Anti-Inflammatory Lindolin Alkaloids Repress the Transcription of the Microsomal Prostaglandin E₂ Synthase-1 Gene in...

The known indole-3-acetyl anthranilate lindolin A from the early-diverging fungus Linderina pennispora, along with three novel semisynthetic congeners, were identified as selective inhibitors of prostaglandin E₂ (PGE₂) formation. Lindolins specifically suppress the expression of the microsomal prostaglandin E₂ synthase-1 (mPGES-1) gene in M1-polarized human macrophages, resulting in markedly reduced mPGES-1 protein levels and a consequent decrease in PGE₂ production, while leaving other lipid mediators largely unaffected. The biosynthesis of lindolins involves the promiscuous N-acyltransferase LinB, which accepts a variety of substituted anthranilic acids as acceptor substrates, thereby enabling the in vitro generation of an analog library. Structure-activity relationship studies revealed that four lindolin analogs with enhanced anti-inflammatory activity possess an ortho-substituted carboxyl group, a structural feature shared with the clinically used antiallergic drug tranilast. Due to their high selectivity toward the mPGES-1 gene expression, lindolins represent promising lead structures for the development of selective mPGES-1 inhibitors with a novel mode of action. Moreover, these findings highlight early-diverging fungi as underestimated source of compounds with pharmaceutical potential.