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Cu(II) mediated oxidation of cemtirestat yields its disulfide under physiological conditions in vitro

Pavol Bodo, Lucia Kovacikova, Andrej Bohac, and Milan Stefek

Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia



Received: 26 April 2022  Accepted: 11 July 2022


The aim of this study was to investigate interaction of cemtirestat, an efficient aldose reductase inhibitor and antioxidant, with Cu2+ ions under physiological conditions in vitro. UV–Vis spectral changes of cemtirestat (50 µM) in the presence of increasing concentrations of CuCl2 in 1.0 mM phosphate buffer at pH 7.4 were characterized by time dependent decrease in the cemtirestat base peak at 302 nm and concurrent increase in a novel peak at 270 nm. The titration equivalence point determined at 25 µM CuCl2 indicates that 1 mol of CuCl2 interacts with 2 mol of cemtirestat. In the presence of the reducing agent tris(2-carboxyethyl)phospine (TCEP, 1 mM), the UV–Vis peak at 270 nm of the novel product shifted back to 302 nm (that is corresponding to cemtirestat). The results pointed to Cu(II) mediated oxidation of cemtirestat to its disulfide. This preliminary finding was proved by comparison of TLC retention data and UV–Vis/mass spectra with standard—independently synthesized cemtirestat disulfide. To conclude, cemtirestat disulfide was proved as a main reaction product of cemtirestat exposed to Cu2+ ions under physiological conditions in vitro. Molecular mechanism of Cu(II) mediated oxidation of cemtirestat yielding cemtirestat disulfide and comprising autooxidation of intermediary formed Cu+ ion was suggested.

Keywords: Cemtirestat; Aldose reductase inhibitor; Cu(II) mediated oxidation; Cemtirestat disulfide

Full paper is available at

DOI: 10.1007/s11696-022-02368-w


Chemical Papers 76 (11) 6783–6788 (2022)

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