Synthesis And Biological Activities Of Mitochondria-targeted Anti-tumor Drug And Its Mechanism

The importance of mitochondria as an emerging and perspective target for anti-tumour agents is corroborated by the recent findings that tumours differ in the level of expression of a number of genes and mutations even among patients with the same type of tumour, and, even worse, there are differences in mutations within the same tumour. This indicates that it will be unlikely to suppress cancer by targeting a single gene or a single pathway that may alter amongst cancer patients and that can be subject to mutations. Rather, it is necessary to search for a target that is invariant and whose exploitation may present a general strategy for efficient treatment across the landscape of neoplastic pathologies. As mitochondria are key regulators of cell death and as mitochondrial functions are often altered in neoplasia, mitochondrially-targeted compounds represent a perspective method to eradicate chemotherapy-refractory cancer cells.Recently, most studies of biological activities and mechanism of mitochondrially-targeted drugs were performed in vitro by cell culture by staining with mitochondria tracker which depends on the release or entrapment of fluorescence dye in mitochondria. The direct influence of mitochondria-targeted drugs on mitochondrial function, however, is seldom reported. To overcome this limitation, herein we investigated the direct and immediate effects of mitochondrial-targeted drugs on the function of mitochondria isolated from rat liver. All data will helps us to learn more about the mechanisms underlying biological activities of mitochondrial-targeted drugs on subcellular (mitochondrial) level.Furthermore, as the essential biological molecules, protein and DNA have been playing many vital roles in all kinds of biological phenomena, and being the important object for life sciences investigated. Thus, the study on the interaction of protein& DNA with mitochondrial-targeted drugs, is essential for the ADME (absorption, distribution, metabolism and excretion) in early stage of drug research and development, and can also help us to understand the mechanisms in molecular and gene levels.This thesis includes six chapters:Chapter1:A brief survey of recent research development in the field of mitochondrial-targeted anti-tumour drugs has been given in this chapter.Chapter2:We systematically investigated the biological activities of a-TOS on isolated mitochondrion, HSA and DNA. The results show that a-TOS with high concentration not only cause inhibition of mitochondrial respiration and mitochondrial permeability transition (MPT), but also strongly disturb mitochondrial membrane and ultrastructure. a-TOS possesses moderate binding affinity to HSA in site I due to the formation of a-TOS-HSA complex, and binds to DNA in major groove region.Chapter3:We measured the effect of two isomers (o-F16, m-F16) of F16on mitochondrial and HSA function. We observe that o-F16, like F16, can significantly induce the mitochondrial permeability transition (MPT), collapse membrane potential and affect respiration. On the contrary, m-F16can hardly collapse membrane potential and has less impact on mitochondrion. According to the experimental results, we propose a potential model to explain the structure-activity relationship of F16and its isomers.Chapter4:By using experimental and theoretical approaches, we systematically investigated the interaction between betulinic acid (BA) and HSA. The results show that BA possesses moderate binding affinity to HSA in site I due to the formation of BA-HSA complex by van der Waals and hydrogen bond forces.Chapter5:By replacing the previous saturated linker with phenylethynyl (unsaturated group), we designed and synthesized a new conjugate F16-phenylethynyl-bodipy, and we find such novel compound has potential mitochondrial-targeted activity.Chapter6:We report herein a novel pH-sensitive VE-5-FU adduct with antioxidant and anticancer properties. This hybrid could be released in an acidic medium rather than in a neutral medium. This dual-acting adduct could have potential application for delivering the bifunctional drug for antioxidant-based cancer chemoprevention to the target site of lower pH value, such as the stomach.