Development Of Inhibitor Of MbtI Against Mycobacterium Tuberculosis And Synthetic Liposomal Anti-Tumor Vaccine Self-Assembled With NKT Cell Agonist

There are two sections in this thesis. The first section focuses on the synthesis inhibitor of MbtI enzyme whose design is based on transient-state simulation. The inhibitor is used to block the biosynthesis of siderophore in mycobacterium tuberculosis.The second section is centered on the development of fully synthetic liposomal anti-tumor vaccine self-assembled with NKT agonist.Tuberculosis (TB) is caused by mycobacterium tuberculosis which poses a global health problem nowadays. The currently available anti-TB drugs cannot effectively suppress TB, especially drug-resistant TB. It is urgent to develop the anti-TB therapy with a novel mode of action. Mycobacterium tuberculosis (Mtb) produces aryl-capped siderophores known as the mycobactins to sequester the essential iron element for survival in mammalian host. In view of the key role of siderophores, blocking the formation of siderophores is considered as potential anti-TB strategy. Salicylic acid is the starting materials for the synthesis of siderophore mycobactins. MbtI can catalyze the conversion of chorismate to salicylic acid. The inhibitor aganist MbtI could potentially prevent the formation of siderophore. MbtI and EntC (from Escherichia coli) have the similar structure and function, both of which belong to the family of chorismate-utilizing enzymes (CUEs). To the best of our knowledge, the most active inhibitor aganist CUEs is Bartlett inhibitor,but it is no report of Bartlett inhibitor aganist MbtI . In this thesis we designed an asymmetric synthetic route to Bartlett inhibitors, which also permit the modification around the cyclohexene skeleton. The inhibition activity of Bartlett inhibitor and its analog to MbtI is described.The second section of thesis is to prepare fully synthetic liposomal anti-tumor vaccine against STn, a typical tumor-assoicated carbohydrate antigen. We hypothesized that Th1 or Th2 cytokine-biased NKT cell agonist would influence the immunological activity of vaccine. We prepared liposomal anti-tumor vaccine self-assembled with NKT cell agonist of different cytokine profile selectivity. The immunological activities of the vaccines were evaluated. This vaccine design strategy could be used as a potential anti-TB therapy to target siderophore in Mycobacterium tuberculosis.