A Multicomponent Reaction-Based Platform Opens New Avenues in Aryl Hydrocarbon Receptor Modulation

A multidisciplinary
platform is presented to address aryl hydrocarbon
receptor (AhR) modulation. A rewired Yonemitsu multicomponent reaction
with indole 2-carboxaldehydes and nucleophilic species was designed
to access a family of 6-substituted indolocarbazoles. The conformational
behavior of these compounds was examined to rationalize their axial
chirality. In silico docking and molecular simulations
highlighted key features implicated in their binding to AhR. Furthermore,
the synthesis of linkable derivatives allowed the direct development
of conjugated entities. Reporter gene and target gene expression analyses
identified these novel structures as potent noncytotoxic activating
AhR ligands, that can be extended to bifunctional molecules. The anti-inflammatory
properties of these AhR agonists were assessed in interleukin-13 treated
keratinocytes. Altogether, the synergistic research in synthetic and
computational chemistry integrated with biological studies opens novel
avenues toward understanding the biological roles of AhR and the development
of targeted therapeutics.