ORCID Identifier(s)

0000-0002-0338-2927

Graduation Semester and Year

2019

Language

English

Document Type

Thesis

Degree Name

Master of Science in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Frederick M MacDonnell

Abstract

Ruthenium polypyridyl complexes (RPCs) are promising anticancer agents due to their robustness and tunability of their polypyridyl ligands. Their axial chirality generally allows for more selective binding to biological molecules. The ruthenium complexes [Ru(phen)3]Cl2 (RPC 1), [Ru(DIP)3]Cl2 (RPC 2), [(phen)2Ru(tatpp)]Cl2 (RPC 3), [(phen)2Ru(tatpp)Ru(phen)2]Cl4 (RPC 4), and [(phen)2Ru(dppz)]Cl2 (RPC 5) have all been investigated, and RPCs 2, 3, and 4 have shown lower micromolar cytotoxicity against malignant cell lines without irradiation. Herein we show that microtubules (MTs) may be the target of some RPCs in cells and all these RPCs 1-5 promote tubulin polymerization in vitro. How they interact with MTs is still yet to be discovered. We examined how the different enantiomers of RPC 2 and 3 affected the cytotoxicity, the cellular uptake, and the MT polymerization. Chapter 1 of this thesis reviews prior literature and discusses other metal complexes as well as RPCs that have anticancer potential for their cellular target and correlation to their structures. Chapters 2 and 3 presents how the stereochemistry of the RPCs in their chloride salt affects their ability to stabilize MTs in addition to entering the cell in the first place. Chapter 2 also presents evidence that MT stabilization by RPCs may not be simple due to electrostatic interactions. MT stabilization is done by comparing the in vitro polymerization of free tubulin with and without the presence of the microtubule stabilizing agent (MSA) as a factor of increased light scattering at 340 nm. Cellular uptake is done in the non-small cell lung carcinoma cell line, H358. The amount of ruthenium was analyzed using ICP-MS and the protein concentration using a bicinchoninic acid assay and UV-Vis spectrometry. Although there were no significant chiral differences in MT stabilization, there was a difference in cellular uptake of enantiopure RPC 2. Chapter 4 outlines the resolution of the RPCs by use of Na2[As2(+ or -) tartrate2] and Na2[Sb2(+ or -)tartrate2], as well discussing the optimization of the syntheses of Na2[Sb2(+ or -)tartrate2] and K2[Sb2(+ or -)tartrate2].

Keywords

Stereochemistry, Chemotherapy, Ruthenium, Polypyridyl, Complexes, Metal, Microtubules, Tubulin, Lambda, Delta, RPC, Enantiomer, Racemic, Racemate, Enantiopure, Resolution, Cytotskeleton, Tartrate, Antimony, Polymerization, Uptake, DIP, Phendione, Nocodazole, Paclitaxel, Taxane, Stabilization, Cytotoxicity

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

Included in

Chemistry Commons

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