从天然产物及其衍生物中发现具有生物活性的小分子化合物，并揭示其作用靶标是天然药物化学研究中亟待解决关键问题。我们发现海洋来源吩嗪衍生物在体外细胞毒活性和大鼠肿瘤移植模型实验中具有显著的抗肝癌活性。通过针对肝癌细胞(HepG2)凋亡特点设计的氧化应激相关生物分子时间进程，我们推测并初步证实吩嗪分子可以通过靶向抑制硫氧还蛋白还原酶1(TrxR1)活性，上调活性氧水平(ROS)诱导HepG2凋亡。TrxR1是生物体内调节平衡氧化-抗氧化状态的重要蛋白，而吩嗪分子作为TrxR1抑制剂发挥抗肿瘤作用还没有相关报道。因此，本项目基于氧化应激进程探索吩嗪类化合物的作用靶点为TrxR1并在酶学、细胞和动物水平三个层面上证实，阐明吩嗪分子与TrxR1蛋白关键序列的结合形成稳定复合物的机制。这些研究目标的实现不仅在拓展吩嗪分子药用功能方面具有重要的科学意义，而且能够明确TrxR1作为抗肝癌药物靶点的应用前景。

Revealing the target of bioactive Natural products or Natural products – like molecules is one of the crucial problems to be solved in the research of Natural medicinal chemistry. We found that marine-derived phenazine analogue has significant anti-cancer activity both in vitro and in vivo. With the time course strategies of oxidative stress related biological molecules, we found that phenazine derivate could target to inhibit TrxR1 activity, and induce apoptosis of liver hepatocellular (HepG2) cells through activation of reactive oxygen species (ROS) level. TrxR1 is the critical enzyme in regulating the redox balance and ROS in vivo. However, to best of our knowledge, the phenazines are still not reported as TrxR1 inhibitor. Therefore, based on time-course strategies of oxidative stress, this project plans to identify TrxR1 is the effectively direct target of phenazines at the enzyme, cellular and molecular levels, and elucidate their binding sites and stable interaction mechanism between phenazine and key sequences of TrxR1. The realizations of these objectives show its great scientific significance not only in expanding medicinal development of phenazine molecular, but also in the application of TrxR1 as an anti-cancer drug target.