Quinones are a class of cyclic organic compounds that are widely distributed in nature and have been shown to exhibit anti-inflammatory, antioxidant, and anticancerous activities. However, the molecular mechanisms/signaling by which these molecules exert their effect are still not fully understood. In this study, a group of quinone-derived compounds were examined for their potential inhibitory effect against human IRAK1 and IRAK4 kinases in vitro. We have identified five compounds: 1,4-naphthoquinone, emodin, shikonin, plumbagin, and menadione (vitamin K3) as active and selective inhibitors of human IRAK1 enzyme in vitro. The biochemical binding and molecular interactions between the active compounds and IRAK1’s catalytic site were demonstrated in silico using structural-based docking and dynamic simulation analysis. Also, 1,4-naphthoquinone was found to effectively inhibit the growth of cancer cell lines overexpressing IRAK1. Furthermore, 1,4-naphthoquinone potently suppressed the production and secretion of key proinflammatory cytokine proteins IL-8, IL-1β, IL-10, TNF-α, and IL-6 in LPS-stimulated PMA-induced human THP-1 macrophages. In conclusion, 1,4-naphthoquinone is an effective inhibitor of IRAK1 kinases and their mediated inflammatory cytokines production in LPS-stimulated PMA-induced human THP-1 macrophages.

中文翻译：

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1,4-萘醌是 IRAK1 激酶和 THP-1 分化巨噬细胞中炎性细胞因子产生的有效抑制剂

醌是一类在自然界中广泛分布的环状有机化合物，已被证明具有抗炎、抗氧化和抗癌活性。然而，这些分子发挥作用的分子机制/信号仍未完全了解。在这项研究中，研究了一组醌衍生化合物在体外对人 IRAK1 和 IRAK4 激酶的潜在抑制作用。我们已经确定了五种化合物：1,4-萘醌、大黄素、紫草素、白花红素和甲萘醌（维生素 K3）作为体外人 IRAK1 酶的活性和选择性抑制剂。活性化合物与 IRAK1 催化位点之间的生化结合和分子相互作用在计算机上得到了证明使用基于结构的对接和动态仿真分析。此外，还发现 1,4-萘醌可有效抑制过度表达 IRAK1 的癌细胞系的生长。此外，在 LPS 刺激的 PMA 诱导的人类 THP-1 巨噬细胞中，1,4-萘醌有效抑制关键促炎细胞因子蛋白 IL-8、IL-1β、IL-10、TNF-α 和 IL-6 的产生和分泌. 总之，1,4-萘醌是 IRAK1 激酶及其在 LPS 刺激的 PMA 诱导的人类 THP-1 巨噬细胞中介导的炎性细胞因子产生的有效抑制剂。