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

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.

Cinnamic acid derivatives: inhibitory activity against Escherichia coli ß-glucuronidase and structure-activity relationships.

Gut microbial ß-glucuronidase (GUS) is a potential therapeutic target to reduce gastrointestinal toxicity caused by irinotecan. In this study, the inhibitory effects of 17 natural cinnamic acid derivatives on Escherichia coli GUS (EcGUS) were characterised. Seven compounds, including caffeic acid ethyl ester (CAEE), had a stronger inhibitory effect (IC50 = 3.2-22.2 µM) on EcGUS than the positive control, D-glucaric acid-1,4-lactone. Inhibition kinetic analysis revealed that CAEE acted as a competitive inhibitor. The results of molecular docking analysis suggested that CAEE bound to the active site of EcGUS through interactions with Asp163, Tyr468, and Glu504. In addition, structure-activity relationship analysis revealed that the presence of a hydrogen atom at R1 and bulky groups at R9 in cinnamic acid derivatives was essential for EcGUS inhibition. These data are useful to design more potent cinnamic acid-type inhibitors of EcGUS.