Table of Contents

    Topic review

    Liquid-Chromatographic Methods for Carboxylic Acids

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    Submitted by: MAKOTO TSUNODA

    Definition

    Carboxyl-bearing low-molecular-weight compounds such as keto acids, fatty acids, and other organic acids are involved in a myriad of metabolic pathways owing to their high polarity and solubility in biological fluids. Various disease areas such as cancer, myeloid leukemia, heart disease, liver disease, and lifestyle diseases (obesity and diabetes) were found to be related to certain metabolic pathways and changes in the concentrations of the compounds involved in those pathways. Therefore, the quantification of such compounds provides useful information pertaining to diagnosis, pathological conditions, and disease mechanisms, spurring the development of numerous analytical methods for this purpose.

    1. Introduction 

    Quantification of low-molecular-weight compounds, as exemplified by metabolomics studies, has become increasingly important in the life sciences. Metabolite analysis provides metabolic and biochemical status of particular biological systems and valuable insights into disease development and diagnosis [1][2][3][4][5][6]. There are numerous classes of low-molecular-weight compounds, and they are categorized based on their functional groups, including amine, thiol, and carboxylic groups. Low-molecular-weight carboxylic acids are involved in various metabolic pathways. For example, the tricarboxylic acid (TCA) cycle, which is the principal energy-producing process in cells, involves nine carboxylic acid compounds. Fatty acids are integral components of lipids, and consist of carboxylic acids with long aliphatic chains.

    Hence, highly sensitive and selective methods for the determination of biologically important carboxylic acids are required for biological investigations, and, thus far, numerous analytical methods have been developed. For selective determination, solid-phase extraction or solvent extraction pretreatment is commonly performed, followed by separation techniques such as liquid chromatography (LC), gas chromatography (GC), and capillary electrophoresis. The choice of detection method is important for trace amounts of carboxylic acids in biological samples. Ultraviolet absorbance detection is rarely implemented due to the absence of chromophores in carboxylic acids. Fluorescence detection following derivatization and mass spectrometry has the advantage of high sensitivity.

    2. Analytical methods for fatty acids in biological samples

    APF: 6-oxy-(acetyl piperazine)fluorescein, NOEPES: 2-(2-naphoxy)ethyl 2-(piperidino)ethanesulfonate, HEC: 9-(2-hydroxyethyl)-carbazole, DBD-ED: 4-N,N-dimethylaminosulfonyl-7-N-(2-aminoethyl)amino-2,1,3-benzoxadiazole, NT: 2-(2,3-naphthalimino)ethyl trifluoromethanesulfonate, AMPP: N-(4-aminomethylphenyl)pyridinium, AminoxyTMT: aminoxy tandem mass tags, DBD-PZ-NH2: 7-(N,N-dimethylaminosulfonyl)-4-(aminoethyl)piperazino-2,1,3-benzoxadiazole, DAABD-AE: 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole, MePZBD-AE: [4-(4-N-methyl)piperazinosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole, APZBD-NHMe: [4-(4-N-aminoethyl)piperazinosulfonyl]-7-methylamino-2,1,3-benzoxadiazole, DMPP: 2,4-dimethoxy-6-piperazin-1-yl pyrimidine, DMED: 2-dimethylaminoethylamine, AEMP: 2-(2-aminoethyl)-1-methylpyrrolidine, NAPP: N-(3-aminopropyl)pyrrolidine.

    3. Analytical methods for TCA cycle and glycolysis-related compounds in biological samples

    9-CMA: 9-chloromethyl anthracene, DBD-PZ: 7-(N,N-dimethylaminosulfonyl)-4-piperazino-2,1,3-benzoxadiazole.

    4. Analytical methods for amino acid metabolites in biological samples

     

    PHP-THβC: (1R, 3S)-1-(D-gluco-1, 2, 3, 4, 5-pentahydroxypentyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, DOPAC: 3,4-dihydroxyphenylacetic acid, HVA: homovanillic acid, 3-HG: 3-hydroxyglutaric acid, DAABD-AE: 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole, DmPABr: dimethylaminophenacyl bromide

    5. Analytical methods for perfluorinated carboxylic acids (PFCAs) in biological samples

    PFASs: polyfluoroalkyl substances, MASH: 10-methyl-acridone-2-sulfonohydrazide.

    6. Analytical methods for α-keto acids and 2-hydroxyglutaric acid (2-HG) in biological samples

    OPD: o-phenylenediamine, DMB: 1,2-diamino-4,5-methylenedioxybenzene, O-PFBO: O-(2,3,4,5,6-pentafluorobenzyl)oxime, DATAN: (+)-o,o’-diacetyl-l-tartaric anhydride, TSPC: N-(p-toluenesulfonyl)-L-phenylalanyl chloride.

    7. Analytical methods for 2-aminothiazoline-4-carboxylic acid (ATCA), 2-methylthiazolidine-4-carboxylic acid (MTCA), and 2-thiothiazolidine-4-carboxylic acid (TTCA) in biological samples

    MISBSE: molecularly imprinted stir bar sorption extraction.

    8. Analytical methods for other carboxylic acids in biological samples

    Target Compounds

    Biological Sample

    Sample Treatment

    Derivatization Reagent

    Separation Mode

    Detection Method

    LOD

    Recovery

    Ref.

    7 Bile acids

    Human saliva

    SPE and solvent extraction

    2-Picolylamine

    RPLC

    MS/MS

    1.5–5.6 fmol

    [75]

    3 Bile acids, 8 fatty acids

    Human plasma and saliva

    Solid phase extraction

    APBQ

    RPLC

    MS/MS

    0.19–0.51 fmol

    [76]

    7 Bile acids, 9 fatty acids

    Human serum

    Solvent extraction

    DBCETS

    RPLC

    FL: 300/395 nm

    0.28–0.70 ng/mL

    92–102%

    [77]

    4 Bile acids

    C. bovis

    Centrifugation

    2-bromo-4′-nitroacetophenone

    RPLC

    UV: 263 nm

    0.25–0.31 ng

    94–99%

    [78]

    7 Bile acids

    Human feces

    Solid phase extraction

    Phenacyl bromide

    RPLC

    UV: 254 nm

    1.22–1.46 pmol

    72–102%

    [79]

     

    Human feces

    Solid phase extraction

    None

    PRLC

    MS/MS

    [79]

    Dihydroxyoxocholestenoic acids

    Human CSF and plasma

    Solid phase extraction

    Isotope-label ed Girard’s P Reagent

    RPLC

    MS

    0.02–0.05 ng/mL

    [80]

    7 THGC glucuronides

    Human urine

    Centrifugation

    Isotope-labeled DAPPZ

    RPLC

    MS/MS

    0.008–0.16 µg/mL (LOQ)

    [81]

    Orotic acid

    Urine

    Dilution

    None

    RPLC

    MS/MS

    0.15 µM

    [82]

    Metabolome

    Human urine

    Centrifugation

    Isotope-label ed DmPABr

    RPLC

    MS

    [83]

    Metabolome

    Human urine

    Centrifugation

    Isotope-labeled dansyl hydrazine

    RPLC

    MS

    [84]

    APBQ: 1-(3-aminopropyl)-3-bromoquinolinium bromide, DBCETS: 2-(7H-dibenzo[a,g]carbazol-7-yl)ethyl 4-methylbenzenesulfonate, DAPPZ: 1-[(4-dimethylaminophenyl)-carbonyl]piperazine, DmPABr: dimethylaminophenacyl bromide.

    The entry is from 10.3390/molecules25214883

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