Comparison of (bio-)transformation methods for the generation of metabolite-like compound libraries of p38α MAP kinase inhibitors using high-resolution screening.

D. Falck, F.R. Pirkolachachi, M. Giera, M. Honing, J. Kool, W.M.A. Niessen

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Four hydrophobic p38α mitogen-activated protein kinase inhibitors were refluxed with 7.5% hydrogen peroxide at 80. °C and irradiated with visible light in order to generate more hydrophilic conversion products. The resulting mixtures were analyzed in a high-resolution screening (HRS) platform, featuring liquid chromatographic separation coupled in parallel with a fluorescence enhancement based continuous-flow affinity bioassay towards the p38α mitogen-activated protein kinase and with high-resolution (tandem) mass spectrometry on an ion-trap-time-of-flight hybrid instrument. The results were compared with similar data where chemical diversity was achieved by means of electrochemical conversion or incubation with either human liver microsomes or cytochrome P450s from Bacillus megaterium (BM3s). In total, more than 50 conversion products were identified. The metabolite-like compound libraries studied are discussed in terms of the reactions enabled, the retention of affinity, and the change in hydrophilicity by modification, in summary the ability to generate bioactive, more hydrophilic potential lead compounds. In this context, HRS is demonstrated to be an effective tool as it reduces the effort directed towards laborious synthesis and purification schemes. © 2013 Elsevier B.V.
Original languageEnglish
Pages (from-to)235-244
JournalJournal of Pharmaceutical and Biomedical Analysis
Issue number88
Publication statusPublished - 2014


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