CN112961060B - Isotope labeled N, N-dimethylethylenediamine, preparation method thereof and analysis method of short-chain fatty acid - Google Patents
Isotope labeled N, N-dimethylethylenediamine, preparation method thereof and analysis method of short-chain fatty acid Download PDFInfo
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Abstract
The invention discloses isotope-labeled N, N-dimethylethylenediamine, a preparation method thereof and an analysis method of short-chain fatty acids (SCFAs). The isotope-labeled N, N-dimethylethylenediamine is13C2-DMED, preparation thereof: using N-carbobenzoxy ethylenediamine hydrochloride as substrate raw material, and reacting with H13CHO and NaBH3After CN reaction, Pd-C catalytic hydrogenation reaction is carried out, and finally, ammonia water is added for stirring and neutralization. The invention uses DMED and13C2-DMED is a pair of isotopically labelled reagents, which react with SCFAs to obtain derivatives of SCFAs; then, the HILIC-MS is used for analyzing and detecting the SCFAs in the biological sample. After SCFAs are labeled by DMED, the detection sensitivity is improved by four orders of magnitude in the ESI positive ion mode. The method is successfully used for high-sensitivity detection of SCFAs in complex matrix samples such as mouse feces and the like.
Description
Technical Field
The invention relates to a13C2A method for synthesizing DMED and establishing an analysis method of short-chain fatty acid in organisms, belonging to the field of organic chemistry and analytical chemistry.
Background
Short Chain Fatty Acids (SCFAs) are a class of carboxylic compounds with 1-6 carbon atoms, such as acetic acid, propionic acid, valeric acid, lactic acid, and the like. They are produced by the digestion and degradation of dietary fibers by intestinal bacteria and can also be converted from other metabolites in the organism. SCFAs have important physiological functions in organisms, can be used as histone deacetylase inhibitors and G protein-coupled receptor activators, and are closely related to metabolic diseases. Therefore, analytical detection of SCFAs is important.
The analysis method of SCFAs reported so far mostly adopts hydrophilic interaction chromatography (HILIC) separation, and then performs SCFAs measurement under mass electrospray ionization (ESI) negative ion mode. However, SCFAs do not contain easily ionizable groups, so the mass spectral response in ESI negative ion mode is low.
The chemical marker-HILIC-MS strategy can solve the above problems to a certain extent. This strategy increases the mass spectral response of SCFAs in the positive ion mode by introducing easily ionizable groups. So far, no chemical marker-HILIC-MS analysis method for detecting SCFAs has been reported.
Disclosure of Invention
The invention aims to provide isotope-labeled N, N-dimethylethylenediamine, a preparation method thereof and an analysis method of SCFAs.
In order to solve the technical problems, the invention provides the following technical scheme:
providing an isotopically labeled N, N-dimethylethylenediamine13C2-DMED, of the formula:
provide a kind of13C2-method for the preparation of DMED, the reaction equation is as follows:
the method specifically comprises the following steps:
1) dissolving substrate N-carbobenzoxy ethylenediamine hydrochloride in methanol, and adding H13Aqueous CHO solution and NaBH3CN, stirring and mixing uniformly, dripping acetic acid to make the system neutral, reacting at normal temperature, and performing column chromatography separation to obtain a product A;
2) carrying out Pd-C catalytic hydrogenation reaction on the product A obtained in the step 1) under the HCl acidification condition to obtain a product B;
3) dissolving the product B obtained in the step 2) in dichloromethane solution of ammonia, and stirring to obtain isotope-labeled N, N-dimethylethylenediamine (I: (II) ((III))13C2-DMED)。
According to the scheme, in the step 1), N-carbobenzoxy ethylenediamine hydrochloride, formaldehyde and NaBH3The molar ratio of CN is 1: (10-1000): (1-3).
According to the scheme, in the step 1), the reaction is carried out for 24-48h at normal temperature.
According to the scheme, in the step 1), the eluent used for column chromatography and the mixed solution of ethyl acetate and triethylamine in the volume ratio of 100:3 are adopted.
According to the scheme, in the step 2), the molar mass ratio of the product A to the Pd-C is as follows: 1 mmol: (15-30 mg).
According to the scheme, the step 2) comprises the following specific steps: dissolving the product A in methanol, acidifying with concentrated hydrochloric acid, adding Pd-C, and reacting at 40-60 deg.C under 35-45atm for 18-30 h; after the reaction is finished, filtering, and spin-drying the filtrate to obtain the product, wherein the mass volume ratio of the concentrated hydrochloric acid to the Pd-C is (0.5-1mL) to (15-30 mg).
According to the scheme, in the step 3), the stirring neutralization time is 3-6 h.
According to the scheme, in the step 3), the molar volume ratio of the product B to ammonia is as follows: 1 mmol: (25-30 mL).
According to the scheme, in the step 3), the preparation process of the dichloromethane solution of ammonia comprises the following steps of mixing ammonia water and dichloromethane according to the volume ratio of 1:1, mixing, and after the two are layered, reserving a dichloromethane layer for later use.
Provides an analysis method of SCFAs, using DMED and13C2-DMED is a pair of isotopically labelled reagents, which react with SCFAs to obtain derivatives of SCFAs; then, the HILIC-MS is used for analyzing and detecting the SCFAs in the biological sample.
According to the scheme, the SCFAs are carboxyl metabolites with the carbon number of 1-6.
According to the above scheme, DMED or13C2The process of labelling SCFAs with DMED is: adding a sample containing SCFAs into ACN, taking Triphenylphosphine (TPP) and dithiodipyridine (DPDS) as catalysts, and adding a marker DMED or DPDS13C2-DMED, and the labeling is completed after 30-60 minutes of reaction at 40-60 ℃. Preferably, the molar ratio of TPP, DPDS and labeling reagent is 1:1: 1.
According to the above scheme, DMED and13C2DMED as a pair of isotopically labelled reagents, wherein DMED is used to label SCFAs in a biological sample,13C2-DMED-labeled SCFAs standards as internal standards to aid in characterization, both samples before entering HILIC-MS analysisAnd (4) mixing.
According to the above protocol, the column used for liquid phase separation in HILIC-MS was BEH HILIC (2.1X 100mm,1.7 μm, Waters.). The column temperature was 40 ℃ and the flow rate was 0.4 mL/min. The mobile phases A and B were 20mM ammonium formate (v/v) and ACN, respectively. The mobile phase gradient is: 97% B in 0-4 min, 97-92% B in 4-10 min, 92-87% B in 10-13 min, 87-60% B in 13-15 min, 60% B in 15-16 min, 60-97% B in 16-17 min, and 97% B in 17-24 min.
The invention has the beneficial effects that:
1. the invention provides13C2DMED can be used for the analytical detection of SCFAs by DMED and13C2the-DMED is jointly used as a pair of isotope labeling reagents and reacts with the SCFAs to obtain derivatives of the SCFAs, easily-ionized groups are introduced, mass spectrum response under an ESI positive ion mode is greatly improved, the HILIC-MS combined method is adopted to analyze and detect the SCFAs in the biological sample, and the detection sensitivity is improved by 3-4 orders of magnitude.
2. The invention not only greatly improves the detection sensitivity of the SCFAs, but also is successfully used for the high-sensitivity detection of the SCFAs in mouse excrement and other complex matrix samples.
3. The invention provides a preparation method13C2The method of the DMED has simple and easy operation of the preparation process and high product purity.
Drawings
FIG. 1 shows the results obtained in example 113C2Precise molecular mass determination of DMED.
FIG. 2 shows the results obtained in example 113C2Determination of the chemical purity of the DMED.
FIG. 3 is a secondary mass spectrum of the labeled product of example 2 after DMED labeling of different SCFAs, wherein (a) acetic acid; (b) lactic acid; (c) butyric acid; (d) sorbic acid.
Fig. 4 is a chromatogram of the SCFAs marker product of example 3, wherein (a) the chromatogram of the marker product of the SCFAs standard; (b) chromatograms of SCFAs marker products detected in mouse feces.
Detailed Description
The features and advantages of the present invention will be further understood from the following detailed description taken in conjunction with the accompanying drawings. The examples provided are merely illustrative of the method of the present invention and do not limit the remainder of the disclosure in any way.
Example 1
Providing an isotopically labeled N, N-dimethylethylenediamine (13C2-DMED), comprising the steps of:
(1) the substrate (carbobenzoxy ethylenediamine hydrochloride, 970mg, 5mmol) was weighed into 15mL of methanol, and 20% H was added thereto13Aqueous CHO solution (3.3mL) and NaBH3CN (553.8mg, 8.6mmol), stirring for 15min, slowly dropping acetic acid into the system to make the system neutral, reacting at room temperature for 24h, and separating by column chromatography (eluent ethyl acetate: triethylamine 100: 3) to obtain pure product (colorless oily liquid).
(2) All the product (900mg, 4mmol) obtained in step (1) was put into the reaction, 10mL of methanol was added, acidified with hydrochloric acid (2mL of concentrated hydrochloric acid), and reacted with 100mg of Pd-C at 40atm and 50 ℃ for 24 hours. After the reaction is finished, filtering, and spin-drying the filtrate (spin-steaming at 70 ℃) to obtain the product (yellowish oily liquid).
(3) The reaction liquid obtained in the second step is dried in a spinning way, dissolved in dichloromethane solution of ammonia (30mL of ammonia water and 30mL of dichloromethane are fully and uniformly shaken), stirred for 4 hours, filtered and dried in a spinning way to obtain N, N-dimethyl ethylenediamine (A), (B), (C) and D)13C2-DMED) (colorless oily liquid).
Synthesized13C2High resolution characterization of the DMED, as shown in FIG. 1, can be obtained13C2The exact molecular weight of DMED is 91.1134Da, indicating that the isotopic labeling reagents were successfully synthesized. Simultaneously, the purity of the synthesized reagent is monitored by high performance liquid chromatography to obtain13C2Chemical purity of-DMED was greater than 95% (fig. 2).
Example 2
1.DMED/13C2Chemical labelling of DMED
With DMED or13C2-performing derivatization reaction between the labelled reagent DMED and SCFAs, and specifically comprising the following steps:
to ACN solution (100ng/mL, 300. mu.L) containing Short Chain Fatty Acids (SCFAs), the catalysts TPP (20. mu. mol/mL, 20. mu.L) and DPDS (20. mu. mol/mL, 20. mu.L), DMED or DPDS were added in sequence13C2-DMED (20 μmol/mL, 20 μ L) at 40 ℃ for 30 minutes, wherein SCFAs are acetic acid, lactic acid, butyric acid and sorbic acid, respectively.
The labeling reaction is shown below:
FIG. 3 is a second-order mass spectrum of the corresponding labeled products after acetic acid, lactic acid, butyric acid and sorbic acid are effectively labeled by DMED, and it can be seen that: different labeled products can produce characteristic secondary fragments to assist in characterization. In addition, we monitored the conversion of this reaction in ESI negative ion mode and found that the conversion of all four SCFAs was greater than 95% (as shown in table 1 below).
TABLE 1 conversion of four SCFAs
2. Comparison of sensitivity before and after labeling
We examined the sensitivity of this method by determining the limit of detection of the derivatized product in a standard solution under multiple reaction monitoring anion mode. The specific method comprises the following steps of; using DMED to mark 10ng/mL of acetic acid, lactic acid, butyric acid and sorbic acid, then carrying out LC-MS detection on the reaction solution to obtain a signal-to-noise ratio (the signal-to-noise ratio is far more than 10) under the concentration of 10ng/mL, and then diluting the reaction solution step by step until the signal-to-noise ratio is equal to 3, wherein the concentration at this time is the detection limit of the SCFAs marked by the DMED. Wherein the detection limit is selected when the signal-to-noise ratio is 3. Then, under the condition of multi-reaction monitoring anion mode, the detection limits of four SCFAs are monitored, and the change of the sensitivity of the SCFAs marked by the DMED is compared. After being labeled by DMED, the detection limit of SCFAs is as low as 0.02 ng/mL. Sensitivity was generally improved by 4 orders of magnitude compared to the detection limit of underivatized SCFAs, as shown in table 2 below.
TABLE 2 comparison of detection limits before and after SCFAs labeling
Example 3
Selection of DMED and DMED from example 113C2DMED carries out the detection of SCFAs in mouse faeces.
Sample preparation: stored at-80 ℃ for further use.
The extraction procedure of SCFAs from the mouse stool sample was as follows: to 100mg of mouse feces, 400. mu.L of ACN was added and sonicated for 5 min. Centrifuging at 12000g for 5min at 4 deg.C, collecting supernatant, continuously extracting twice, mixing supernatants, and blowing nitrogen at low temperature. Subsequently, the extract was reconstituted with 200 μ L ACN.
The chemical labeling procedure for SCFAs in mouse stool samples was as follows: referring to the labeling conditions in example 2, 200. mu.L of the reconstituted system was labeled with DMED, using13C2Standard substance of SCFAs marked by DMED (the concentration of acetic acid, lactic acid, butyric acid and sorbic acid is 50ng/mL), and then the standard substance is mixed evenly for HILIC-MS analysis.
The specific conditions of HILIC-MS are as follows: the experiments were performed using an LC-ESI-MS/MS system, including Shimadzu LC-30AD HPLC system (Tokyo, Japan) and Shimadzu MS-8045 mass spectrometer (Tokyo, Japan), equipped with an ESI ion source (Turbo Ionspray).
The column used for liquid phase separation was BEH HILIC (2.1X 100mm,1.7 μm, Waters.). The column temperature was 40 ℃ and the flow rate was 0.4 mL/min. The mobile phases A and B were 20mM ammonium formate (v/v) and ACN, respectively. The mobile phase gradient is: 97% B in 0-4 min, 97-92% B in 4-10 min, 92-87% B in 10-13 min, 87-60% B in 13-15 min, 60% B in 15-16 min, 60-97% B in 16-17 min, and 97% B in 17-24 min. The injection volume was 2. mu.L. The autosampler pan temperature was set at 4 ℃ and three replicates were run for each sample.
All the labeled SCFAs products labeled by the DMED are detected in the MRM (+) mode, and the LC-MS system automatically optimizes the voltage. The parent-daughter ion channels corresponding to the two most intense daughter ions for each analyte are used for qualitative and quantitative purposes, respectively. Quantifying the SCFAs labeled product which can be completely separated by utilizing peak area; for SCFAs-labeled products that were not completely separated, peak heights were used for quantification. The optimal ESI source parameters are as follows: DL temperature: 250 ℃, heating module temperature: 400 ℃, atomizing gas: 3L/min, dry gas: 15L/min, heating gas: 10L/min, interface temperature: at 300 ℃. Labsolution software (version 5.53sp2, Shimadzu, Tokyo, Japan) was used to control the system and process software.
And (3) detection results: three SCFAs, acetic acid, lactic acid and butyric acid, were successfully detected in the mouse fecal extract (fig. 4). Wherein (a) represents a chromatogram of a DMED-labeled SCFAs standard; (b) represents the chromatogram of SCFAs in the feces of a DMED-labeled mouse.
The preferred embodiments and examples of the present invention have been disclosed in the accompanying drawings, but the present invention is not limited to the above embodiments and examples, and can be modified and improved without departing from the spirit and scope of the invention, and therefore the scope of the invention is to be determined by the claims.
Claims (10)
1. An isotopically labeled N, N-dimethylethylenediamine characterized by the structural formula:
is marked as13C2-DMED。
2. A process as claimed in claim 113C2-a process for the preparation of DMED, characterized in that the reaction equation is as follows:
the method specifically comprises the following steps:
1) dissolving substrate N-carbobenzoxy ethylenediamine hydrochloride in methanol, and adding H13Aqueous CHO solution and NaBH3CN, stirring and mixing uniformly, dripping acetic acid to make the system neutral, reacting at normal temperature, and performing column chromatography separation to obtain a product A;
2) carrying out Pd-C catalytic hydrogenation reaction on the product A obtained in the step 1) under the HCl acidification condition to obtain a product B;
3) dissolving the product B obtained in the step 2) in dichloromethane solution of ammonia, and stirring to obtain the isotope-labeled N, N-dimethylethylenediamine.
3. The production method according to claim 2,
in the step 1), N-carbobenzoxy ethylenediamine hydrochloride, formaldehyde and NaBH3The molar ratio of CN is 1: (10-1000): (1-3);
in the step 2), the molar mass ratio of the product A to the Pd-C is as follows: 1 mmol: (15-30 mg);
in the step 3), the molar volume ratio of the product B to ammonia is as follows: 1 mmol: (25-30 mL).
4. The production method according to claim 2,
in the step 1), reacting for 24-48h at normal temperature; eluent used for column chromatography and mixed solution of ethyl acetate and triethylamine with the volume ratio of 100: 3;
in the step 2), the concrete steps are as follows: dissolving the product A in methanol, acidifying with concentrated hydrochloric acid, adding Pd-C, and reacting at 40-60 deg.C under 35-45atm for 18-30 h; after the reaction is finished, filtering, and spin-drying the filtrate to obtain a product, wherein the mass-volume ratio of the concentrated hydrochloric acid to the Pd-C is (0.5-1mL) to (15-30 mg);
in the step 3), stirring and neutralizing for 3-6 h; the preparation process of the dichloromethane solution of ammonia comprises the following steps of mixing ammonia water and dichloromethane according to the volume ratio of 1:1, mixing, and after the two are layered, reserving a dichloromethane layer for later use.
5. A method for the analysis of SCFAs, characterized in that DMED and the method according to claim 1 are used13C2DMED is a pair of isotopically labelled reagents: DMED-13C2-DMED, reacting with SCFAs to obtain derivatives of SCFAs; then, analyzing and detecting SCFAs in the biological sample by adopting a HILIC-MS combined method; wherein the SCFAs are short chain fatty acids and the DMED is N, N-dimethylethylenediamine.
6. The assay of claim 5, wherein the SCFAs are carboxyl-based metabolites with a carbon number between 1 and 6.
7. The assay of claim 5, wherein DMED or13C2The process of labelling SCFAs with DMED is: adding a sample containing SCFAs into acetonitrile, taking triphenylphosphine and dithiodipyridine as catalysts, and adding a marker DMED or13C2-DMED, and the labeling is completed after 30-60 minutes of reaction at 40-60 ℃.
8. The assay of claim 7, wherein the molar ratio of triphenylphosphine, dithiodipyridine, and label is 1:1: 1.
9. The assay of claim 5, wherein DMED and13C2DMED as a pair of isotopically labelled reagents, wherein DMED is used to label SCFAs in a biological sample,13C2-DMED labelled SCFAs standards as internal standard to aid in the characterisation, both samples were mixed before entering the HILIC-MS analysis.
10. The analytical method of claim 5, wherein the chromatographic column for liquid phase separation in HILIC-MS is BEH HILIC, wherein the chromatographic column has the following specifications: 2.1 × 100mm,1.7 μm, waters; the column temperature is 40 ℃, and the flow rate is 0.4 mL/min; mobile phases a and B were 20mM ammonium formate and acetonitrile, respectively; the mobile phase gradient is: 97% B in 0-4 min, 97-92% B in 4-10 min, 92-87% B in 10-13 min, 87-60% B in 13-15 min, 60% B in 15-16 min, 60-97% B in 16-17 min, and 97% B in 17-24 min.
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