Bioorganic Chemistry (2019)
Update date:2022-08-17
Topics:
Qiu, Qianqian
Zhu, Jilan
Chen, Qiutong
Jiang, Ziqian
Xu, Jiting
Jiang, Xueting
Huang, Wenlong
Liu, Zhongquan
Ye, Jing
Xu, Xiaojuan
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major impediment for clinical cancer therapy. 19 novel aromatic amides with triazole-core as MDR reversal agents were designed and synthesized via click chemistry to reverse MDR. Among them, compound 42 was identified as the most promising candidate with high potency (EC50 = 78.1 ± 5.4 nM), low cytotoxity (SI > 1282) and persistent duration in reversing doxorubicin (DOX) resistance in K562/A02 cells. 42 also enhanced the potency of other P-gp associated cytotoxic agents with different structures. In further study, remarkably increased intracellular accumulation of Rh123 and DOX in K562/A02 cells was achieved by compound 42, while CYP3A4 activity had no change by compound 42. These results indicate that compound 42 as a relatively safe modulator of P-gp-mediated MDR has good potential for further development.
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Doi:10.1039/c4cc08656b
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