Synthesis and antitumor evaluation of arctigenin derivatives based on antiausterity strategy

A series of new (−)-arctigenin derivatives with variably modified O-alkyl groups were synthesized and their preferential cytotoxicity was evaluated against human pancreatic cancer cell line PANC-1 under nutrient-deprived conditions. The results showed that monoethoxy derivative 4i (PC50, 0.49 μM), diethoxy derivative 4h (PC50, 0.66 μM), and triethoxy derivative 4m (PC50, 0.78 μM) showed the preferential cytotoxicities under nutrient-deprived conditions, which were identical to or more potent than (−)-arctigenin (1) (PC50, 0.80 μM). Among them, we selected the triethoxy derivative 4m and examined its in vivo antitumor activity using a mouse xenograft model. Triethoxy derivative 4m exhibited also in vivo antitumor activity with the potency identical to or slightly more than (−)-arctigenin (1). These results would suggest that a modification of (−)-arctigenin structure could lead to a new drug based on the antiausterity strategy.

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► Fifteen new (−)-arctigenin derivatives with variably modified O-alkyl groups were synthesized.
► Preferential cytotoxicity of the synthetic derivatives was evaluated against PANC-1 cells.
► Compounds 4h, 4i, 4m showed potent preferential cytotoxicity against PANC-1 cells.
► Compound 4m exhibited in vivo antitumor activity with the potency identical to (−)-arctigenin.