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.

炎症会导致各种疾病的发展，例如哮喘，心血管疾病，某些类型的癌症和代谢紊乱。由5-脂氧合酶（5-LO）由花生四烯酸生物合成的白三烯（LT）构成了强大的促炎性脂质介体家族。δ-牛油酸（δ-GA）（1）（一种天然维生素E类似物）被选择用于进一步的结构优化，因为它在无细胞和基于细胞的测定中选择性抑制了5-LO的活性，而不会损害15-LO产生专门的前解析介体。在当前研究过程中开发的半定量预测5-LO抑制潜力的模型允许设计24种半合成的garcinamides。根据预测模型，生物学评估表明，八种化合物有效抑制了人重组5-LO（IC ₅₀ <100 nM）。有趣的是，四种化合物的功效远比1种强在激活的原代人嗜中性粒细胞测定中。结构-活性的关系揭示了变构结合位点上可能带有芳香环的补充疏水口袋。