.0-9.0 by using hydrochloric acid to prepare an R2 reagent;
(3) respectively adding 5-fluorocytosine pure powder into 6 parts of Tris-HCl buffer solution, stirring and dissolving until the final concentrations are respectively 0.0 mu g/mL, 4.0-6.0 mu g/mL, 8.0-12.0 mu g/mL, 16.0-24.0 mu g/mL, 32.0-48.0 mu g/mL and 64.0-96.0 mu g/mL, then respectively adding sodium chloride, bovine serum albumin, ethylenediamine tetraacetic acid and sodium azide into each solution, and uniformly stirring to obtain the 5-fluorocytosine calibration solution.
8. The method for preparing a 5-fluorocytosine immunodetection reagent according to claim 7, wherein the preparation of the anti-5-fluorocytosine specific antibody comprises the steps of:
a. dissolving potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride and magnesium chloride in deionized water to obtain buffer solution A;
b. dissolving bovine serum albumin in the buffer solution A to prepare a carrier protein solution;
c. dissolving a 5-fluorocytosine derivative represented by the structural formula (i) in claim 1 in the buffer solution a to prepare a 5-fluorocytosine derivative solution;
d. when the 5-fluorocytosine derivative solution just becomes clear, the 5-fluorocytosine derivative solution is added dropwise into the carrier protein solution, and then the mixed solution is stirred for 12 hours;
e. dialyzing the reacted mixed solution by using the buffer solution A as dialysate to obtain a solution which is a 5-fluorocytosine immunogen solution, and adding NaN into the 5-fluorocytosine immunogen solution3Storing at-20 deg.C;
f. diluting the 5-fluorocytosine immunogen solution into a 5-fluorocytosine artificial antigen solution by using a potassium phosphate buffer solution, mixing the 5-fluorocytosine artificial antigen solution with an equivalent amount of Freund's complete adjuvant, and injecting the experimental animal; after 21 days, mixing the same 5-fluorocytosine artificial antigen solution with the same amount of Freund incomplete adjuvant, and injecting the mixture once to the experimental animal; injecting the mixture once every 21 days by the same method, collecting blood from the experimental animal after 4 months from the initial injection of the experimental animal, and separating and purifying to obtain the polyclonal antibody.
9. The method for preparing a 5-fluorocytosine immunodetection reagent according to claim 7, wherein the preparation of the 5-fluorocytosine enzyme-labeled conjugate comprises the steps of:
a. dissolving potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride and magnesium chloride in deionized water to obtain buffer solution B;
b. dissolving glucose-6-phosphate dehydrogenase in the buffer solution B to obtain glucose-6-phosphate dehydrogenase solution;
c. dissolving a 5-fluorocytosine derivative represented by the structural formula (i) in claim 1 in the buffer solution B to prepare a 5-fluorocytosine derivative solution;
d. when the 5-fluorocytosine derivative solution just becomes clear, the 5-fluorocytosine derivative solution is added dropwise into the glucose-6-phosphate dehydrogenase solution, and then the mixed solution is stirred for 12 hours;
e. dialyzing the reacted mixed solution by using the buffer solution B as dialysate to obtain a solution, namely a 5-fluorocytosine enzyme-labeled conjugate solution, and adding BSA and NaN into the 5-fluorocytosine enzyme-labeled conjugate solution3And stored at 4 ℃.
10. Use of the 5-fluorocytosine immunodetection reagent according to claim 6, wherein: use of the 5-fluorocytosine immunoassay reagent according to claim 6 for the determination of the 5-fluorocytosine content in a biological sample which is a human or animal fluid physiological sample which is serum, plasma, whole blood, urine, saliva, lymph fluid, interstitial fluid, cerebrospinal fluid, amniotic fluid or lacrimal fluid.
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| CN114685342A (en) * | 2020-12-25 | 2022-07-01 | 长沙博源医疗科技有限公司 | Levetiracetam derivative, immunogen, anti-levetiracetam specific antibody, preparation method and application thereof |
| CN114685526A (en) * | 2020-12-25 | 2022-07-01 | 长沙博源医疗科技有限公司 | Topiramate derivative, immunogen, anti-topiramate specific antibody, preparation method and application thereof |
| CN114751834A (en) * | 2020-12-25 | 2022-07-15 | 长沙博源医疗科技有限公司 | Venlafaxine derivative, immunogen, anti-venlafaxine specific antibody, and preparation method and application thereof |
| CN114685342B (en) * | 2020-12-25 | 2024-05-10 | 长沙博源医疗科技有限公司 | Levetiracetam derivative, immunogen, anti-levetiracetam specific antibody, and preparation methods and application thereof |
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