Protolichesterinic acid derivatives: α-Methylene-γ-lactones as potent dual activators of PPARγ and Nrf2 transcriptional factors

PPAR gamma and Nrf2 are important transcriptional factors involved in many signaling pathways, especially in the anti-infectious response of macrophages. Compounds bearing a Michael acceptor moiety are well known to activate such transcriptional factors, we thus evaluated the potency of alpha,beta-unsaturated lactones synthesized using fluorous phase organic synthesis. Compounds were first screened for their cytotoxicity in order to select lactones for PPAR gamma and Nrf2 activation evaluation. Among them, two alpha-methylene-gamma-lactones were identified as potent dual activators of PPAR gamma and Nrf2 in macrophages. (C) 2014 Elsevier Ltd. All rights reserved.