Easy transformation of indoles to substituted tryptanthrins with powerful AHR activity

Malassezia furfur isolates from diseased skin preferentially biosynthesize compounds which are among the most active known Aryl-hydrocarbon Receptor (AhR) inducers, such as indirubin and tryptanthrin. In our effort to study their production from Malassezia spp., we investigated the role of indole-3-carboxaldehyde (I3A), the most abundant metabolite of Malassezia when grown on tryptophan agar, as a possible starting material for the biosynthesis of both alkaloids. Treatment of I3A with H₂O₂ and use of diphenyldiselenide as a catalyst resulted in the simultaneous one-step transformation of I3A to indirubin and tryptanthrin in good yields. The same reaction was first applied on simple indole and then on substituted indoles and indole-3-carboxaldehydes, leading to a series of mono- and bi-substituted indirubins and tryptanthrins bearing halogens, alkyl or carbomethoxy groups. Afterwards, they were evaluated for their activity on AhR in four different cell lines stably transfected with a luciferase reporter gene. Among them, 3-bromotryptanthrin interestingly showed 10 times higher activity than dioxin in the human HepG2 7.5 cell line at 6h. In conclusion, I3A could be the starting material used by Malassezia for the production of both indirubin and tryptanthrin through an oxidating mechanism. Additionally, some of the prepared tryptanthrins showed significantly increased activity and selectivity against the human cell line.