Abstract
p-Cresyl sulfate is one of the bound uremic toxins whose level increases in the sera of patients with the severity of chronic kidney disease and is therefore used as a standard for clinical investigations. Our first attempts to obtain p-cresyl sulfate led exclusively to the product of sulfonation of the aromatic ring instead of sulfation on the OH moiety. Nevertheless, this initial discouraging result allowed us to handle both p-cresyl sulfate and 2-hydroxy-5-methylbenzenesulfonic acid obtained by different synthetic pathways. Interestingly, the comparison between the two isomers pointed out that the two molecules show the same fragmentation pattern and are indistinguishable by mass spectrometry. They cannot be separated on several commercially available columns. The only difference between the two compounds is a 10-fold higher ionization yield under negative ion electrospray ionization. NMR spectral studies definitely confirmed the different molecular structures. We present here an unambiguous biomimetic synthetic route for p-cresyl sulfate and the spectroscopic characterization of both the compounds by nuclear magnetic resonance and mass spectrometry.
Highlights
The aryl sulfates, p-cresyl sulfate and indoxyl sulfate (IxS), are protein-bound uremic toxins (UTx), the levels of which increase in the sera of patients with the severity of chronic kidney disease (CKD), and both have been shown to have a strong negative correlation with renal function (estimated glomerular filtration rate) [1,2,3,4]
This study starts from the awareness, given by NMR spectra, that initial synthetic approaches unexpectedly produced only 2-hydroxy-5-methylbenzenesulfonic acid (2), instead of the desired p-cresyl sulfate (pCS)
1 H and 13 C magnetic resonance spectroscopy can distinguish the different molecular structures, since this technique is strongly sensitive to symmetry in the molecular connectivity
Summary
The aryl sulfates, p-cresyl sulfate (pCS) and indoxyl sulfate (IxS), are protein-bound uremic toxins (UTx), the levels of which increase in the sera of patients with the severity of chronic kidney disease (CKD), and both have been shown to have a strong negative correlation with renal function (estimated glomerular filtration rate (eGFR)) [1,2,3,4]. 4-hydroxyphenylacetate decarboxylase (EC 4.1.1.83), an [FeS] enzyme [5], whose active site entails the presence of a glycyl radical enzyme [10]. Another pathway may entail p-hydroxyphenylpyruvic acid as the direct precursor of p-cresol, through the action of another glycyl radical enzyme [11]. Molecules 2019, 24, 3704; doi:10.3390/molecules24203704 www.mdpi.com/journal/molecules as the direct precursor of p-cresol, through the action of another glycyl radical enzyme [11]
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