Design and Synthesis of α-Galactosylceramide Analogs for Biased Cytokine Responses

Alpha-Galactosylceramides are known to activate invariant natural killer (iNK) T cells which are a subset of T cells that regulates immune responses in both mice and humans. Upon activation, iNKT cells produce T helper (Th)1 (pro-inflammatory) and/or Th2 (anti-inflammatory) cytokines that have implications in several disease areas, including cancer, infectious diseases, allergies and autoimmune conditions. To date, the alpha-galactosylceramide, KRN7000, is the most studied experimental glycolipid; it activates iNKT cells to produce both Th1 and Th2 responses. The simultaneous release of Th1 and Th2 cytokines elicited by KRN7000 has an antagonistic effect because production of Th1 cytokines offsets the immunological impact of Th2 cytokines and vice versa. Therefore, novel analogs of KRN7000 have been synthesized with the goal of identifying compounds that provide a biased Th1 or Th2 response. This thesis described the design and synthesis of carbohydrate modified analogs of KRN7000; the goal is to identify compounds that induce a biased cytokine response. During the pursuit of one analog, the N-GalCer analog of KRN7000, a simple, efficient and solvent-free method was developed for the synthesis of both alpha- and beta-glycosyl amides.