Tunicamycins have long served as important biochemical tools to interrogate unfolded protein responses (UPRs) in the endoplasmic reticulum by targeting DPAGT1 (dolichyl-phosphate N-acetylglucosamine-phosphotransferase 1), the first committed enzyme in N-glycan biosynthesis. Despite their utility, the broad and unselective cytotoxicity of tunicamycins has severely limited their translational and in vivo applications. We discovered that structural modification at the ω-position of the tunicamycin V (TM-V: TM-C15:1-iso) lipid chain overcomes this key limitation. Two newly designed analogues, TM-C13:0-ω-Hydroxyguanidyl (8) and TM-C13:0-ω-Guanidyl (9), demonstrated superior DPAGT1 inhibition relative to TM-V. Importantly, these analogues exhibited no detectable toxicity toward normal cells (IC₅₀ > 100 μM). In contrast, they showed potent antiproliferative activity against solid tumor cell lines (IC₅₀ = 0.53-1.54 μM), resulting in markedly improved selectivity indices (SI ≥65-192) compared with TM-V (SI = 0.46-2.2). These findings establish a new class of tunicamycin analogues that preserve the natural product core while decoupling therapeutic activity from off-target toxicity, enabling mechanistic studies of ER stress and supporting the development of well-tolerated anticancer agents.
Keywords: Antimetastatic agents, Antiproliferative agents, DPAGT1 inhibitors, Glycoprotein biosynthesis blockade, Guanidyl analogues, Hydroxyguanidyl analogues, Muraymycin A1, Muraymycin B9, N-glycan biosynthesis inhibition, Non-cytotoxicity, Triple-negative breast cancer, Tunicamycins, ω-Lipid-chain modification
Bioorganic chemistry
Journal Article
English
41946001
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