CN102603707A - 2,3,4,5,-tetra(3',4'-dihydroxyl phenyl)thiophene and application thereof as MALDI (matrix assisted laser desorption ionization) matrix in analyzing small molecules - Google Patents

2,3,4,5,-tetra(3',4'-dihydroxyl phenyl)thiophene and application thereof as MALDI (matrix assisted laser desorption ionization) matrix in analyzing small molecules Download PDF

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CN102603707A
CN102603707A CN2012100305316A CN201210030531A CN102603707A CN 102603707 A CN102603707 A CN 102603707A CN 2012100305316 A CN2012100305316 A CN 2012100305316A CN 201210030531 A CN201210030531 A CN 201210030531A CN 102603707 A CN102603707 A CN 102603707A
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聂宗秀
陈素明
陈力
陈芮
王佳宁
侯剑
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Abstract

The invention discloses 2,3,4,5,-tetra(3',4'-dihydroxyl phenyl)thiophene and application of 2,3,4,5,-tetra(3',4'-dihydroxyl phenyl)thiophene as an MALDI (matrix assisted laser desorption ionization) matrix in analyzing small molecules. The analysis method using 2,3,4,5,-tetra(3',4'-dihydroxyl phenyl)thiophene as the MALDI matrix is suitable for performing mass spectrum analysis on the small molecules with m/z being less than 1000. And adaptive molecule varieties comprise amine matters such as amino acids, vitamins, excitants, caffeine, urea, dopamine, melamine, aniline, purines and pyrimidines, etc., wherein background interference is not produced because of only a few fixed background peaks when the method is used for detecting the molecules with m/z being less than 1000. The method for preparing 2,3,4,5,-tetra(3',4'-dihydroxyl phenyl)thiophene provided by the invention can be effectively applied to fields such as the organic and biological mass spectrum, the mass spectrum imaging, the protein spectroscopy, the metabonomics, the biomarker discovery, the environment analysis and the like.

Description

2,3,4,5-four (3 ', 4 '-dihydroxy phenyl) thiophene and analyze micromolecular application as MALDI matrix
Technical field
The present invention relates to a kind of 2,3,4,5-four (3 ', 4 '-dihydroxy phenyl) thiophene and analyze micromolecular application as MALDI matrix.
Background technology
Since Karas et al. in 1988 and Tanaka et al. report adopted substance assistant laser desorpted ionized flight time mass spectrum (MALDI-TOF MS) technology effectively to carry out the mass spectral analysis of biomacromolecule, the MALDI-TOFMS technology enjoyed various countries investigator's favor.But because MALDI-TOF MS technology matrix commonly used; Like α-itrile group-4-hydroxycinnamic acid (CHCA), 2; 5-resorcylic acid (DHB), sinapinic acid (SA), 3-hydroxyl-2-VPP (3-HPA), anthratriol (DI) and 3-quinolylamine (3-AQ) etc. in analytic process the association between the chipping and molecule etc. can be the scope of m/z＜500 in the serious matrix background interference phenomenon of generation; Therefore, adopt these matrix can not effectively analyze the micromolecular compound of m/z＜500.
For fear of the generation of matrix background interference phenomenon, investigators are through to many feasible the improving one's methods of having researched and proposed of MALDI-TOF MS mechanism.As successively introducing inorganics matrix, polymeric matrix, carbon material matrix (like carbon nanotube, soccerballene, Graphene etc.) thereby, new matrix such as mixed-matrix or adopt no matrix desorb/ionization method to overcome with the deficiency of organic molecule as matrix analysis micromolecular compound through porous silicon surface being carried out chemically modified.
But be to use methods such as inorganics, carbon material matrix to exist problems such as preparation is loaded down with trivial details, expense is higher, sensitivity is lower, can not demonstrate fully quick, the high-sensitive characteristics of MALDI-TOF MS analytic sample.When porous silicon surface generation desorb/ionization, at first will carry out etching on the silicon wafer surface makes it produce the surface of nanostructure; Though can direct analysis polypeptide and antiviral on such surface; But, therefore just need on same nanostructured surface, carry out repeated treatments to obtain the reusable surface of ability because the repeated use effect on this surface is bad.Analytical effect can descend greatly when in addition, porous silicon surface being carried out chemically modified length consuming time and the repeated use of process modification porous silicon.Proton sponge can not produce interference as a kind of organic substrate in the lower molecular weight scope, but it can only analyze the organic acid compound.
Therefore, provide a kind of working method simple, with low cost; Applied widely; In less than m/z 500, not having or have only the matrix and the specimen preparation analytical procedure of very low background peaks, is important and strong the replenishing to current mass spectroscopy based on MALDI, has Practical significance widely.
Summary of the invention
An object of the present invention is to provide 2,3,4,5-four (3 ', 4 '-dihydroxy phenyl) thiophene and preparation method thereof.2,3,4, the structural formula of 5-four (3 ', 4 '-dihydroxy phenyl) thiophene is suc as formula shown in the IV:
Figure BDA0000134983260000021
(formula IV)
The preparation method comprises the steps:
1) under the condition of palladium catalyst and alkali existence, make 3 shown in tetrabromothiophene shown in the formula I and the formula II, 4-dimethoxy benzene ylboronic acid reacts, and obtains 2,3,4 shown in the formula III, 5-four (3 ', 4 '-Dimethoxyphenyl) thiophene;
2) with 2,3,4 shown in the formula III, 5-four (3 ', 4 '-Dimethoxyphenyl) thiophene and boron tribromide react, and obtain 2,3,4 shown in the formula IV, 5-four (3 ', 4 '-dihydroxy phenyl) thiophene.
Wherein, palladium catalyst described in the step 1) specifically can be Pd (PPh 3) 4, said catalyst P d (PPh 3) 4Add-on can be the 0.1%-20% of tetrabromothiophene mole number.
Said alkali specifically can be K 3PO 4, said K 3PO 4Add-on can be 3, the 50-200% of 4-dimethoxy benzene ylboronic acid mole number.K 3PO 4As alkali, with the palladium catalyst effect, form strong electrophilic organic palladium midbody on the one hand; With the aryl boric acid effect, generate ate complex tetravalence borate midbody on the other hand, the tool nucleophilicity, two kinds of intermediate materials interact and generate product then.
The mol ratio of compound can be 1 shown in compound shown in the said formula I and the formula II: (4-10).
The temperature of reaction of said reaction is 50-150 ℃, and the reaction times is 5-24 hour.
Said being reflected at by 1 carried out in the reaction medium that 4-dioxane and water are formed, wherein, 1,4-dioxane, K 3PO 4Volume ratio (1-10) with water: (0.1-2).
Step 2) mol ratio of compound shown in the formula III and boron tribromide described in is 1: (8-40).
The reaction medium of said reaction is a methylene dichloride.
The process of said reaction is following: earlier-78-0 ℃ of reaction 1-5 hour down; Then at room temperature reaction 1-5 hour; Be cooled to 0--10 ℃ at last.
Figure BDA0000134983260000022
(formula I) (formula II) (formula III)
Another object of the present invention provides 2,3,4, a purposes of 5-four (3 ', 4 '-dihydroxy phenyl) thiophene.
Provided by the present invention 2,3,4, the purposes of 5-four (3 ', 4 '-dihydroxy phenyl) thiophene is its application in preparation substance assistant laser desorpted ionized (MALDI) matrix.
A further object of the present invention provides the method for a kind of substance assistant laser desorpted ionized (MALDI) mass spectroscopy.
Mass spectrometric analysis method provided by the present invention is with 2,3,4, and 5-four (3 ', 4 '-dihydroxy phenyl) thiophene is a MALDI matrix.This method is specially adapted to micromolecular mass spectroscopy, the especially m/z of m/z (matter/lotus than) less than 1000 less than 500 micromolecular mass spectroscopy.
When with 2,3,4, when 5-four (3 ', 4 '-dihydroxy phenyl) thiophene is MALDI matrix, do not limit the concentration of matrix solution is special, can be mixed with the concentration of 10mg/mL usually to saturated solution.Solvent gets final product with the mass spectrum subsequent analysis is compatible in principle, can be water usually, methyl alcohol, and ethanol, acetonitriles etc. comprise their system of dissolving each other.
The molecular species that above-mentioned mass spectrometric analysis method is fit to specifically comprises amino acid, VITAMINs, stimulant, amine substances such as theine, urea, Dopamine HCL, trimeric cyanamide, phenyl amines, purine class, miazines etc.
Adopt mass spectrometric analysis method of the present invention to detect the m/z value, have only a small amount of fixed background peaks and do not produce background interference less than 1000 the branch period of the day from 11 p.m. to 1 a.m.
Mass spectrometric analysis method of the present invention can be at organic and biological mass spectrometry, mass spectrum imaging, and the protein spectroscopy, metabolism group, biomarker finds that fields such as environmental analysis obtain effective application.
The sample that is fit to analyze is gone back the encompass complex mixed system except that pure article or simple mixtures.Include but not limited to various biological tissue cell samples, micro-biological samples, body fluid, dialyzate, chemosynthesis system, and environmental monitoring sample, like water, atmosphere, soil sample etc.
The present invention is with 2,3,4, and 5-four (3 ', 4 '-dihydroxy phenyl) thiophene normally uses time flight mass spectrum (TOF-MS) as the mass analysis means as the MS of the matrix of MALDI, but also compatible with other mass spectrum mass analyzers.
Method of the present invention not only can be used for the MALDI mass spectroscopy of homogeneous system, can also be used for the application like heterogeneous body systems such as mass spectrum imagings.
During concrete the use; Matrix solution generally is made into the concentration of 10mg/mL to saturated solution; Do not have particular requirement with the molar weight proportioning of determinand; Because need matrix absorption laser transfer energy to give determinand, all determinands are ionized, the molar weight of matrix gets final product than determinand is big generally speaking.
When adopting method of the present invention to carry out MALDI-TOF MS analysis, the mol ratio of said testing compound and matrix can be (1-5): (1-100), specifically can be 1: 20; With the sample of said compound and the matrix in the said matrix solution with mol ratio (1-5): (1-100) mix after, draw 0.5-1 μ L mixed solution point sample.Solvent in the liquid to be mixed can adopt the MALDI-TOF MS of negative ion scan pattern that said compound is analyzed after in air, volatilizing fully.
When testing sample is the COMPLEX MIXED system in present method; Usually need not special processing; (mol ratio of sample and matrix can be 1-5 to the supernatant (also can be turbid solution) of drawing mixed system: 1-100), put and behind the MALDI target plate, promptly can be used for mass spectroscopy with certain proportion and matrix solution mixing.
When using as mass spectrum imaging, when sample is tissue slice, can matrix solution (1mg/ml is to saturation concentration) be sprayed at sample surfaces, carry out the mass spectrum imaging analysis of standard then.
Thereby the present invention has overcome organic molecule matrix commonly used technically is easy to generate the defective that serious matrix background interference phenomenon causes effectively analyzing the small molecules sample in the lower molecular weight district.
The matrix that the present invention adopts need not to add ionization reagent, has reduced the requirement to sample process.
Because (m/z 0-1000) almost do not have background interference in test specification, thereby can analyze multiple COMPLEX MIXED system yet.And the sample compatibility is good, and need not special complex process can analyze.
Description of drawings
Fig. 1 is 2,3,4, the synthetic route chart of 5-four (3 ', 4 '-dihydroxy phenyl) thiophene.
Fig. 2 is 2,3,4, the MALDI-TOF mass spectrum of 5-four (3 ', 4 '-dihydroxy phenyl) thiophene.
Fig. 3 is the mass spectroscopy figure of beta-stimulants; Be followed successively by the mass spectrum of clenbuterol, Ractopamine hydrochloride, salbutamol, terbutaline from top to bottom.
Fig. 4 is amino acid whose mass spectroscopy figure; Be followed successively by the mass spectrum of l-arginine, Histidine, leucine, tryptophane from top to bottom.
Fig. 5 is the mass spectroscopy figure of VITAMINs; Be followed successively by the mass spectrum of VITMAIN B1, Wei ShengsuB2, vitamin B3, Y factor from top to bottom.
Fig. 6 is the mass spectroscopy figure of theine, urea, Dopamine HCL, guanine (from top to bottom).
Fig. 7 is trimeric cyanamide, benzidine, to the mass spectroscopy figure of monomethylaniline (from top to bottom).
Fig. 8 is micromolecular mass spectroscopy figure in the urine sample.
Fig. 9 is micromolecular mass spectroscopy figure in the serum.
Embodiment
The present invention will be described through specific embodiment below, but the present invention is not limited thereto.
Experimental technique described in the following embodiment like no specified otherwise, is ordinary method; Said reagent and material like no specified otherwise, all can obtain from commercial sources.
The model of the substance assistant laser desorpted ionized time-of-flight mass spectrometer that following embodiment is used is BIFLEXTM III (Bruker) and ultrafleXtreme (Bruker).
The mass spectrum background of matrix is very simple, and mass signal does not have other signal except the peak of molecular ion peak and sodium ion, potassium ion, to test sample book, comprise that complex system is all noiseless.(see figure 2)
Embodiment 1, Synthetic 2,3,4,5-four (3 ', 4 '-dihydroxy phenyl) thiophene
Tetrabromothiophene (1,0.4g, 1.0mmol) 1, add Pd (PPh in the 4-dioxane solution (5mL) 3) 4(0.07g, 6mol%), stirring at room is after 30 minutes, adds 3,4-dimethoxy benzene ylboronic acid (2,5.0mmol), K 3PO 4(4.0mmol) with 1mL water.Mixture stirred 12 hours down at 90 ℃, was cooled to room temperature later on successively with the ETHYLE ACETATE dilution, and anhydrous sodium sulfate drying filters then.Solution is after Rotary Evaporators is removed solvent, and residuum separates with silica gel column chromatography that (ETHYLE ACETATE: sherwood oil=1: 50 v/v), obtains intermediate product 2; 3,4,5-four (3 ', 4 '-Dimethoxyphenyl) thiophene solid (3; 0.56g, 0.9mmol), productive rate 90%.(0.56g 0.9mmol) is dissolved in the 5mL methylene dichloride, is cooled to-78 ℃ then with 3.(0.68mL, 7.2mmol) 2.5mL stir and returned to room temperature in 2 hours later on and continue to stir 2 hours to drip the dichloromethane solution of boron tribromide with this understanding.Then reaction mixture is cooled to 0 ℃, drips 10mL water to mixture.The separate dichloromethane organic phase is used anhydrous sodium sulfate drying, remove behind the solvent with silica gel column chromatography separate (ETHYLE ACETATE: sherwood oil=1: 1, v/v); Obtain final product 2,3,4,5-four (3 '; 4 '-dihydroxy phenyl) the thiophene solid (4,0.37g, 0.72mmol), productive rate 80%.
The structure appraising datum is following:
1H?NMR(300MHz，DMSO-d6)：δ＝6.17-6.20(dd，J＝7.9Hz，2H)，6.31(d，J＝2.1Hz，2H)，6.41-6.44(dd，J＝8.1Hz，2H)，6.50(d，J＝8.1Hz，2H)，6.57(d，J＝8.1Hz，2H)，6.62(d，J＝2.1Hz，2H).ESI-MS：m/z?515.2，[M-H] -.Elemental?analysis：calcd?for?C 28H 20O 8S：C?65.11，H?3.90％；found?C?65.14，H?3.98％.
Embodiment 2, various small molecules analysis (comprising beta-stimulants, amino acid, VITAMINs, amine substances such as theine, urea, Dopamine HCL, trimeric cyanamide, phenyl amines, purine class, miazines etc.)
Get the various sample solutions that prepare (concentration is 1mM) and matrix solution (concentration is 20mM) mixes with 1: 1 volume ratio, add 1 μ L biased sample to the MALDI target plate then, get into mass spectroscopy behind the air drying.The mass spectrum condition is: voltage: acceleration voltage: 19.000kv; Postpone extraction voltage: 14.920kv; Reflector voltage: 20.000kv; Lens voltage: 7.000kv; Frequency: 1.000Hz; Energy of lasers: 75-80%; Accumulative frequency: 90 times; Positive ion mode.
Under MALDI ionization mode, matrix can make the testing compound positively charged with prototropy to testing compound, thereby by mass spectrometric detection.Experiment showed, this matrix for above beta-stimulants (Fig. 3), amino acid (Fig. 4), VITAMINs (Fig. 5), theine, urea, Dopamine HCL, guanine (Fig. 6), trimeric cyanamide, benzidine, phenyl amines materials such as (Fig. 7) all have analytical performance preferably.The amount of determinand is 2.5nmol among the figure, can find out that this utilizes the matrix sensitivity for analysis higher.The compound of in figure, listing, to the similar compound of each type material among the figure, this matrix all can obtain analytical results preferably.
Embodiment 3, the medium and small analysis of molecules of urine sample
Get the freshly voided urine 2mL of healthy male volunteers, centrifugal removal deposition and insolubles are got 1 μ L then and are mixed with 1 μ L matrix solution (concentration is 20mM), take out 1 μ L mixed solution at last and join on the MALDI target plate, get into mass spectroscopy behind the air drying.The mass spectrum condition is: voltage: acceleration voltage: 19.000kv; Postpone extraction voltage: 14.920kv; Reflector voltage: 20.000kv; Lens voltage: 7.000kv; Frequency: 1.000Hz; Energy of lasers: 75-80%; Accumulative frequency: 90 times; Positive ion mode.
As can be seen from Figure 8, produced more fignal center, explained that small molecules is ionized in a lot of urine samples, produced mass signal in the small molecules zone.Therefore, this matrix can be used for the small molecules metabolite analysis of urine sample.In addition, undressed urine sample contains a large amount of salt, and the result shows that also this matrix has higher salt tolerance.
Embodiment 4, the medium and small analysis of molecules of serum
Get 1 μ L horse serum and mix, take out 1 μ L mixed solution at last and join on the MALDI target plate, get into mass spectroscopy behind the air drying with 1 μ L matrix solution.The mass spectrum condition is: voltage: acceleration voltage: 19.000kv; Postpone extraction voltage: 14.920kv; Reflector voltage: 20.000kv; Lens voltage: 7.000kv; Frequency: 1.000Hz; Energy of lasers: 75-80%; Accumulative frequency: 90 times; Positive ion mode.
As can be seen from Figure 9, small molecules is ionized in a large amount of serum, has produced higher mass signal.This example explanation, this matrix can be applied to the small molecules metabolite analysis in the serum.

Claims (10)

1. structural formula is suc as formula the compound shown in the IV:
Figure FDA0000134983250000011
(formula IV).
2. the method for the compound shown in the preparation claim 1 Chinese style IV comprises the steps:
1) under the condition of palladium catalyst and alkali existence, the compound shown in compound shown in the formula I and the formula II is reacted, obtain the compound shown in the formula III;
2) compound shown in the formula III and boron tribromide are reacted, obtain the compound shown in the formula IV;
Figure FDA0000134983250000012
(formula I) (formula II) (formula III).
3. method according to claim 2 is characterized in that: palladium catalyst described in the step 1) is Pd (PPh 3) 4, said catalyst P d (PPh 3) 4Add-on be the 0.1%-20% of the compound mole number shown in the formula I; Said alkali is K 3PO 4, said K 3PO 4Add-on be the 50-200% of the compound mole number shown in the formula II;
The mol ratio of compound shown in compound and the formula II is 1 shown in the I of formula described in the step 1): (4-10);
The temperature of reaction of reacting described in the step 1) is 50-150 ℃, and the reaction times is 5-24 hour;
Be reflected at described in the step 1) by 1, carry out in the reaction medium that 4-dioxane and water are formed, wherein, 1, the volume ratio of 4-dioxane and water (1-10): (0.1-2);
Step 2) mol ratio of compound shown in the formula III and boron tribromide described in is 1: (8-40);
Step 2) reaction medium of reaction is a methylene dichloride described in;
Step 2) process of reaction is following described in: earlier-78-0 ℃ of reaction 1-5 hour down; Then at room temperature reaction 1-5 hour; Be cooled to 0--10 ℃ at last.
4. the application of the compound shown in the claim 1 Chinese style IV in the substance assistant laser desorpted ionized matrix of preparation.
5. the method for a substance assistant laser desorpted ionized mass spectroscopy is characterized in that: with the compound shown in the claim 1 Chinese style IV as substance assistant laser desorpted ionized matrix.
6. method according to claim 5 is characterized in that: said method is applicable to m/z less than 1000 micromolecular mass spectroscopy.
7. method according to claim 6 is characterized in that: said method is applicable to m/z less than 500 micromolecular mass spectroscopy.
8. according to each described method among the claim 5-7, it is characterized in that: the sample that said method is fit to analyze comprises pure article, simple mixtures and COMPLEX MIXED system.
9. according to each described method among the claim 5-8, it is characterized in that: when adopting said method that testing sample is analyzed, testing sample and said matrix are with mol ratio (1-100): mixed (1-5).
Among the claim 5-9 each described method in following any Application for Field: organicly find and environmental analysis with biological mass spectrometry, mass spectrum imaging, protein spectroscopy, metabolism group, biomarker.
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CN103776892A (en) * 2014-01-16 2014-05-07 陕西师范大学 Matrix with selectivity for micromolecule MALDI-TOF MS (Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry) detection and application thereof
CN103776892B (en) * 2014-01-16 2014-12-17 陕西师范大学 Matrix with selectivity for micromolecule MALDI-TOF MS (Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry) detection and application thereof
CN107430089A (en) * 2015-03-31 2017-12-01 日油株式会社 The substance assistant laser desorpted mass spectrometry of high molecular weight peo derivative
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CN108147983A (en) * 2016-12-05 2018-06-12 中国科学院化学研究所 A kind of sulfosalt bonding benzene polyphenol type molecular glass photoresist and its preparation method and application
CN108147983B (en) * 2016-12-05 2020-01-31 中国科学院化学研究所 type sulfonium salt bonded benzene polyphenol type molecular glass photoresist and preparation method and application thereof
CN115215763A (en) * 2022-06-22 2022-10-21 闽江学院 Mass spectrum matrix material and preparation method thereof
CN117066505A (en) * 2023-07-31 2023-11-17 广东省农业科学院农业生物基因研究中心 Laser desorption/ionization mass spectrometry method for detecting vitamins
CN117066505B (en) * 2023-07-31 2024-03-19 广东省农业科学院农业生物基因研究中心 Laser desorption/ionization mass spectrometry method for detecting vitamins

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