Synthesis and Evaluation of the AhR Activity of Indolo[3,2-b]carbazole Derivatives

The Aryl-hydrocarbon Receptor (AhR) is implicated in the regulation of several genes, including those encoding CYP1A1. Although it is an orphan receptor, the amount of data about its relationship with skin homeostasis and nosology is constantly increasing. Interestingly, 6-formylindolo[3,2-b]carbazole (6-FICZ), one of the most active AhR inducers and amongst the proposed receptor’s endogenous ligands, has been detected in Malassezia furfur isolates from lesional skin, as well as in skin scales from patients with seborrhoeic dermatitis. Aiming to study the structure–activity relationships of the indolo[3,2-b]carbazole (ICZ) scaffold and to clarify if the formyl group of 6-FICZ has any specific role in AhR induction, a series of analogues of ICZ (substituted at position 6 with methyl, formyl and hydroxymethyl groups) were synthesized and evaluated for their activity on AhR in cell lines of four different species. A new simple method for the synthesis of 6-FICZ was developed. 6-Methylindolo[3,2-b]carbazole (6-MICZ) showed higher activity than 6-FICZ in human, rat and guinea pig cell lines, and all synthesized derivatives showed comparable activity in the mouse cell line. Therefore, the formyl group does not seem to play a significantly specific role in the affinity for AhR, and 6-FICZ seems less likely to be an endogenous ligand.