Unprecedented sesquiterpene-polycyclic polyprenylated acylphloroglucinol adduct against acute myeloid leukemia via inhibiting mitochondrial complex V

Abstract

Monosescinol A (1), the first example of sesquiterpene–polycyclic polyprenylated acylphloroglucinol (PPAP) adduct, which represented a new subclass of PPAP-type natural products, along with two new congeners with normal spiro 6/6/5 tricyclic architecture, were isolated from Hypericum longistylum. Monosescinol A possessed an unprecedented 6/5/5/6/6 pentacyclic carbon skeleton that might be assembled from the 6/6/5 carbon skeleton, via the splitting decomposition of C-3/C-14, and the attack from the C-3 in the PPAP core to C-28 in sesquiterpene section. In addition, we have firstly confirmed that 24R configuration was existed in sec‑Bu containing PPAPs by single crystal diffraction data analysis of monosescinol B (2), that might provide an enlightenment in the configurational determination of sec‑Bu containing PPAPs. Significantly, further pharmacological research has found that compound 1 exhibited remarkable pharmacological effects against acute myeloid leukemia (AML) cell lines, with direct inhibition of mitochondrial complex V and an increase in mitochondrial membrane potential, and led to an induction of oxidative stress, endogenous inflammation, and apoptosis of AML cells.