二硫化合物是自然界中广泛存在的一类分子。链状二硫醚易于被硫醇还原，而环状（特别五元或六元环）二硫化合物很难被还原，但有报道环状二硫醚可以被硫氧还蛋白还原酶（TrxR）还原。我们的项目将以系统研究环状（五元/六元）二硫和二硒化合物与TrxR的相互作用为基础而展开。首先通过化学合成制备环状二硫/二硒化合物库，进而系统研究这些化合物与TrxR以及谷胱甘肽（GSH，细胞内最为主要的硫醇）的相互作用，筛选出能够被TrxR但不被GSH以及其它生物硫醇还原的化合物。在发现被TrxR选择性识别的化合物基础上，结合我们前期关于TrxR探针的工作，将进一步开展如下两方面的研究：（１）合成一系列潜在的TrxR探针分子，期待发现具有不同发射波长以及快速响应的TrxR探针分子，以丰富研究TrxR的工具；（２）合成依赖TrxR激活的前药分子，为基于TrxR为靶点的抗肿瘤药物研发提供新的策略。

Disulfides, including cyclic disulfides and linear disulfides, are a class of naturally occurring compounds. The linear disulfides are prone to be non-selectively reduced by thiols, while the cyclic disulfides, especially the five- or six-membered molecules, are resistant to thiol reduction, but may be reduced by the mammalian thioredoxin reductase (TrxR). Our proposal is based on the investigation of the interaction between the cyclic disulfides/diselenides and TrxR. Firstly, we will prepare a small library containing diverse cyclic disulfides/diselenides, and study their interaction with the TrxR and glutathione (GSH), the most abundant small molecule thiol in human cells. We expect to find several cyclic disulfides/diselenides that could be selectively reduced by TrxR, but not by GSH or other thiols. Secondly, after discovering such compounds, and in combination of our previous development of the selective TrxR probe, we will further perform the following studies: 1) A series of potential TrxR probes will be synthesized, and we expect to discover several specific TrxR probes with improved properties, such as varying emission wavelengths and/or shorter response time. These probes will afford more tools for studying the fucnction of TrxR in vivo; 2) Some TrxR-dependent prodrugs will be prepared, and their efficacy will be evaluated in vitro and in cellular models. We expect the development of TrxR-dependent prodrugs will provide a novel TrxR-targeting strategy for cancer chemotherapy.