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

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.