Discovery of cytotoxic 1,4-benzodioxane oxyneolignan analogues from Glechoma longituba.

Six previously undescribed 1,4-benzodioxane oxyneolignans, (±)-glechlongins A-C [(±)-1, (±)-2, (±)-3], were isolated from a whole plant extract of Glechoma longituba. All these compounds featured a non-methylated 1,4-benzodioxane. The structures of the enantiomers were elucidated via HRESIMS, NMR and experimental electronic circular dichroism calculations. Additionally, (±)-1, (±)-2, (±)-3 exhibited significant cytotoxicity against various human cancer cell lines. In particular, the racemate (±)-1 exerted selective and potent proliferation-inhibitory effects on t(8; 21) AML cells. In further mechanistic investigations, compound (±)-1 was found to significantly induce cellular differentiation in t(8; 21) AML by downregulating the expression of the AML1-ETO oncogene and inhibiting its downstream signaling transduction. This study is anticipated to provide an active lead structure for the treatment of t(8; 21) AML.