Photoactivation provides a mechanistic explanation for pan-assay interference behaviour of 2-aminopyrroles in lipoxygenase inhibition

Guo, H., Eleftheriadis, N., Rohr-Udilova, N., Dömling, A. & Dekker, F. J. 24-Jul-2017 In : European Journal of Medicinal Chemistry. 139, p. 633-643 11 p.

Research output: Scientific - peer-reviewArticle

Human 15-lipoxygenase-1 (h-15-LOX-1) is a promising drug target in inflammation and cancer. In this study substitution-oriented screening (SOS) has been used to identify compounds with a 2-aminopyrrole scaffold as inhibitors for h-15-LOX-1. The observed structure activity relationships (SAR) proved to be relatively flat. IC50's for the most potent inhibitor of the series did not surpass 6.3 μM and the enzyme kinetics demonstrated uncompetitive inhibition. Based on this, we hypothesized that the investigated 2-aminopyrroles are pan assay interference compounds (PAINS) with photoactivation via a radical mechanism. Our results demonstrated clear photoactivation of h-15-LOX-1 inhibition under UV and visible light. In addition, the investigated 2-aminopyrroles decreased viability of cultured human hepatocarcinoma cells HCC-1.2 in a dose-dependent manner with LD50 ranging from 0.55 ± 0.15 μM (21B10) to 2.75 ± 0.91 μM (22). Taken together, this indicates that photoactivation can play an important role in the biological activity of compounds with a 2-amino-pyrrole scaffold as investigated here.

Original languageEnglish
Pages (from-to)633-643
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
StateE-pub ahead of print - 24-Jul-2017


  • Journal Article

View graph of relations

ID: 47542324