Year of Award

2014

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Medicinal Chemistry

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Nicholas R. Natale

Commitee Members

Howard Beall, Charles Thompson, Keith Parker, Stephen Lodmell

Keywords

Medicinal Chemistry

Abstract

The development of multidrug resistance in tumor cells has been recognized as a major obstacle to successful cancer treatment. Tumor cells in vitro and in vivo can develop multidrug resistance (MDR) to the lethal effects of the cytotoxic drugs used to treat them, with about 40% of cancers going on to develop MDR. There are multiple factors that lead to MDR but the factor that we will be exploring in this dissertation is the expression of multiple drug resistance gene 1 and the over expression of multi drug resistance protein 1(MDR1, also known as P-glycoprotein or P-gp). MDR1 has also been shown to be a major contributor to the development of MDR in cancer, via preventing entry of therapeutically relevant drugs into the cancerous cell. As such, MDR1 is highly investigated as a drug target both for controlling absorption, distribution, metabolism and excretion (ADME) of clinically relevant compounds and for the production of MDR inhibitors. Our efforts in producing novel compounds to reverse MDR by inhibiting MDR1 have shown marked improvement from generation to generation of drug development. Our first generation of compounds had activitys that ranged from 10.9% to our lead compound showed a 61.2% inhibiton when compared to cyclosporine A. Our second generation had a slight increase in activity when we explored tethered compound with our lead compound showing a 63.0% inhibition when compared to cyclosporine A. Further exploration of tethered and dimer compounds in generation 3 showed a dramatic increase in inhibitory activity with our lead compound showing over a 200% inhibition when compared to cyclosporine A. With such a positive trend in activity generation 4 and 5 compounds where then designed to be more selective for MDR1. Currently, both generation 4 and 5 are in hand and are waiting for biological testing. Generation 4 compounds explore the effect that more steric groups in the 3-isoxazolyl position would have on MDR1 inhibition. While generation 5 componds explored chiralities effect on MDR1 inhibition and how it can be utilized in refining selectivity. Reversal of MDR is of interest for the clinical application; if a compound could effectly and safely reverse MDR, it would allow for major advancements in cancer chemotherapy. If successful, halting the function of MDR1 will stop the outward efflux of chemotherapeutic agents out of the cell. In combination with chemotherapeutic treatments, inhibitors could allow for greater penetration of drugs into an MDR cell and potential allow for the repurposing of out of date drugs where MDR has redered the drug ineffective. The exploration of this concept and the advancements that our group has added to this field will be explained in due course.

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© Copyright 2014 Scott Steiger