Opening or Closing the Lock? When Reactivity Is the Key to Biological Activity

Thiol-mediated processes play a key role to induce or inhibit inflammation proteins. Tailoring the reactivity of electrophiles can enhance the selectivity to address only certain surface cysteines. Fourteen 2′,3,4,4′-tetramethoxychalcones with different α-X substituents (X=H, F, Cl, Br, I, CN, Me, p-NO2-C6H4, Ph, p-OMe-C6H4, NO2, CF3, COOEt, COOH) were synthesized, containing the potentially electrophilic α,β-unsaturated carbonyl unit. The assessment of their reactivity as electrophiles in thia-Michael additions with cysteamine shows a change in the reactivity of more than six orders of magnitude. Moreover, a clear correlation between their reactivity and an influence on the inflammation proteins heme oxygenase-1 (HO-1) and the inducible NO synthase (iNOS) is demonstrated. As the biologically most active compound, the α-CF3-chalcone is shown to inhibit the NO production in RAW264.7 mouse macrophages in the nanomolar range.