Design and synthesis of inositol phosphate glycan conjugates

Some evidence suggests that inositol phosphate glycans (IPGs) having conserved structural elements serve as second messengers for insulin signal transduction. These compounds and a series of their analogues have been shown to possess insulin-mimetic activity in a number of assays. Synthetic IPGs have been prepared, and heavily truncated structures have also demonstrated insulin-mimetic activity. The smallest such analogue is a disaccharide containing phosphorylated myo-inositol and glucosamine.; The mechanism of IPG action is largely unknown, although it has been observed that some IPG structures are transported into insulin-sensitive cells by way of an active transport process. The nature of the transport machinery and the tolerance of transport to structural variability is unknown, but the potential of this mechanism as a means for drug delivery is the impetus for the work that is presented here. In order to assess the possibility of delivering drugs as IPG conjugates, a general method for conjugating an IPG carrier has been developed as a necessary first step. A strategy for preparing IPG disaccharide conjugates and the requisite synthesis of an appropriately modified IPG is herein reported.; The synthesis of this IPG requires the preparation of an orthogonally-protected and optically pure myo-inositol. An efficient strategy for preparing this myo-inositol from D-xylose has been developed. Studies aimed at optimizing the diastereoselectivity of a samarium-promoted pinacol coupling that is critical to this synthesis and some mechanistic studies of this reaction are also reported.