MIF tautomerase inhibitor potency of α,β-unsaturated cyclic ketones

Abstract

The pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), is currently enjoying a renewed interest owing to its recently revealed functions. Among these its enzymatic tautomerase activity remains the most perplexing. There is a notion that some aspects of MIF signaling might involve its catalytic action. Though a true in vivo substrate for MIF has not been identified yet small molecule inhibitors of MIF are sought currently as potential anti-inflammatory agents. We have reported earlier that ketone bodies and some plant phenols feature acidic CH groups that appear to be good markers of their inhibitor potency toward MIF phenylpyruvate tautomerase. These molecules, like phenylpyruvate itself, belong to the keto-carboxylic acids or to the α,β-unsaturated ketones. Some ketones of similar structure have earlier been reported to have anti-inflammatory effect. In this paper we report tautomerase inhibition by certain synthetic α,β-unsaturated cyclic ketones, a novel class of small molecule MIF inhibitors.