ORCID Identifier(s)

0000-0001-5229-2955

Graduation Semester and Year

2021

Language

English

Document Type

Thesis

Degree Name

Master of Science in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Frederick M MacDonnell

Second Advisor

Sherri A McFarland

Abstract

Many Ru(II) Polypyridyl Complexes (RPCs) are being investigated as they show potent cytotoxicity and acceptable toleration in animals. Some of these RPCs are thought to target DNA and/or mitochondria in cells. Recently, [Ru(dip)3]2+ (dip= 4,7-diphenylphenanthroline) with cytotoxicity ranging from 1-4 µM, has shown to target microtubules (MTs) and exhibit strong microtubule stabilizing activity (MSA). Determination of [Ru(dip)3]2+:MT stoichiometry was difficult due to poor solubility. Therefore, to study this new metallo-organic target, a less lipophilic RPC is needed to enhance solubility, while still achieving cytotoxicity. The purpose of this thesis is to test the following hypothesis. We postulate that by systematically altering the dip ancillary ligands of [Ru(dip)3]Cl2 with more hydrophilic ligand such as 1,10-phenathroline (phen), the biological effects can be maintained and overall display MSA, which is elucidated in Chapter 1. Chapter 2 outlines the synthetic approach for two less lipophilic complexes, [Ru(dip)2phen]Cl2 and [Ru(phen)2dip]Cl2, based on systematically altering dip ancillary ligands with phen, a more hydrophilic ligand. To quantify lipophilicity, the partition coefficients (logP) were determined via the shake-flask method, where lipophilicity was directly related to the number of dip ligands. Chapter 3 discusses the similarities and differences across these family of complexes. The cytotoxicity against malignant cell lines H358 and MCF-7 was investigated, in which the cytotoxicity correlated with the lipophilicity; [Ru(phen)3]Cl2 << [Ru(phen)2dip]Cl2 < [Ru(dip)2phen]Cl2 < [Ru(dip)3]Cl2. In both cell lies, cellular uptake displayed a correlation with lipophilicity and sub-cellular localization studies displayed that as the number of dip ligands decreased, so did their accumulation within the cytoskeleton; [Ru(dip)3]Cl2 and [Ru(dip)2phen]Cl2 >40 % in the cytoskeleton. Yet, all RPCs displayed MSA in a tubulin polymerization assay, with [Ru(dip)2phen]Cl2 and [Ru(dip)3]Cl2 acting similarly. A MT binding stoichiometry study of Ru(dip)2phen]Cl2 is discussed, and its findings are compared to isothermal titration calorimetry data obtained previously using [Ru(dip)3]Cl2.

Keywords

Ruthenium, Ruthenium polypyridyl complex, Ruthenium polypyridyl complexes, Phen, Dip, Microtubule, Tubulin, Polymerization, Microtubule stabilizing agent, Microtubule targeting agent, Lipophilicity, Uptake, Cytotoxicity, Compartmentalization, Localization

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

Included in

Chemistry Commons

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