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

Abstract

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. IC'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 LD 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.

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

“…Pan Assay Interference Compounds studies consider that some poor drug-likeness compounds bring false positive results [152,153], but pyrazolone is not on the list. Besides, the toxicity of pyrazolone derivatives is still alarming [154], because the loss and harm caused by the side effects of antipyrine and aminopyrine including leukopenia and agranulocytosis are still vivid.…”

Isoxazole Strategy for the Synthesis of α-Aminopyrrole Derivatives

“…One subclass of pyrroles, α-aminopyrroles, has shown promising diverse biological activity. We mention here only the recently published work on this topic: derivatives of 2-amino-1-benzyl-4,5-diphenyl-1 H -pyrrole-3-carbonitrile are a broad spectrum inhibitor of metallo-β-lactamases; 2-amino-5-benzoyl-4-(2,4-dichlorophenyl)-3-(3-chlorobenzoyl)-1 H -pyrrole is a potent and selective human 15-lipoxygenase-1 inhibitor; ethyl-2-amino-pyrrole-3-carboxylates are potent anticancer agents that affect tubulin polymerization, induce G2/M cell-cycle arrest, and effectively inhibit soft tissue; 5-acetyl-2-((2-fluoro-4-iodophenyl)­amino)-1 H -pyrrole-3-carboxamides are inhibitors of MEK kinase . Pyrroles with an unsubstituted pyrrole nitrogen and α-amino group have a special importance, being precursors for pyrrole-fused nitrogen polyheterocycles .…”

Novel 15-Lipoxygenase-1 Inhibitor Protects Macrophages from Lipopolysaccharide-Induced Cytotoxicity

“…Inhibition of 15-LOX-1 enzyme activity was performed using an activity assay as described previously by us. ,, The activity of 15-LOX-1 was monitored by measuring the conversion of LA into the UV-active 13-HpODE (λ max 234 nm). This assay was used to determine IC 50 of each compound.…”

“…More researchers reported the discovery of indole-based or indole-like 15-LOX-1 inhibitors, 371 and Haydi- 4b (with IC 50 values of 0.006 and 3.84 μM, respectively). , Our group previously discovered 15-LOX-1 inhibitor Eleftheriadis- 14d , which also contains an indole core and demonstrates good potency (IC 50 = 90 nM) . Furthermore, a 1,3-oxazole-based compound ( ML351 ), a purine-based compound (Anders-6b), and pyrrole-based compound ( 21B10 ) were identified as 15-LOX-1 inhibitors as well (Figure ). These inhibitors proved to be effective in various disease models, thus indicating the potential of 15-LOX-1 inhibitors for drug discovery.…”