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Selenium is an underexplored element that can be used for bioisosteric replacement of lower molecular weight chalcogens such as oxygen and sulfur. More studies regarding the impact of selenium substitution in different chemical scaffolds are needed to fully grasp this element's potential. Herein, we decided to evaluate the impact of selenium incorporation in a series of tryptophan 2,3-dioxygenase (TDO2) inhibitors, a target of interest in cancer immunotherapy. First, we synthesized the different chalcogen isosteres through Suzuki-Miyaura type coupling. Next, we evaluated the isosteres' affinity and selectivity for TDO2, as well as their lipophilicity, microsomal stability and cellular toxicity on TDO2-expressing cell lines. Overall, chalcogen isosteric replacements did not disturb the on-target activity but allowed for a modulation of the compounds' lipophilicity, toxicity and stability profiles. The present work contributes to our understanding of oxygen/sulfur/selenium isostery towards increasing structural options in medicinal chemistry for the development of novel and distinctive drug candidates.

Original publication

DOI

10.1016/j.ejmech.2021.113892

Type

Journal article

Journal

European journal of medicinal chemistry

Publication Date

07/10/2021

Volume

227

Addresses

Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), B-1200 Brussels, Belgium; Ludwig Institute for Cancer Research, Brussels B-1200, Belgium; de Duve Institute, UCLouvain, Brussels B-1200, Belgium.