Identification and Structural Analysis of New Nrf2 Activators by Mechanism‐Based Chemical Transformation of 15‐Deoxy‐Δ^12, 14‐PGJ₂

Abstract

Mechanism-based chemical transformation of 15-deoxy-Δ -PGJ (15d-PGJ ) resulted in a series of new NF-E2-related factor-2 (Nrf2) activators and detailed elucidation of the function of each electrophilic binding site. In addition, HO-1 expression resulting from Nrf2 activation through enhanced dissociation of the Keap1-Nrf2 complex by the new activators was proved.

15‐Deoxy‐Δ12,14‐prostaglandin J2 binds and inactivates STAT3 via covalent modification of cysteine 259 in H‐Ras‐transformed human breast epithelial cells

“…This moiety has been known to interact covalently with a cysteine residue of a target protein through Michael addition, resulting in alteration of the protein structure and function [7,8]. For instance, 15d-PGJ 2 was found to directly interact with thiol groups of the Keap1, a negative regulator of the redox-sensitive transcription factor Nrf2 [33]. Subsequent studies have shown that 15d-PGJ 2 covalently modifies IjB kinase and TrxR, thereby provoking intracellular oxidative stress and cell death [49,50].…”

“…15d-PGJ 2 was purchased from Cayman Chemical Co. (Ann Arbor, MI, USA). 15d-PGJ 2 analogues were synthesized as described previously [33]. Dulbecco's modified Eagle's medium (DMEM)/Ham's nutrient mixture F-12 (1 : 1) and horse serum was obtained from Gibco BRL (Grand Island, NY, USA).…”