Syntheses and evaluation of the antioxidant activity of novel methoxypsoralen derivatives

A series of 5- and 8-methoxypsoralen (MOP) analogs, suitable for structure-antioxidative/anti-inflammatory activity relationship studies, were synthesized using as key-reactions the selective monobromination of MOPs with N-bromosaccharin and either a Heck reaction or a Suzuki coupling or a Suzuki coupling followed by a Wittig reaction to install side-chains of the acrylate- or benzoate- or cinnamate-type, respectively. The 8-MOP analogs 19 and 24, incorporating at position 5 of the psoralen nucleus a butyl acrylate or a tert-butyl cinnamate moiety, were the most powerful inhibitors of soybean LOX and inhibited effectively lipid peroxidation. Analog 19 was a more potent anti-inflammatory agent than the reference compound indomethacin and of comparable cytocompatibility to 8-MOP whereas analog 24 was a weaker inhibitor of inflammation than indomethacin and significantly more cytotoxic than 8-MOP. The results of the biological tests are discussed in terms of structural characteristics.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Selective monobromination of methoxypsoralens (MOPs) with N-bromosaccharin. ► Introduction of unsaturated chains in brominated MOPs using Pd-mediated reactions. ► n-Butyl E-3-(8-methoxypsoralen-5-yl)propenoate (19) is the most potent LOX inhibitor. ► Analog 19 was the most potent anti-inflammatory agent, even better than indomethacin. ► Analog 19 presented comparable cytocompatibility to the drug 8-MOP.