Design, synthesis and biological evaluation of novel triazole-core reversal agents against P-glycoprotein-mediated multidrug resistance

We designed and synthesized a novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors bearing a triazolphenethyl-tetrahydroisoquinoline scaffold through click chemistry. Then those synthesized compounds were tested on doxorubicin-resistant erythroleukemia K562/A02 cells in a series of experiments. The result is that most of the synthesized compounds exhibit more active MDR reversal activity than verapamil (VRP). However, among them, compound 11 exhibits less cytotoxicity (IC(50)s > 100 mu M), but more potency than the known P-gp inhibitors WK-X-34 and VRP on increasing anticancer drug accumulation in K562/A02 cells. Moreover, this compound can not only maintain a longer chemosensitizing effect (> 24 h) than VRP (< 6 h) with reversibility, but also significantly reverses MDR in a dose-dependent manner. Therefore, considering the low intrinsic cytotoxicity but strong reversal activity in vitro, compound 11 may be a promising lead with a potent and safe resistance modulator in combinational cancer chemotherapy.