Design And Synthesis Of Mitochondrial Function Regulator And Piper Alkaloids HDAC Inhibitors

Part Ⅰ:Design and Synthesis of mitochondrial function regulators and structure-activity relationship studiesMitochondria are the cells’power houses that produce the ubiquitous energy currency (ATP) for cellular life activities. Recent studies about mitochondrial biology have demonstrated that mitochondrial dysfunction is linked with several diseases, including obesity and diabetes. Interestingly, several anti-diabetic drugs or natural products have been shown to exert their beneficial effects for metabolic syndrome though mild regulation of mitochondrial function, with novel mechanisms that energy changes in cells stimulate the AMPK pathway, leading to some beneficial consequences for glucose and lipid metabolism. Hence, discovery of small-molecule regulators of targeting mitochondrial function may be a potential method for therapy of metabolic syndrome.We screened a chemical library, about4000compounds, with mitochondrial membrane potential high throughput screening assay, and identified a novel small-molecule regulator C1which mildly depolarizes ΔΨm, is able to improve glucose and lipid metabolism to exert beneficial effects for metabolic syndrome. Firstly, after primary structure modification based on C1with traditional medicinal chemical methods, we have got a series of compounds and measured some basic datas. But for the time reason, their preliminary structure-activity relationships will be summarized after the whole assessment. Then, we designed and synthesized a series of novel quinoxalinones compounds according to some theories in medicinal chemistry study. Their biological assessments was also in the operation. It could be asserted that some findings from this research could give us encouraging result for further studies. Part Ⅱ:Synthesis of piper alkaloid derivatives and HDAC inhibitory studiesCancers could seriously threaten human health in the world. It was reported that cancer’s occurrence is related with ectopic expression of some genes. As we know, genes expression are regulated by genetic and epigenetic regulation in eukaryote, wherein the latter which could lead gene heritable silence without changing DNA code plays important role in gene expression of eukaryote. As one basic subclass, histone acetylation has gotten extensive research and its role in gene expression regulation has become one of popular fields, while histone deacetylases inhibitors also become a hot method for cancer treatment.In recent years, enormous novel HDAC inhibitors emerge and are now being evaluated in clinical trials and show promising results in adult patients with leukaemia’s and solid tumors. Vorinostat (SAHA) was the first HDAC inhibitor to be approved by the US Food and Drug Administration for cutaneous T-cell lymphoma. Since its simple structure and clear structure-activity relationship, SAHA and its analogues have received extensive attention. As one of projects in our lab, we found that some piperamides share extremely structural similarity with SAHA. Thus in this dissertation, we chose three natural piperamides including piperlonguminine, pipercallosine and retrofractamides A. Firstly we obtained these compounds from total synthesis methods, then investigated their HDAC1, HDAC3and HDAC6inhibitory activities. However, the biological assay showed that these natural compounds with amide structure did not exert inhibitory activity. Then we designed and synthesized a series of derivatives with hydroxamic acid and carboxyl structure. Subsequent evaluation on HDAC1, HDAC3and HDAC6, we got three compounds showing certain degrees of inhibitory activity compared with SAHA. The results lay foundation for further research of these kinds of compounds.