Rational Design, Synthesis And Anticancer Action Mechanisms Research Of Organoselenium Compounds

Cancer is a severe threat to human health. Cancer cells are easy to destroy the structure and function of human body tissues and organs through the unlimited proliferation, eventually lead to the death of human body. In recent years, duo to the advantages of high anticancer activities and low cytotoxicity, organoselenium compounds continue to kindle researcher’s interests. Therefore, it is significant to design novel organoselenium compounds and explore their anticancer action mechanisms.The thesis mainly include three parts:(1) In chapter 2, a novel class of methylene carbamimidoselenoate derivatives was rationally designed and synthesized. By MTT assay and the structure-activity relationship analysis, we found that different substituents of the compounds had important effects on their anticancer activities, as the introduction of a methoxy group(2h) enhanced the cancer cell selectivity of the compound to cancer cells. Their different cellular uptake levels are positively related to their anticancer activities. Further investigation on the intracellular mechanisms demonstrated that 2h entered cancer cells through endocytosis and caused mitochondrial dysfunction and apoptosis by activating the p53 pathway.(2) In chapter 3, based on the chemical property similarity of chalcogen elements, a class of organic heterocyclic compounds containing O, S, Se were designed and synthesized. We found that the introduction of the Se element significantly improved the anticancer activities of the designed compounds. Among them, compound 3j containing chlorine atom substituent showed the best anticancer activity. By further intracellular action mechanisms research, we found 3j can activate caspase-3,-9, and cause the accumulation of intracellular reactive oxygen species, ultimately induced cancer cell apoptosis through the mitochondrial signaling pathways.(3) In chapter 4, a class of selenazolopyridine derivatives were synthesized and characterized by X-ray diffraction, high resolution NMR and mass spectrum. By MTT assay and the structure-activity relationship, we found that 4g had highest growth inhibitory effect on MCF-7 cells. The intracellular mechanism of cell death was evaluated by flow cytometric analysis and ROS assay, which revealed that 4g could induce MCF-7 cells apoptosis by scavenging intracellular ROS.In summary, we deeply studied the reaction mechanisms of the organic synthesis, put forward a set of effective synthetic method and finally synthesized a total of 24 compounds, which enriched the structure library of organoselenium compounds. In the anticancer activities study, we demonstrated its intracellular action mechanisms of cancer cell apoptosis induction. This part of the work has enriched the research of organoselenium compounds’ anticancer activities, providing experimental basis for the clinical application of organoselenium compounds.