Triarylmethane class of compounds as potential modulators of the Aryl Hydrocarbon Receptor (AhR): synthesis and in vitro evaluation

The aryl hydrocarbon receptor (AhR) is a transcription factor and a crucial regulator of several functions in most cell types and tissues. The main outcome of AhR expression is the induction of cytochrome P450 family 1 (CYP1) of metabolizing enzymes, which has been recently suggested as a pharmacological target in endocrine homeostasis, cell-cycle regulation, and treatment of immune, inflammatory and oncological diseases, among others. Herein a novel set of triarylmethane (TAM) class of compounds is evaluated for possible modulatory activity of AhR expression. The biological evaluation of the AhR agonistic/antagonistic effects was performed by means of a cell-based bioassay for the set of TAMs. Similar to higher agonistic activity on AhR expression compared to the endogenous AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) was observed, and none of the TAMs tested showed any potential antagonism. Furthermore, an analysis of substituents influencing the activity of the bioisosters and predictions of the bioavailability parameters, the physicochemical properties and the drug-likeness of the novel TAMs were conducted.