有机阳离子转运体2 (OCT2) 主要表达于肾近曲小管细胞的基底侧膜, 参与了各种药物（如二甲双胍，顺铂，奥沙利铂，西咪替丁和拉米夫定）在肾脏排泄。顺铂是用于治疗各种癌症的抗癌药物，是OCT2的底物。顺铂引起的肾毒性部分归因于肾脏中OCT2的活性，导致顺铂在肾脏中堆积。本研究旨在确定具有强烈OCT2抑制作用的黄酮衍生物。在80个黄酮类化合物中，24个显示出对OCT2的中度到强烈的抑制作用。其中10个黄酮类化合物的IC50值小于5μM。所有10种化合物在表达OCT2的细胞中减轻了顺铂引起的细胞毒性，尽管作用强度因每个位置的功能基团不同而有所不同。多因素分析显示，黄酮醇骨架的R1位置甲基基团和R6位置的甲氧基基团对于OCT2的抑制很重要。了解黄酮醇骨架中功能基团的信息将有助于通过提供与OCT2抑制效果的结构相关联来开发有效的OCT2抑制剂。此外，本研究发现的对OCT2具有强烈抑制作用的化合物可能是减轻顺铂引起肾毒性的潜在药物候选物。版权所有©2023 Elsevier B.V. 保留所有权利。

Organic cation transporter 2 (OCT2) is predominantly expressed in the basolateral membrane of renal proximal tubule cells and contributes to the renal excretion of various drugs such as metformin, cisplatin, oxaliplatin, cimetidine, and lamivudine. Cisplatin, an anticancer agent for various cancers, is a substrate of OCT2, and cisplatin-induced nephrotoxicity is in part attributed to OCT2 activity in the kidney, which increases the renal accumulation of cisplatin. In this study, we aimed to identify flavone derivatives with strong inhibitory effects on OCT2 transport. Among the 80 flavonoids tested, 24 showed moderate to strong inhibitory effects against OCT2 transport activity. The IC50 values were less than 5 μM for 10 flavonoids. All 10 compounds alleviated cisplatin-induced cytotoxicity in cells expressing OCT2, even though the magnitude of the effects varied depending on the functional moieties in each position. Multiple factor analysis revealed that the methyl group at the R1 position and methoxy group at the R6 position of the flavonol backbone are important for OCT2 inhibition. Information on the functional moieties in the flavonol backbone would help develop effective OCT2 inhibitors by providing a structural association with OCT2 inhibitory effects. In addition, the compounds with strong inhibitory effects on OCT2 identified in this study may be potential candidates for clinical use to mitigate cisplatin-induced nephrotoxicity.Copyright © 2023. Published by Elsevier B.V.