Naphthoquinones are among the most active natural products obtained from plants and microorganisms. Naphthoquinones exert their biological activities through pleiotropic mechanisms that include reactivity against cell nucleophiles, generation of reactive oxygen species (ROS), and inhibition of proteins. Here, we report a mechanistic antiproliferative study performed in the yeast Saccharomyces cerevisiae for several derivatives of three important natural naphthoquinones: lawsone, juglone, and β-lapachone. We have found that (i) the free hydroxyl group of lawsone and juglone modulates toxicity; (ii) lawsone and juglone derivatives differ in their mechanisms of action, with ROS generation being more important for the former; and (iii) a subset of derivatives possess the capability to disrupt mitochondrial function, with β-lapachones being the most potent compounds in this respect. In addition, we have cross-compared yeast results with antibacterial and antitumor activities. We discuss the relationship between the mechanistic findings, the antiproliferative activities, and the physicochemical properties of the naphthoquinones.

中文翻译：

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具有增强线粒体毒性的 Lawsone、Juglon 和 β-Lapachone 衍生物

萘醌是从植物和微生物中获得的最活跃的天然产物之一。萘醌通过多效机制发挥其生物活性，包括对细胞亲核试剂的反应性、活性氧 (ROS) 的产生和蛋白质的抑制。在这里，我们报告了在酿酒酵母中进行的机械抗增殖研究对于三种重要的天然萘醌的几种衍生物：指甲花醌、胡桃醌和 β-拉帕醌。我们发现 (i) 胡桃醌和胡桃醌的游离羟基可调节毒性；(ii) 指甲花醌和胡桃醌衍生物的作用机制不同，活性氧的产生对前者更为重要；(iii) 一部分衍生物具有破坏线粒体功能的能力，在这方面，β-拉帕酮是最有效的化合物。此外，我们将酵母结果与抗菌和抗肿瘤活性进行了交叉比较。我们讨论了萘醌的机理发现、抗增殖活性和物理化学性质之间的关系。