Synthesis, Molecular Modeling, and Translational Studies of Medicinal Agents Targeting Sphingolipid Biochemistry

Bioactive sphingolipids (SLs) are a category of lipids with sphingoid bases (SB) as their basic backbone structure. These molecules exhibit distinct pharmacological effects by targeting esterases, amidases, kinases, phosphatases, and membrane receptors. The SLs constitute highly complex metabolic pathway interconnections called Sphingolipidome. Each pathway signifies specific subcellular localizations that regulate the functions of SLs. These Sphingolipidome networks control critical functions of the cell involving cell growth by regulating apoptosis, senescence, cell migration, and inflammatory responses. These cellular functions are implicated in cardiovascular diseases, metabolic disorders, neurodegenerative disorders, autoimmune diseases, and cancers. Imbalances in SL metabolic pathways significantly contribute to the development and progression of these diseases. The pharmacological significance of sphingolipids has resulted in several sphingoid-based inhibitors, activators, and modulators for translational drug discovery efforts. Most of these medicinal agents possess close structural similarity with sphingolipids. This review covers the enantioselective syntheses and drug development efforts of sphingolipid-based medicinal agents of preclinical and clinical studies. These agents include Myriocin, Fingolimod, Fenretinide, Safingol, Spisulosine (ES-285), jaspine B, D-e-MAPP, B13, and α-Galactosylceramide. These agents were subjected to molecular modeling studies to understand the binding interactions with the biological target. The rationale discussion of these medicinal agents will help future drug discovery endeavors based on sphingolipid biochemistry.