Title :

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

Author(s) :

Kozlova, A. [Auteur]
Thabault, L. [Auteur]
Dauguet, N. [Auteur]
Deskeuvre, M. [Auteur]
Stroobant, V. [Auteur]
Pilotte, L. [Auteur]
Liberelle, Maxime [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Van Den Eynde, B. [Auteur]
Frederick, Raphaël [Auteur]
Université de Namur [Namur] [UNamur]

Journal title :

European Journal of Medicinal Chemistry

Volume number :

227

Pages :

113892

Publisher :

Elsevier

Publication date :

2023-05-30

ISSN :

0223-5234

Keyword(s) :

Isostery
Chalcogen
Selenium
Atypical elements
Tryptophan 2
3-dioxygenase
Cancer immunotherapy

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Submission date :

2024-01-16T01:44:09Z
2024-09-18T08:06:30Z