Formyl-phloroglucinol meroterpenoids with Nrf2 inhibitory activity from Eucalyptus globulus leaves

Three previously undescribed formyl-phloroglucinol meroterpenoids eucalypglobulusals K-M (1-3), one phloroglucinol derivative (16), and sixteen known analogues were isolated from the petroleum ether extract of Eucalyptus globulus leaves. The structures of new compounds (1-3, 16) were determined by extensive spectroscopic analysis, X-ray diffraction, experimental and calculated ECD spectroscopic analysis, as well as Mosher esterification experiment. Compound 3 gave the first example of coupling model of guaiane and diformyl-isopentyl phloroglucinol via forming 1-oxa[4,5]-spirocyclic system through C9'/C-15. Among these isolates, eucalypglobulusal L (2), eucalypglobulusal H (8), and eucalrobusone C (10) exhibited moderate cytotoxic activity against a panel of cancer cell lines with IC₅₀ values ranging from 8.18 to 23.13 μM. And formyl/isovaleryl phloroglucinol skeleton was considered as the key structural feature for cytotoxicity activity of both macrocarpal-type and euglobal-type meroterpenoids. Further cellular study showed that compounds 2, 8, and 10 could suppress the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in MDA-MB-231 cells, promote the accumulation of cellular reactive oxygen species (ROS), thereby leading to excessive lipid peroxidation. Compound 2 but not 8 and 10 significantly inhibited glutathione peroxidase 4 expression in MDA-MB-231 cells. Our work highlighted utilization potential of formyl-phloroglucinol meroterpenoids in cancer therapy and their different mechanism of action.