Phenylpropanoid-derived bis(benzylidene)succinic acids as synthetically accessible aryl hydrocarbon receptor-active modulators

Phenylpropanoid-derived hydroxycinnamic acids are ubiquitous constituents of food plants and key intermediates in plant secondary metabolism, where oxidative coupling processes generate structurally diverse phenolic dimers. In this study, we report the first selective synthesis of two bis(benzylidene)succinic acid derivatives, (2 Z ,3 Z )-2,3-bis(4-hydroxybenzylidene)succinic acid and (2 Z ,3 Z )-2,3-bis(4-hydroxy-3-methoxybenzylidene)succinic acid, obtained in good yields from p -coumaric acid and ferulic acid, respectively. The transformation proceeds via a biomimetic single-electron transfer (SET) oxidative coupling mediated by tris(4-bromophenyl)aminium hexachloroantimonate (Magic Blue). Screening of alternative SET reagents, including ceric ammonium nitrate, manganese (III) acetate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), demonstrated that only Magic Blue enabled controlled and selective product formation. Reactivity was strongly substrate-dependent: p -hydroxy-substituted cinnamic acids underwent productive coupling, whereas cinnamic acid was unreactive and caffeic acid underwent rapid, unselective oxidation. Both synthesized compounds were evaluated for aryl hydrocarbon receptor (AhR) activation using a murine AhR-responsive cell reporter assay and displayed dose-dependent receptor activation, reaching approximately 30-fold induction at 100 µM. Under identical conditions, the reference AhR agonist tapinarof produced approximately 100-fold induction at 6.25 µM. Although moderate in potency, these naturally inspired bis(benzylidene)succinic acids expand the chemical space of AhR-active compounds and provide a foundation for further structure–reactivity and structure–activity investigations.