Design, Synthesis, Anticancer Activities And Mechanisms Of Selenadiazole Derivatives

Selenium (Se), as an essential trace element for human health, exerts a variety ofbiological activity such as anti-oxidation, anti-tumor, anti-inflammatory,anti-hypertensive, hypoglycemic effect。 pidemiological, preclinical and clinicalstudies have supported the role of selenocompounds as potential cancerchemopreventive and chemotherapeutic agents. For the high absorbability, favorablebiological activity and low toxicity of organic selenium compound, it has become oneof the research focuses of clinic pharmacy. In this paper, a series of1,2,5-selenadiazole derivatives have been synthesized and characterized, theirbiological activities were also studied. The main results were showed below:1. Four quinoxalinebenzo[1,2,5]selenadiazole derivatives（2a、2b、2c and2d）have been synthesized and characterized by ICP-AES, ESI-MS,1H-NMR, IR and UV.Describes the application of quinoxalinebenzo[1,2,5]selenadiazole derivatives asradiotherapy sensitizers to enhance X-ray-induced inhibitory effects on A375andHela cells.The results showed that, pretreatment of the cells with selenadiazolederivatives dramatically enhance X-ray-induced growth inhibition and colonyformation. Flow cytometry analysis indicates that the sensitization by selenadiazolederivatives was mainly caused by induction of G2/M cell cycle arrest. Westernblotting demonstrated that the combined treatment-induced A375cells growthinhibition was achieved by triggering reactive oxygen species-mediated DNA damageinvolving inactivation of AKT and MAPKs. Further investigation revealed thatselenadiazole derivative in combination with X-ray could synergistically inhibit theactivity of thioredoxin reductase-1in A375cells. Taken together, these results suggest that selenadiazole derivatives can act as novel radiosensitizer with potentialapplication in combating human cancers.2. Four phenylbenzo[1,2,5]selenadiazole derivatives（1a、1b、1c and1d）havebeen synthesized and characterized by ICP-AES, ESI-MS,1H-NMR, IR and UV. TheActivities of the Four phenylbenzo[1,2,5]selenadiazole derivatives were investigated onMCF-7and MDA-MB-231tumor cells by MTT assay. The results showed that,1b,1cand1d displayed greater cytotoxicity to MDA-MB-231than to MCF-7.1c enhancedinhibitory effect compared to12.6times. So we chose the MDA-MB-231tumor cellsfor further study, Flow cytometry analysis indicates that1b was mainly caused byinduction of G2/M cell cycle arrest, but1c and1d inhibited cancer cell growth mainlythrough induction of apoptosis. Pretreatment of the cells with1b,1c and1dsignificantly enhanced ROS generation a time-dependent manner. Western blottingdemonstrated that1b,1c and1d can induce the same degree of MDA-MB-231phosphorylated P53-mediated DNA damage, activation of p53signaling pathway, andactivation of AKT and MAPK signaling pathway inhibited cancer cell growth。 westudied1b,1c and1d role of MDA-MB-231reptiles and migration. The results show1b,1c and1d has good migration and invasion inhibitory effect on MDA-MB-231.These findings raise the selenium compounds more reliable theoretical research inanti-breast cancer.3. two thiadiazole benzo[1,2,5]selenadiazole derivatives（3a and3b）have beensynthesized and characterized by ICP-AES, ESI-MS,1H-NMR, IR and UV. Activitiesof the eight compounds were investigated on A375, A549, MCF-7, and Hela etc.tumor cells by MTT a ssay as well as the toxicity on HK-2cells.In conclusion, several novel Se heterocyclic compounds have been synthsisedand evaluated for their biological activities. Some of which have broad cell toxicity,some have good selectivity. The anticancer mechanism of some compounds was alsoevaluated. These results obtained in this study greatly enriched the researches oforganic Se compounds, and is of potential application and development prospect. It isalso the foundation for researching the before clinical antitumor drugs.