Synthesis of mannosamine derivatives and analogs.

摘要

Gene therapy could provide an important new option for the treatment of many genetic diseases. At the present time, the greatest barrier to developing gene therapy is the limited efficiency of gene transfer to the target cells. A novel strategy for enhancing delivery of a gene is to modify the target cell surface so that a vector can bind more efficiently. It has been demonstrated that the sialic acid biosynthetic pathway can be used to alter the cell surface and build an artificial adenovirus receptor to enhance gene transfer. In our efforts to improve the efficiency of this strategy, we have designed and prepared a series of unnatural mannosamine derivatives, including N-acyl, N-alkyl, and 4-O-alkyl derivatives. Each of these unnatural carbohydrates contains a ketone functionality which could be manipulated by a chemical ligation reaction.; Several N-acyl derivatives were obtained through condensation of mannosamine and a carboxylic acid while both N-alkyl and 4-O-alkyl derivatives could be prepared by modifications of a commercially available methyl glucoside. The synthesis of the N-alkyl derivatives involved a key alkylation step which was accomplished by a new tandem reduction-reductive alkylation of an azido sugar. This procedure also was applied to a variety of aldehydes and azido sugars with different protecting groups and configurations to determine the generality of this new synthetic method.; In order to explore the substrate tolerance of the sialic acid biosynthetic pathway, 2-azido derivatives of mannosamine and carbon analogs of N-acetylmannosamine were designed and synthesized. A phosphine reagent that has been used to detect azides on the cell surface was obtained through variations of reported procedures. The carbon analogs were prepared by chemical elaboration of a commercially available methyl glucoside, including a novel acetolysis reaction in the presence of an ozonide functionality.; A number of these mannosamine derivatives were tested for their ability to enter the sialic acid biosynthetic pathway and be expressed on cell surfaces.