Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry

First Advisor

William Euler

Abstract

The oral hypoglycemic agent Glyburide has been shown to be actively transported from various biological tissues though a pronounced interaction with the ATP binding cassette (ABC) active transport proteins. Specifically, Glyburide is actively transported by the ABC proteins, P-glycoprotein (Pgp), Breast Cancer Resistance Protein (BCRP), and the Multidrug Resistance Proteins (MRP). This active transport occurs at various locations throughout the body but has been identified as being responsible for Glyburide’s unique placental transport behavior. Glyburide has been shown to not cross the placental barrier to any appreciable effect and will leave the placental barrier against the concentration gradient. Understanding this active transport creates the possibility of medicines designed specifically for pregnant women. The objective of this thesis is to investigate the activity of Glyburide and a series of sulfonylurea analogs against these two ABC transporter proteins.

The transport of Glyburide and a series of sulfonylurea analogs in the presence of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) was investigated in cell-based transport assays using two stably transfected Madin-Darby Canine Kidney cell lines, one overexpressing Pgp and the other overexpressing BCRP genes. The results of the transport studies confirm that both Pgp and BCRP play a role in the transport of the sulfonylureas. Further, in addition to Glyburide, the molecules Glimepiride, Glisoxepide, and Gliquidone were confirmed as Pgp and BCRP substrates, all of which has not previously been reported.

Subsequently, the sulfonylurea transport activity with both Pgp and BCRP were used as the basis to build quantitative structure activity relationship (QSAR) and pharmacophore models. These models suggest that there are core molecular features necessary for the Pgp and BCRP activity, specifically that the arylsulfonylurea and benzamido ligands are required for both activities. We also found that increased hydrophobic character and increased bulky groups are key to both activities. The main differences in the activities were surrounding the sulfonylurea and amide moieties, with positive charge increasing the BCRP activity, and negative charge increasing the Pgp activity. Overall, the results of this research serve to provide improved knowledge for the design of pregnancy centered medications.

Available for download on Saturday, April 20, 2019

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