SUBSTRATE-BASED NOVEL DIMERIC PRODRUG INHIBITORS OF HUMAN P-GLYCOPROTEIN
The human multidrug resistance transporter P-glycoprotein (P-gp) is highly expressed at blood- tissue barriers, including the blood-brain barrier (BBB), and poses a serious challenge for the delivery of therapeutics to the brain. Additionally, expression of P-gp is also detected in some blood cancers, and is thought to limit the uptake of therapeutics, leading to a multidrug resistant phenotype (MDR). P-gp has multiple substrate binding sites and uses the energy of ATP hydrolysis to actively transport a variety of hydrophobic compounds out of the cell from the plasma membrane. Our goal is to take advantage of the polyvalency of the substrate binding site to create P-gp inhibitors from substrates through dimerization. Herein, we demonstrate the synthesizes and characterization two libraries of dimeric prodrug inhibitors of P-gp based on the substrates temozolomide and dasatinib, a glioblastoma chemotherapeutic and chronic myelogenous leukemia chemotherapeutic, respectively. In addition to inhibiting P-gp, by containing reversible tethers, these dimers are designed to act as prodrugs and release the therapeutics inside the cell. To improve the efficacy and solubility of our dimers, we synthesized heterodimers with the known substrate quinine to generate libraries of temozolomide-quinine and dasatinib-quinine molecules with varying tether lengths. Both libraries were shown to be potent inhibitors of P- gp efflux at low micromolar concentrations.
- Doctor of Philosophy
- West Lafayette