Investigation of chalcogen bioisosteric replacement in a series of heterocyclic inhibitors of tryptophan 2,3-dioxygenase - Université de Lille
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2023

Investigation of chalcogen bioisosteric replacement in a series of heterocyclic inhibitors of tryptophan 2,3-dioxygenase

A. Kozlova
  • Fonction : Auteur
L. Thabault
  • Fonction : Auteur
N. Dauguet
  • Fonction : Auteur
M. Deskeuvre
  • Fonction : Auteur
V. Stroobant
  • Fonction : Auteur
L. Pilotte
  • Fonction : Auteur
B. van den Eynde
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-04700955 , version 1 (18-09-2024)

Identifiants

Citer

A. Kozlova, L. Thabault, N. Dauguet, M. Deskeuvre, V. Stroobant, et al.. Investigation of chalcogen bioisosteric replacement in a series of heterocyclic inhibitors of tryptophan 2,3-dioxygenase. European Journal of Medicinal Chemistry, 2023, European Journal of Medicinal Chemistry, 227, pp.113892. ⟨10.1016/j.ejmech.2021.113892⟩. ⟨hal-04700955⟩

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