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.

硒是一种未被充分探索的元素，可用于生物等排替代低分子量硫属元素（如氧和硫）。需要更多关于硒替代在不同化学支架中的影响的研究，以充分掌握这种元素的潜力。在这里，我们决定评估硒掺入一系列色氨酸 2,3-双加氧酶 (TDO2) 抑制剂的影响，这是癌症免疫治疗中的一个目标。首先，我们通过 Suzuki-Miyaura 型偶联合成了不同的硫属元素等排体。接下来，我们评估了等排体对 TDO2 的亲和力和选择性，以及它们对表达 TDO2 的细胞系的亲脂性、微粒体稳定性和细胞毒性。全面的，硫属元素等排替代物不会干扰靶向活性，但可以调节化合物的亲脂性、毒性和稳定性。目前的工作有助于我们对氧/硫/硒等构的理解，从而增加药物化学中的结构选择，以开发新的和独特的候选药物。