Discovery to solve multidrug resistance: Design, synthesis, and biological evaluation of novel agents. Issue 10 (23rd August 2019) - Qiu, Qianqian
Abstract: Chemotherapy remains a pillar in the treatment and management of various cancers. However, multidrug resistance (MDR) becomes a severe problem after long‐term administration of chemotherapy drugs. Overexpression of P‐glycoprotein (P‐gp) is a significant cause for tumor MDR. Therefore, P‐gp inhibition is considered as an effective strategy to reverse MDR. A third‐generation P‐gp inhibitor tariquidar was selected as a lead compound, and a new series of triazol‐ N ‐ethyl tetrahydroisoquinoline based compounds were designed as novel P‐gp inhibitors and synthesized through click chemistry. These compounds presented higher reversal activities than the positive‐control verapamil (VRP). Among 18 compounds, compound11 without cytotoxicity reversed MDR in a dose‐dependent manner, with a persistent longer chemosensitizing effect and reversibility compared to others. Mechanism studies discovered that compound11 could escalate the intracellular accumulation of rhodamine‐123 and doxorubicin in K562/A02 cells as well as inhibit their efflux from cells. The results obtained suggest that compound11 is more potent than VRP administered under the same conditions; it may be a potent and safe candidate for P‐gp modulation for further development. Abstract : A new series of triazol‐ N ‐ethyl tetrahydroisoquinoline‐based compounds were synthesized through click chemistry and tested for their P‐glycoprotein (P‐gp) inhibition activity. They presented higher multidrug resistance reversal activities than the positive‐control verapamil. Compound11 could escalate the intracellular accumulation of rhodamine‐123 and doxorubicin in K562/A02 cells and may be used as a potent and safe candidate for P‐gp modulation for further development.