| Sphingolipid metabolism with ceramide as a central hub is a critical regulator of the
sphingolipid rheostat. By balancing pro-apoptotic ceramide against pro-survival sphingosine-1-
phosphate (S1P), this system determines the cell fate. Natural sphingoid bases such as Jaspine B
and Spisulosine have been shown to interfere with ceramide biosynthesis in cancer cells, leading
to cytotoxic outcomes. Interference in ceramide flux and mitochondrial membrane potential can
trigger apoptosis and suppress tumor growth. This dissertation investigates the stereoselective
synthesis of oxy- and deoxysphingolipids analogs from inexpensive, enantiopure amino acids to
develop ceramide mimetics that selectively modulate ceramide biosynthesis, triggering cancer
cell death pathways.
This methodology facilitated concise and scalable syntheses of scaffolds inspired by
Spisulosine and Jaspine B, as well as novel analogs with variations in chain length, head groups,
and stereochemistry. The synthetic routes prioritize operational simplicity, stereochemical
precision, and adaptability for analog development.
These findings demonstrate that chiral-pool strategies based on amino acids provide an
effective platform for generating bioactive sphingolipid analogs that directly modulate ceramidemediated apoptosis in cancer cells. The synthetic and biological insights obtained contribute to
the rational design of sphingolipid-targeted anticancer agents and provide new chemical tools for
investigating ceramide-dependent mechanisms of tumor suppression.
Key words: Sphingolipids, natural products, ceramide, chiral pool, enantioselective synthesis,
Jaspine B, Spisulosine |