AbstractsChemistry

My Ph.D. projects were the designs and syntheses of new drug candidates, consisting of three sub-topics: the exploration of sugar roles in glycopharmaceutics, the new sparks in histone deacetylase inhibitor (HDACi) design, and the further development of nitric oxide (NO) donors. Chapter one discussed two drug design strategies in glycopharmacteutics: glycorandomization and antibody directed enzymatic prodrug therapy (ADEPT). The natural existing antibiotics rebeccamycin (Reb) and geldanamycin (GA) were employed. Chapter two discussed three new strategies in HDACi designs. In my first HDACi project, Huisgen cycloaddition, the so called "click chemistry" was employed to synthesize a library of HDACi. Such a combinatorial design provided a rapid and flexible synthetic approach to a new HDACi library. In my second HDACi project, an alpha-glucoside prodrug of SAHA was synthesized. This prodrug was aimed to enhance SAHA's in vivo half life. In my third HDACi project, a SAHA mimic was designed in which the hydroxamic acid (HA) functionality was replaced with a C-NONOate functionality. However, such replacement resulted in a ten times loss of HDAC binding affinity. Detailed structural analysis revealed that the new analog had one less hydrogen bond in the HDAC-binding complex than SAHA. This project showed that besides the Zn(II) chelating effect, HA also contributed to SAHA's inhibitory potency via hydrogen bond formation. Chapter three discussed two types of NO donors. The first type included two N-alkyl N'-hydroxyl guanidine derivatives. My goal in this project was to provide ~20 g compound for the animal tests. The second type of NO donor was a glyco-conjugated N-NONOate containing a phenolic linker. The sugar moiety was an on/off control for NO release via the corresponding glycosidase. Real time UV analysis confirmed the release of NO from the new designed donor. For the O-nitro substituted phenolic linker, the dissociation of the N-NONOate fragment was a rapid process at psychological conditions, with a half life of less than 4 min.