A novel tool for structure assignment of hydroxylated metabolites of(arylpiperazinylbutyl)oxindole derivatives based on relative HPLC retention times

Szabó, Éva and Koványi-Lax, Györgyi and Szénási, Gábor and Dancsó, András and Kiss, Loránd and Kormány, Róbert and Simig, Gyula and Németh, Gábor and Volk, Balázs (2019) A novel tool for structure assignment of hydroxylated metabolites of(arylpiperazinylbutyl)oxindole derivatives based on relative HPLC retention times. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 170. pp. 102-111. ISSN 0731-7085

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Abstract

tIncubation of oxindole derivatives containing an arylpiperazine pharmacophore in rat liver microsomesin vitro formed several metabolites hydroxylated at various positions of the aromatic rings of the oxin-dole carbocycle or the arylpiperazine moiety. In order to substitute the sites of metabolic attack onthese positional isomers, the exact structure of the molecules had to be identified. As polarities of thecompounds depend on the site of hydroxylation, we measured retention times of the metabolites usingreversed-phase HPLC. It was noted that the relative retention times (RRT, the ratio of the retention timeof the metabolite and the parent compound) fell into distinct narrow ranges for metabolites identifiedby MS spectra as positional isomers. These RRT ranges correlated with the positions of hydroxylation.The hypothesis was validated by synthesis of hydroxy compounds of known structure and by deter-mination of their RRT values. Change in the chromatographic parameters such as column type, eluent,gradient time and temperature did not impede the identification of the sites of hydroxylation as the RRTpattern remained similar to the original one. The new empirical method proposed in our study can beused for tentative identification of hydroxy metabolites and orient the direction of efforts to synthesizemetabolically stable compounds.

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