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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.
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.
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.
9-CMA: 9-chloromethyl anthracene, DBD-PZ: 7-(N,N-dimethylaminosulfonyl)-4-piperazino-2,1,3-benzoxadiazole.
Target Compounds |
Biological Sample |
Sample Treatment |
Derivatization Reagent |
Separation Mode |
Detection Method |
LOD |
Recovery |
Ref. |
|||
Kinurenic acid |
Rat plasma |
Centrifugation |
None |
RPLC |
FL: 251/398 nm |
0.16 nM |
97–98% |
[40] |
|||
3 Trp metabolites |
Mouse plasma and brain |
Centrifugation |
None |
RPLC |
UV, FL |
0.03–1.33 µM |
83–116% |
[41] |
|||
6 Trp metabolites |
Pig urine, plasma |
Centrifugation |
None |
RPLC |
MS |
10–100 ng/mL (LOQ) |
– |
[42] |
|||
Glycated Trp |
Chicken plasma |
Solvent extraction |
None |
RPLC |
MS |
– |
– |
[43] |
|||
PHP-THβC |
Chicken plasma |
Cation-exchange resin |
None |
RPLC |
MS |
– |
– |
[44] |
|||
5 Trp and Tyr metabolites |
Human urine |
Centrifugation |
None |
RPLC |
UV: 220, 280 nm, FL: 280/350, 315/425 nm |
– |
– |
[45] |
|||
DOPAC, HVA |
Rat kidney |
Microdialysis |
Ethylenediamine |
Ion exchange chrom atography |
FL: 417/495 nm |
50, 100 fmol |
– |
[46] |
|||
Nicotinic acid |
Human plasma |
Solvent extraction |
None |
RPLC |
MS/MS |
6.57 ng/mL (LOQ) |
70–72% |
[47] |
|||
Glutaric acid, 3-HG |
Human urine |
Centrifugation |
DAABD-AE |
RPLC |
MS/MS |
20–25 nM |
94–121% |
[48] |
|||
64 amino acid derivatives |
Human urine, pancreatic cancer cells |
Centrifugation |
DmPABr |
RPLC |
MS/MS |
0.11–2192 nM |
– |
[49] |
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
PFASs: polyfluoroalkyl substances, MASH: 10-methyl-acridone-2-sulfonohydrazide.
Target Compounds |
Biological Sample |
Sample Treatment |
Derivatization Reagent |
Separation Mode |
Detection Method |
LOD |
Recovery |
Ref. |
|||||
4 α-Keto acids |
Human serum |
Centrifugation |
OPD |
RPLC |
FL: 350/410 nm |
1 µM |
86–109% |
[58] |
|||||
7 α-Keto acids |
Human neutrophil |
Centrifugation |
OPD |
RPLC |
FL: 360/415 nm |
0.035–0.125 µM |
79–108% |
[59] |
|||||
3 α-Keto acids |
Human CML cell |
Gel extraction |
OPD |
RPLC |
FL: 360/415 nm |
18–40 nM |
84–96% |
[60] |
|||||
6 α-Keto acids |
Human CML cell |
Centrifugation |
DMB |
RPLC |
FL: 367/446 nm |
1.3–5.4 nM |
86–118% |
[61] |
|||||
3 α-Keto acids |
Mouse tissue |
Acid extraction |
OPD |
RPLC |
MS |
5 nM |
76–95% |
[62] |
|||||
10 α-Keto acids |
Rat plasma |
Centrifugation |
O-PFBO |
RPLC |
MS/MS |
0.01–0.25 µM |
96–109% |
[63] |
|||||
3 α-Keto acids |
Human plasma |
Centrifugation |
None |
RPLC |
MS/MS |
0.04 µg/mL |
81–98% |
[64] |
|||||
(R)-2-HG |
Human serum |
Solid phase extraction |
DATAN |
RPLC |
MS/MS |
0.060 µM |
31–32% |
[65] |
|||||
(R)-2-HG |
Human urine, cancer tissues |
Solvent extraction |
TSPC |
RPLC |
MS/MS |
1.2 fmol |
88–109% |
[66] |
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.
Target Compounds |
Biological Sample |
Sample Treatment |
Derivatization Reagent |
Separation Mode |
Detection Method |
LOD |
Recovery |
Ref. |
|||||||
ATCA |
Rat plasma and organ |
Solid phase extraction |
None |
RPLC |
MS/MS |
– |
– |
[67] |
|||||||
ATCA |
Human urine |
MISBSE |
None |
RPLC |
MS/MS |
5 µg/L |
– |
[68] |
|||||||
ATCA |
Rat plasma |
Solid phase extraction |
None |
RPLC |
MS/MS |
12 µg/L |
– |
[69] |
|||||||
ATCA |
Human postmortem blood |
Solid phase extraction |
None |
HILIC |
MS/MS |
2.5 µg/L |
81–89% |
[70] |
|||||||
ATCA |
Human postmortem blood |
Solid phase extraction |
None |
HILIC |
MS/MS |
9 µg/L (LOQ) |
88–96% |
[71] |
|||||||
ATCA |
Human post-mortem blood |
Liquid-liquid extraction |
None |
HILIC |
MS/MS |
0.43 µg/L |
86–101% |
[72] |
|||||||
MTCA |
Human blood and urine |
Centrifugation |
Acetic anhydride |
RPLC |
MS/MS |
0.1 mg/L |
– |
[73] |
|||||||
TTCA |
Urine |
Acid extraction |
None |
RPLC |
UV: 271 nm |
35 µg/L |
78–87% |
[74] |
MISBSE: molecularly imprinted stir bar sorption extraction.
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.