Design, synthesis and bioactivity study on 5-phenylfuran derivatives as potent reversal agents against P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cell

• Published in: European journal of medicinal chemistry 2021-04, Vol.216, p.113336-113336, Article 113336
• Main Authors: Li, Ya-Sheng, Yang, Xi, Zhao, Dong-Sheng, Cai, Yue, Huang, Zhi, Wu, Rui, Wang, Si-Jia, Liu, Gui-Jun, Wang, Jian, Bao, Xiao-Ze, Ye, Xin-Yi, Wei, Bin, Cui, Zi-Ning, Wang, Hong
• Format: Article
• Language: English
• Subjects: 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Binding Sites; Cell Line, Tumor; Cell Proliferation - drug effects; Doxorubicin - pharmacology; Drug Design; Drug Resistance, Neoplasm - drug effects; Furan; Furans - chemistry; Furans - metabolism; Furans - pharmacology; Humans; MCF-7/ADR; Molecular Docking Simulation; Molecular simulation; P-glycoprotein; Paclitaxel - pharmacology; Structure-Activity Relationship; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - metabolism; Tetrahydroisoquinolines - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113336

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 0.73 μM, RF = 69.6 with 5 μM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure–activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies. [Display omitted] •Eighteen 5-alkoxyphenyl-2-(6,7-dimethoxy-1,2,3,4-tetrahydroiso- quinolinecarboxamide)furan derivatives were designed and synthesized.•Title compounds were tested as reversal agents against P-glycoprotein mediated multidrug resistance in MCF-7/ADR cells.•SARs demonstrated that the alkoxy-substituent effect was key in enhancing the P-gp inhibitory activity and corroborated by docking study.•P-gp efflux function was abrogated effectively by compound 16 without down-regulating P-gp expression.•>60 fold increase in intracellular concentration was achieved for doxorubicin and vincristine.