Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors.

Dinh, Chau Phi; Ville, Alexia; Neukirch, Konstantin; Viault, Guillaume; Temml, Veronika; Koeberle, Andreas; Werz, Oliver; Schuster, Daniela; Stuppner, Hermann; Richomme, Pascal; Helesbeux, Jean-Jacques; Séraphin, Denis

Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring.