期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 227, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113892
关键词
Isostery; Chalcogen; Selenium; Atypical elements; Tryptophan 2,3-dioxygenase; Cancer immunotherapy
资金
- Belgian Fonds National de la Recherche Scientifique (F.R.S.-FNRS) [3.05557.43, 28252254, 32704190]
- Belgian Fondation contre le Cancer
- French Community of Belgium [ARC 14/19-058]
- Fonds Speciaux de recherche (FSR) at UCLouvain
- J. Maisin Foundation
This study explored the impact of selenium incorporation in TDO2 inhibitors, demonstrating that chalcogen isosteric replacements can modulate the properties of compounds without disturbing their on-target activity.
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. (C) 2021 Published by Elsevier Masson SAS.
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