Identification of novel Nrf2-activating neuroprotective agents: Elucidation of structural congeners of (-)-galiellalactone and congener-based novel Nrf2 activators

[Display omitted] •We identified novel Nrf2/ARE signaling pathway activators, natural (-)-galiellalactone 1 and its cyclohexene ring-truncated [3.3] bicyclic lactone variants 3l and 3p.•(-)-Galiellalactone 1 and its variants 3l and 3p induced the ARE-mediated upregulation of downstream antioxidative and phase II detoxifying enzymes, HO-1 and NQO1. In particular, variant 3l remarkably increased the HO-1 expression.•(-)-Galiellalactone 1 and its variants 3l and 3p exhibited neuroprotective effects on the neuroblastoma SH-SY5Y cells against 6-OHDA-induced cytotoxic damages. Herein, (-)-galiellalactone 1 congeners responsible for the nuclear factor erythroid 2-related factor 2 (Nrf2)-activating neuroprotective effects were elucidated. Additionally, novel congener-based Nrf2 activators were identified using a drug repositioning strategy. (-)-Galiellalactone, which comprises a tricyclic lactone skeleton, significantly activates antioxidant response element (ARE)-mediated transcription in neuroblastoma SH-SY5Y cells. Interestingly, two cyclohexene-truncated [3.3] bicyclic lactone analogs, which possess an exocyclic α-methylene-γ-butyrolactone moiety, exhibited higher Nrf2/ARE transcriptional activities than the parent (-)-galiellalactone. We confirmed that the cyclohexene moiety embedding the [3.3] bicyclic lactone congener does not play the essential role of (-)-galiellalactone for Nrf2/ARE activation. Nrf2/ARE activation by novel analogs resulted in the upregulation of downstream antioxidative and phase II detoxifying enzymes, heme oxygenase-1, and NAD(P)H quinone oxidoreductase 1, which are closely related to the cytoprotective effects on neurodegenerative diseases. (-)-Galiellalactone and its [3.3] bicyclic variants 3l and 3p increased the expression of antioxidant genes and exhibited neuroprotective effects against 6-hydroxydopamine-mediated neurotoxicity in the neuroblastoma SH-SY5Y cell line.