Synthesis And Biological Evaluation Of Disulfides As Anticancer Agents With Thioredoxin Inhibition

The thioredoxin system is comprised of the redox-active protein thioredoxin(Trx),the enzyme thioredoxin reductase(Trx R)and NADPH.In cells,the Trx system plays a role in redox regulation,which can protect cells from oxidative stress by removing reactive oxygen species(ROS)and regulating redox balance.Trx is essential for many creatures and plays a vital role in a large number of physiological processes.As an important antioxidant,Trx is closely related to many human diseases,such as diabetes,neurodegenerative diseases,cataracts and cancer.Compared to normal cell lines,cancer cells usually harbor elevated ROS as a result of their uncontrolled proliferation and high metabolic rate.To maintain the redox balance,cancer cells also upregulate the antioxidant system to counteract the increased ROS levels.Many studies have shown that nearly all tumor cell lines with high levels of ROS and Trx.If the activity of Trx is effectively inhibited,the tumor cells can be selectively killed due to the relatively higher ROS level induced by the deficiency in effective antioxidants.Therefore,to develop a drug with Trx inhibition is a promising tumor treatment strategy.The focus of this paper is to synthesize and screen a drug molecule that can selectively inhibit Trx,and to evaluate its inhibitory effect on Trx and anti-tumor efficacy.1.Firstly,the different forms,structural characteristics and physiological functions of known mammalian Trx are summarized.Then,we have an overview of the role of ROS in the development of cancer and anti-tumor is briefly summarized.Finally,the development of Trx inhibitors is briefly reviewed,and disulfide bond-based drug molecules are further introduced.2.Secondly,a small molecular library of disulfides was designed and synthesized.We established an efficient and fast method to screen Trx inhibitors by using the probe NBL-SS that was developed by our group to detect the in situ activity of Trx in living cells.Then we evaluated their cytotoxicity in different types of cancer cell lines,and found that compound 68 and 69 exhibited potency as an inhibitor for Trx.Next,through the reaction kinetic model,we found compound 68 with a faster response to Trx than 69.Moreover,the related biological tests of 68 were performed and found that 68 could inhibit Trx by targeting sulfhydryl groups.Eventually,68 led to the accumulation of ROS and induced apoptosis of tumor cells.3.Finally,we summarized the innovation and the main content of this paper,and gave study prospect of further applications of disulfides in drug dedign.