Spirocyclic Adduct Formation of Tryptanthrin with Indole Monoamines under Biomimetic Acidic Conditions.

Tryptanthrin is a natural indole-quinazoline alkaloid and a major component of the traditional blue dye indigo naturalis (IN). Although oral administration of IN has shown therapeutic effects in patients with ulcerative colitis and evidence supports its anti-inflammatory activity, its development as a drug has been limited. We hypothesized that ingested IN could engage in biomimetic reactions with human microbial metabolites, particularly reactive monoamines, leading to the formation of anti-inflammatory products. Under acid-promoted and elevated-temperature conditions, tryptanthrin selectively reacted with tryptamine to yield spirocyclic compound 1 rather than a typical imine. Kinetic evaluation revealed that endogenous organic acids, such as short-chain fatty acids and lactic acid, promoted this reaction at body temperature in aqueous solvent systems. Analogous transformations with other endogenous indole monoamines, including serotonin, 5-methoxytryptamine, and the xenobiotic indoleamine 5-chlorotryptamine, afforded spirocyclic adducts 2-4, respectively, and their kinetic data supported a chemically plausible reaction pathway. Compounds 1-4 retained anti-inflammatory activity by reducing IL-1β secretion associated with inflammasome activation in stimulated macrophages while maintaining favorable passive membrane permeability. Collectively, the formation of spirocyclic adducts of tryptanthrin with indole monoamines under biomimetic conditions provides chemical novelty and scaffold diversification without compromising druglike physicochemical properties.