Ye Gao-Jie, Cai Chao-Yun, Dong Xing-Duo, Wu Zhuo-Xun, Teng Qiu-Xu, Wang Jing-Quan, Chen Zhe-Sheng, Wang Bo
School of Chemistry, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, United States.
Bioorg Chem. 2023 Jun;135:106481. doi: 10.1016/j.bioorg.2023.106481. Epub 2023 Mar 17.
Three series of phenylurea indole derivatives were synthesized with potent inhibitory activities on ABCG2 with simple and efficient synthetic routes. Among these compounds, four phenylurea indole derivatives 3c-3f with extended π system were discovered as the most potent ABCG2 inhibitors, while these compounds showed no inhibition on ABCB1. Compounds 3c and 3f were selected for further investigation to explore the mechanisms of action on reversing ABCG2-mediated multidrug resistance (MDR). The results revealed that compounds 3c and 3f increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing cells, but they did not alter the expression level or localization of ABCG2 in cells. In addition, both 3c and 3f significantly stimulated the ATP hydrolysis of ABCG2 transporter indicating that they can be competitive substrates of ABCG2 transporter, and thereby increase the accumulation of mitoxantrone in ABCG2-overexpressing H460/MX20 cells. Both 3c and 3f was docked into the drug-binding site of the human ABCG2 transporter protein (PDB 6FFC) with high affinities. This study showed that extending the π system of phenylurea indole derivatives enhanced their inhibitory activities on ABCG2, which may provide a clue for the further research to discover more potent ABCG2 inhibitors.
通过简单高效的合成路线合成了三类苯基脲吲哚衍生物，它们对ABCG2具有强效抑制活性。在这些化合物中，发现四种具有扩展π体系的苯基脲吲哚衍生物3c - 3f是最有效的ABCG2抑制剂，而这些化合物对ABCB1没有抑制作用。选择化合物3c和3f进行进一步研究，以探索其逆转ABCG2介导的多药耐药性（MDR）的作用机制。结果表明，化合物3c和3f增加了米托蒽醌（MX）在过表达ABCG2的细胞中的积累，但它们没有改变细胞中ABCG2的表达水平或定位。此外，3c和3f均显著刺激了ABCG2转运蛋白的ATP水解，表明它们可以作为ABCG2转运蛋白的竞争性底物，从而增加米托蒽醌在过表达ABCG2的H460/MX20细胞中的积累。3c和3f都以高亲和力对接至人ABCG2转运蛋白（PDB 6FFC）的药物结合位点。该研究表明，扩展苯基脲吲哚衍生物的π体系可增强其对ABCG2的抑制活性，这可能为进一步研究发现更有效的ABCG2抑制剂提供线索。
