Isolation and Characterization of the Cyanobacterial Macrolide Glycoside Moorenaside, an Anti-Inflammatory Analogue of Aurisides Targeting the Keap1/Nrf2 Pathway.

A new 14-membered ring brominated macrolide glycoside, named moorenaside (1), was discovered from a marine cyanobacterial sample collected from Shands Key in Florida. The structure of 1 was established by analysis of spectroscopic data including its relative configuration. The absolute configuration was inferred from optical rotation data and comparison with related compounds. The structure of 1 features an α,β-unsaturated carbonyl system, which is also found in aurisides. The presence of this motif in 1 prompted us to evaluate its effect on Keap1/Nrf2 signaling, a cytoprotective pathway culminating in the activation of antioxidant genes activated upstream by the cysteine alkylation of Keap1. Moorenaside exhibited moderate ARE luciferase activity at 32 μM. Due to the established crosstalk between Nrf2 and NF-κB pathways, we investigated the anti-inflammatory effects of 1 in LPS-induced mouse macrophages (RAW264.7 cells), a commonly used model for inflammation. Moorenaside significantly upregulated Nqo1 (Nrf2 target gene) and downregulated iNos (NF-κB target gene) at 32 μM by 5.0- and 2.5-fold, respectively, resulting in a significant reduction of nitric oxide (NO) levels. Furthermore, we performed RNA-sequencing and demonstrated the transcriptional activity of 1 on a global level and identified canonical pathways and upstream regulators involved in inflammation, immune response, and certain oxidative-stress-underlying diseases such as multiple sclerosis and chronic kidney disease.