新型TrxR抑制剂的设计、合成和抗肿瘤活性研究

Thioredoxin reductase (TrxR) serves as a carcinogenesis enzyme which is highly related to tumorigenesis and progression and is a new target for tumor therapy. Most TrxR inhibitors currently target selenol and thiol sites in the C-terminal. However, these TrxR inhibitors still lack for satisfying specificity because the thiol group is a key site for a variety of other enzymes. Due to the special electronic structure of the gold ion, the gold complex can selectively bind to the selenol site on TrxR, which have higher selectivity than other TrxR inhibitors. In our previous study, we focused on the structure-activity relationship, bioactivity and mechanism of action of the gold N-heterocyclic carbenes complexes. We found that most of gold complexes triggered very efficient inhibition impact on TrxR and exhibited higher anti-tumor potency than cisplatin at the cellular level. This project will be based on the previous work, and focuses on the binding mode of TrxR and its inhibitor. The combination approach of traditional medicinal chemistry and modern drug design techniques would be applied to design three classes of novel gold complexes as TrxR inhibitors. The designed molecules are synthesized either by employing target-oriented synthetic strategy or by other high efficient synthetic methods. Next, these complexes would be assayed for their activities efficiency at cellular and animal levels. The privilege molecules are selected to explore their mechanism of action. This study will extend the understanding and provide fundamental exploitation of developing novel TrxR inhibitors.

硫氧还蛋白还原酶（TrxR）与肿瘤的发生、发展密切相关，是肿瘤治疗的新靶点。目前大多数TrxR抑制剂主要靶向C-末端硒/硫醇基位点，而硫醇基是多种酶的关键位点，这一相似性导致目前的TrxR抑制剂特异性不高。由于金离子具有特殊的电子结构，金配合物能选择性的与TrxR上的硒醇基结合，具有更高的选择性。在我们前期针对氮杂环卡宾金配合物的构效关系、生物活性和作用机理的研究中，发现合成的大部分金配合物都对TrxR有较好的抑制活性，且在细胞水平上表现出比顺铂更强的抗肿瘤活性。据此，本项目根据TrxR和其抑制剂的结合模式，结合经典药物设计和现代设计方法，初步设计了三类新颖的含金结构的TrxR抑制剂。将采用定向合成等其它高效化合物制备技术，合成新的金配合物。然后从细胞和动物水平对金配合物进行抗肿瘤活性评价,并对成药性好的配合物进行作用机制研究。此研究可为新型TrxR抑制剂的研发奠定基础。

硫氧还蛋白还原酶（TrxR）与肿瘤的发生、发展密切相关，是肿瘤治疗的新靶点。目前大多数TrxR抑制剂主要靶向C-末端硒/硫醇基位点，而硫醇基是多种酶的关键位点，这一相似性导致目前的TrxR抑制剂特异性不高。由于金离子具有特殊的电子结构，金配合物能选择性的与TrxR上的硒醇基结合，具有更高的选择性。我们在本项目支持下，主要进行了以下三方面工作：（1）扩大对4,5-二芳基咪唑类氮杂环卡宾配合物的抗肿瘤构效关系和作用机理的研究；（2）以金诺芬结构为母核进行抗肿瘤的结构优化和构效关系深入研究，尤其是针对吡喃葡萄糖结构部分，将引入不同结构的烷硫基、芳硫基等基团替代；（3）设计并合成了一系列的席夫碱金配合物，并进行抗肝癌机制研究。通过本项目的支持，对以TrxR为靶点的小分子金抑制剂进行了系统研究，为重要疾病靶标发展新型小分子抗肿瘤药物提供先导化合物。