Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice

Abstract

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine playing crucial role in immunity. MIF exerts a unique tautomerase enzymatic activity that has relevance concerning its multiple functions and its small molecule inhibitors have been proven to block its pro-inflammatory effects. Here we demonstrate that some of the E-2-arylmethylene-1-tetralones and their heteroanalogues efficiently bind to MIF's active site and inhibit MIF tautomeric (enolase, ketolase activity) functions. A small set of the synthesised derivatives, namely compounds (4), ( 23), ( 24), ( 26) and ( 32), reduced inflammatory macrophage activation. Two of the selected compounds ( 24) and ( 26), however, markedly inhibited ROS and nitrite production, NF-jB activation, TNF-a, IL-6 and CCL-2 cytokine expression. Pre-treatment of mice with compound ( 24) exaggerated the hypothermic response to high dose of bacterial endotoxin. Our experiments suggest that tetralones and their derivatives inhibit MIF's tautomeric functions and regulate macrophage activation and thermal changes in severe forms of systemic inflammation.

Macrophage migration inhibitory factor (MIF) promotes intervertebral disc degeneration through the NF‐κB pathway, and the MIF inhibitor CPSI‐1306 alleviates intervertebral disc degeneration in a mouse model

“…45,67 Because MIF often exerts its physiological effects in the form of a trimer, inhibiting the formation of MIF trimers can suppress MIF's biological activity. 68 CPSI-1306 precisely achieves this by disrupting the trimeric formation of MIF within the body, thereby inhibiting MIF's biological activity. 45 As a result, they reduce the binding of MIF trimers to CD74, inhibit various intracellular effects, interrupt its cascading amplification of inflammatory effects, and thus hinder the progression of IDD.…”

“…Therefore, to prevent and treat intervertebral disc degenerative diseases, we selected CPSI‐1306, a small‐molecular inhibitor with oral activity, which has been verified to treat a variety of inflammatory diseases and malignant tumors by inhibiting MIF and has achieved good effects 45,67 . Because MIF often exerts its physiological effects in the form of a trimer, inhibiting the formation of MIF trimers can suppress MIF's biological activity 68 . CPSI‐1306 precisely achieves this by disrupting the trimeric formation of MIF within the body, thereby inhibiting MIF's biological activity 45 .…”

Facile access to 2‐amino‐4‐aryl‐5H‐chromeno[4,3‐b]pyridine‐3‐carbonitriles through a strategy of one‐pot Michael/cyclization reaction

“…As a fused ring, chroman-4-ones can be synthesized from some phenols [32,33]. The formed chroman-4-ones easily reacted with aldehydes for the preparation of (E)-3-benzylidenechroman-4-ones [34,35], and (E)-3-benzylidenechroman-4-ones can further participate in many reactions to produce various products, such as reduced product [36], cyclopropanes [37], cyclopentachromans [38], fivemembered heterocycles [39], six-membered heterocycles [40]. Therefore, chroman-4-ones can be used as the key raw material for the construction of polyheterocycles.…”

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

“…MIF also promotes an important tautomerase activity (IUBMB Enzyme Nomenclature: EC 5.3.2.1) [48,49] by catalyzing the tautomeric keto-enol transformation of several substrates such as keto-phenyl-pyruvate to enol-phenyl-pyruvate and vice versa. Accordingly, the tautomeric activity can be divided into enolase and ketonase sub-activities [50,51].…”

“…Previously, we demonstrated that E-2-arylmethylene-1-tetralones and their heteroanalogues bind the active site of MIF and inhibit MIF tautomerase activity. The best selected inhibitor of the tetralone family with both ketonase and enolase inhibitory potential repressed ROS, nitrite and cytokine production, as well as NF-κB activation in LPS-induced macrophages, and regulated thermal alterations in an experimental model of systemic inflammation [51]. In our study, we identified a potent and selective tautomerase inhibitor, KRP-6 (Figure 2), which strongly inhibited MIF's ketonase (IC 50 = 4.31 ± 1.34 µmol/L) but failed to reduce its enolase activity (IC 50 = 1260 ± 159 µmol/L) [51].…”