Late-Stage Modification and Diversification of α- Galactosylceramide Analogs

For the past two decades, one of the primary areas of research in the Howell group has been the investigation of derivatives of the α-galactosylceramide KRN7000 as they relate to iNKT cell activation. Specifically, efforts have focused on the development of glycolipids with targeted modifications to the sugar head, the sphingoid base, and the acyl chain that selectively promote either a pro-inflammatory or anti-inflammatory response, as well as addressing potency. While differentiating between these two opposing immune responses is a crucial component of developing KRN7000 derivatives as potential drug candidates, there are other factors related to both the functionality and the processes for preparing these compounds that are equally worthy of exploration. The research to be conducted for this doctoral thesis will be focused on two projects related to these other factors. The main project features the inclusion of a diazirine moiety at the terminus of the acyl chain on two glycolipids, with a goal of avoiding the anergy associated with KRN7000 (the development of tolerance over time). Additionally, alternative synthetic routes for several glycolipid intermediates to streamline production and more efficiently produce multiple derivatives from common starting materials will be explored.