Discovery of aromatic amides with triazole-core as potent reversal agents against P-glycoprotein-mediated multidrug resistance.
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.
['Qiu|Qianqian|Q|', 'Zhu|Jilan|J|', 'Chen|Qiutong|Q|', 'Jiang|Ziqian|Z|', 'Xu|Jiting|J|', 'Jiang|Xueting|X|', 'Huang|Wenlong|W|', 'Liu|Zhongquan|Z|', 'Ye|Jing|J|', 'Xu|Xiaojuan|X|']
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 D000577:Amides D000970:Antineoplastic Agents D001549:Benzamides D057930:Click Chemistry D051544:Cytochrome P-450 CYP3A D004317:Doxorubicin D055808:Drug Discovery D018432:Drug Resistance, Multiple D019008:Drug Resistance, Neoplasm D006801:Humans D020014:K562 Cells D009369:Neoplasms D014230:Triazoles
Reversal agents Multidrug resistance P-glycoprotein Click chemistry