Synthesis and evaluation of lansiumamide B analogues to ameliorate acute lung injury by reducing oxidative stress and inflammation via Keap1/Nrf2/NF-κB pathway

Abstract

Acute lung injury (ALI), occurring with oxidative stress and inflammation, is a life-threatening disease, characterized by significant morbidity and mortality rates. There is a deep need to develop novel drugs. In this work we synthesized 46 novel lansiumamide B analogues with newly developed transition-metal-free strategy. Upon investigation, M11 exhibited highest inhibition rate of inflammatory cytokines and ROS release in LPS-induced Raw264.7 cells with good dose dependent manner and safety. In addition, M11 alleviated ALI induced lung injury and oxidative stress, and inhibited collagen formation and polarization of M1 macrophages. Reverse virtual screening and transcriptomics analysis suggested that M11 might target Keap1/Nrf2 signaling pathway. Further study demonstrated that M11 promoted Nrf2 nuclear translocation and the protein of downstream HO-1. Besides, M11 suppressed phosphorylation NF-κB. Overall, M11 could be an effective anti-oxidative stress and inflammation agent for ALI.

Keywords: Acute lung injury; Anti-inflammation; Lansiummaide B analogues; Oxidative stress.