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

Abstract

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.