College of Science and Health Theses and Dissertations

Date of Award

Fall 11-21-2017

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Lihua Jin, PhD

Second Advisor

Kyle A. Grice, PhD

Third Advisor

Graham Griffin, PhD

Abstract

This work aimed at understanding the interactions of 1) three physiologically relevant transition metal ions copper(II), cobalt(II) and manganese(II) with five tri- or tetra-dentate metal chelators (ligand or L) and 2) the resulting ML complexes with two known metalloenzyme inhibitors, 8-hydroxyquinoline (8-HQ) and acetohydroxamic acid (AHA). The ultimate goal of the work was to identify ligands that can form enzyme active site M2+ structural mimetics capable of interacting with metalloenzyme active site inhibitors. The ligands studied were N-(2-(1-methylimidazolyl)methyl)iminodiacetic acid (DA2Im), nitrilotriacetic acid (NTA), tris(2-aminoethyl)amine (TREN), tris(2-pyridylmethyl)amine (TPA), and bis(2-picolyl)amine (BPA) and they were chosen to mimic the coordination environment for the common enzyme active site transition metal ions. Isothermal titration calorimetry (ITC), UV-Vis absorbance spectroscopy and computational chemistry were used for the study. The appropriate ligand to form the copper active site structural mimetic was identified as bis(2-picolyl)amine (BPA) as BPA was found to bind Cu2+ strongly forming a 1:1 Cu(BPA) binary complex. Upon addition of 8-HQ, Cu(BPA) formed a Cu(BPA)(8-HQ) ternary complex. Cu(TREN) and Cu(TPA) however did not form CuL(8-HQ) ternary complex but rather had the TREN or TPA displaced by 8-HQ, yielding the Cu(8-HQ)2 complex. Results from this work helped us better understand the binding reactivity of Cu2+, Co2+ and Mn2+ ions with the small molecule ligands and the enzyme active site inhibitors. The experiments also helped us estimate the energetic contribution of the active site metal ion to enzyme inhibitor binding. Results of this study will be useful to developing new therapeutics targeting metalloenzymes involved in diseases such as cancer.

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no

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Chemistry Commons

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