Click chemistry-derived bivalent quinine inhibitors of P-glycoprotein-mediated cellular efflux.
P-glycoprotein (P-gp) effluxes a diverse set of drug substrates out of cells in an ATP dependent manner, thereby limiting the effective accumulation of therapeutic agents. Herein we demonstrate the use of click chemistry to rapidly generate bivalent quinine dimers, containing an intervening triazole ring, as potential inhibitors of P-gp mediated efflux. Calcein-AM substrate accumulation assays were performed in an MCF7/DX1 cell line that overexpresses P-gp to monitor the inhibitory activity of the clicked quinine dimers. A small library of potent P-gp inhibitors with varying tether lengths is reported, with the best dimer demonstrating low micromolar efficacy.
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA.
Jerrin
J
Kuriakose
Christine A
CA
Hrycyna
Jean
J
Chmielewski
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D057930:Click Chemistry; D019281:Dimerization; D006801:Humans; D011803:Quinine / Q000138:chemical synthesis / Q000737:chemistry*; D014230:Triazoles / Q000737:chemistry
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014230:Triazoles; D011803:Quinine