Design, synthesis and evaluation of original 1-H-indol-3-yl heterocyclic derivatives as tryptophan 2,3-dioxygenase inhibitors

Tryptophan 2, 3-dioxygenase (TDO2) is a heme-containing enzyme constitutively expressed at high concentrations in the liver and responsible for L-tryptophan (L-Trp) homeostasis. TDO2 catalyses the cleavage of L-Trp’s pyrrole ring to produce N’-formylkynurenine; the first step of the kynurenine pathway. The expression of TDO2 in cancer cells leads to the depletion of L-Trp and an increase of KP catabolites, overall resulting in the suppression of the anti-tumour immune response. The present work describes the development of new (1H-indol-3-yl)-heterocyclic derivatives as TDO2 inhibitors through rational design, inspired from existing inhibitors. Evaluation of these compounds provided new insights regarding the structural modulations that can be accommodated inside the active site of TDO2 and their effect on inhibitory potency. Finally, in this same series of inhibitors, we also investigated the integration of a selenium atom as a bioisostere of lower molecular weight chalcogens. (BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 2021