Discovery of (quinazolin-6-yl)benzamide derivatives containing a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety as potent reversal agents against P-glycoprotein-mediated multidrug resistance

• Published in: European journal of medicinal chemistry Vol. 264; p. 116039
• Main Authors: Xue, Wen-han, Liu, Kai-li, Zhang, Ting-jian, Dong, Gang, Wang, Jia-hui, Wang, Jing, Guo, Shuai, Hu, Jie, Zhang, Qing-yu, Li, Xin-yang, Meng, Fan-hao
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier 15.01.2024
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; BREAST-CANCER; CARBOXYL; P-gp; TRANSPORTERS; TKIs; GP; MDR; INHIBITORS; MCF7/ADM; Accumulation
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.116039

P-glycoprotein (P-gp) is an important factor leading to multidrug resistance (MDR) in cancer treatment. The coadministration of anticancer drugs and P-gp inhibitors has been a treatment strategy to overcome MDR. In recent years, tyrosine kinase inhibitor Lapatinib has been reported to reverse MDR through directly interacting with ABC transporters. In this work, a series of P-gp inhibitors (1-26) was designed and synthesized by integrating the quinazoline core of Lapatinib into the molecule framework of the third-generation P-gp inhibitor Tariquidar. Among them, compound 14 exhibited better MDR reversal activity than Tariquidar. The docking results showed compound 14 displayed the L-shaped molecular conformation. Importantly, compound 14 increased the accumulation of Adriamycin (ADM) and rhodamine 123 (Rh123) in MCF7/ADM cells. Besides, compound 14 significantly increased ADM-induced apoptosis and inhibited the proliferation, migration and invasion of MCF7/ ADM cells. It was also demonstrated that compound 14 significantly inhibited the growth of MCF7/ADM xenograft tumors by increasing the sensitivity of ADM. In summary, compound 14 has the potential to overcome MDR caused by P-gp.