Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, NY 11439, USA.
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA.
Biomolecules. 2023 Jan 30;13(2):253. doi: 10.3390/biom13020253.
A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazolinamine showed BCRP inhibitory activity. These lead compounds were further investigated in a battery of mechanistic experiments. Compound changed the localization of BCRP and P-gp in cells, thus inhibiting the efflux of anticancer drugs by the two ATP-binding cassette (ABC) transporters. In addition, both and significantly stimulated the ATP hydrolysis of the BCRP transporter, indicating that they can be competitive substrates of the BCRP transporter, and thereby increase the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide derivative , exhibited a greater inhibitory effect on BCRP after UV activation and can serve as a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. Notably, the dual BCRP and P-gp inhibitors -, -, , and BCRP inhibitor showed improved metabolic stability compared to Ko143.
合成了一系列具有强抑制乳腺癌耐药蛋白（BCRP）和 P-糖蛋白（P-gp）活性的二十二个喹唑啉胺衍生物。其中一个含环丙基的喹唑啉胺被鉴定为 BCRP 和 P-gp 的双重抑制剂，而含叠氮基的喹唑啉胺显示出 BCRP 抑制活性。这些先导化合物在一系列机制实验中得到了进一步研究。化合物改变了 BCRP 和 P-gp 在细胞中的定位，从而抑制了两种 ATP 结合盒（ABC）转运蛋白对抗癌药物的外排。此外，化合物和都显著刺激了 BCRP 转运体的 ATP 水解，表明它们可以作为 BCRP 转运体的竞争性底物，从而增加了米托蒽醌在 BCRP 过表达的 H460/MX20 细胞中的积累。叠氮衍生物在 UV 激活后对 BCRP 表现出更强的抑制作用，可作为研究喹唑啉胺衍生物与 BCRP 相互作用的有价值的探针。值得注意的是，与 Ko143 相比，BCRP 和 P-gp 的双重抑制剂-、-、-、和 BCRP 抑制剂-显示出更好的代谢稳定性。
