The resveratrol derivatives trans‐3,5‐dimethoxy‐4‐fluoro‐4′‐hydroxystilbene and trans‐2,4′,5‐trihydroxystilbene decrease oxidative stress and prolong lifespan in Caenorhabditis elegans

Objectives Resveratrol (trans‐3,4′,5‐trihydroxystilbene (1)) was previously shown to extend the lifespan of different model organisms. However, its pharmacological efficiency is controversially discussed. Therefore, the bioactivity of four newly synthesized stilbenes (trans‐3,5‐dimethoxy‐4‐fluoro‐4′‐hydroxystilbene (3), trans‐4′‐hydroxy‐3,4,5‐trifluorostilbene (4), trans‐2,5‐dimethoxy‐4′‐hydroxystilbene (5), trans‐2,4′,5‐trihydroxystilbene (6)) was compared to (1) and pterostilbene (trans‐3,5‐dimethoxy‐4′‐hydroxystilbene (2)) in the established model organism Caenorhabditis elegans. Methods Trolox equivalent antioxidant capacity (TEAC), 2′,7′‐dichlorofluorescein (DCF), thermotolerance assays, C. elegans lifespan analyses. Key findings All compounds exert a strong in‐vitro radical scavenging activity (6 > 1 > 5 > 2 = 3 = 4), but in vivo, only (3) and (6) reduce reactive oxygen species (ROS) accumulation. Furthermore, (3) and (6) increased the mobility of aged nematodes and prolonged their mean lifespans, while these compounds decreased the thermal stress resistance. Using daf‐16 (FoxO), skn‐1 (Nrf2) and sir‐2.1 (sirtuin) loss‐of‐function mutant strains, the in vivo antioxidant effects of compounds (3) and (6) were abolished, showing the necessity of these evolutionary highly conserved factors. However, short‐time treatment with stilbenes (3) and (6) did not modulate the cellular localization of the transcription factors DAF‐16 and SKN‐1. Conclusion In contrast to resveratrol, the synthetic stilbene derivatives (3) and (6) increase the lifespan of C. elegans, rendering them promising candidates for pharmacological anti‐ageing purposes.