New Insights of Muraymycin A1 and Its Analogs as DPAGT1 Inhibitors.

Muraymycin A1 (MA1, 1), a complex nucleoside antibiotic, is a potent inhibitor of DPAGT1 (dolichylphosphate N-acetylglucosamine phosphotransferase 1), yet its relationship to cytotoxicity has remained unclear. Through a total synthetic route, we generated sufficient quantities of MA1 and key analogs to define the structural features required for selective DPAGT1 inhibition. Synthetic MA1 proved to be a stronger DPAGT1 inhibitor than tunicamycin V (TM-V), a broadly cytotoxic phosphotransferase inhibitor, but uniquely displayed slow antiproliferative activity against breast cancer cells including triple-negative subtypes, while sparing normal cells. The MA1 analogs MA1-NH₂ (3) and MA1-NH₂-Guanidyl (4), readily accessed from a common intermediate, matched MA1 in both enzyme inhibition and selective cytotoxicity. These studies delineate the minimum structural requirements of MA1 necessary for DPAGT1 inhibitory activity. Together, these compounds constitute highly selective biochemical tools for probing N-glycosylation in solid cancers and provide a foundation for developing more targeted anticancer strategies.