Date of Award

2018

Document Type

Thesis

Department

Chemistry

First Advisor

Dr. Tim Hayes

Second Advisor

Dr. Joseph Bradshaw

Third Advisor

Dr. Mark McGraw

Abstract

Metabolism of drugs in the human body can yield both desirable and undesirable results. Some of these side-effects are due to drug-drug interactions, drug-diet interactions, or lack of drug specificity. The enzymes that drugs attack are structurally selective and complex; therefore, many drugs are very general in structure and could possibly react with a variety of enzymes. Indazole has been used as a backbone for several drugs as it has the general structure that may react with most P450s. To determine a derivative, or a group of derivatives, of indazole that may be reactive only with cytochrome P450 2El (CYP2El), several indazole derivatives were employed as inhibitors of various P450s in enzyme­substrate reactions for IC50 assays. We hypothesize that the polarity and steric bulk of substituents to indazole will control the affinity and selectivity of this class of molecules toward P450s, especially CYP2El. We developed IC50 assays that indicated the effectiveness of the inhibitors in relation to indazole itself. These findings will provide insight into (1) the effects of substituents to the indazole ring on affinity toward CYP2E 1, and (2) the structural specificity of CYP2El.

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