Structural Insights into the Anti-Austerity Activity of DC1149B through an SAR Study of Trichodermamides

DC1149B, a fungal secondary metabolite, exhibits potent and highly selective anti-austerity activity against PANC-1 cells, whereas the structurally related trichodermamide A shows neither significant anti-austerity activity nor cytotoxicity. An extensive structure-activity relationship study using chiral trichodermamides and rationally designed analogs revealed that the C-5 β-allylic chloride is indispensable for potent cytotoxicity, whereas the unique seven-membered bicyclo[3.2.2] framework within the fused epidithiodiketopiperazine moiety is crucial for highly selective anti-austerity activity.