Synthesis, characterization, and in vitro biological testing of gold(III) polypyridyl compounds: Insights into cytotoxicity of neutral distorted square pyramidal complexes 公开

Abstract

In an effort to discover potential metallotherapeutic alternatives to the chemotherapy drug cis-platin, two classes of gold(III) coordination complexes have been synthesized and characterized: 1) neutral square pyramidal complexes with 2,9-disubstituted phenanthroline ligands ([(^Rphen)AuCl3]) and 2) complex ions comprised of protonated phenanthroline ligands and gold tetrachloride anions ([^RphenH][AuCl4]). A novel neutral gold(III) 6,6'-dimethyl bipyridine complex also in a square pyramidal geometry ([(^methylbipy)AuCl3]) has also been synthesized and characterized to probe the effect of differing aromatic character of the ligand on solution stability, tumor cell cytotoxicity, and DNA binding. Therefore, all three classes of compounds ([(^Rphen)AuCl3], [^RphenH][AuCl4], and [(^methylbipy)AuCl3]) were assessed for stability against the biological reductants ascorbic acid and glutathione, with the neutral gold(III) phenanthroline complex exhibiting the most stability. Furthermore, these complexes were tested for cytotoxic effects against existing lung and head and neck tumor cell lines. Both the [^RphenH][AuCl4] salts and the neutral coordination complexes ([(^Rphen)AuCl3] were found to be more cytotoxic than cis-platin against a number of cancer cell lines whereas [(^methylbipy)AuCl3] was more potent than cis-platin against only one cancer cell line.These compounds were also examined for DNA binding. The [(^methylbipy)AuCl3] complex displayed only partial DNA binding, suggesting that DNA binding may not be the primary requirement for cancer cell death. Also, protein marker expressions of tumor cell lines treated with [(^sec-butylphen)AuCl3] were analyzed and it was ascertained that the induction of cytotoxicity occurs via a progressive mechanism with increasing concentrations of the drug: from cell cycle arrest to autopahgy to apoptosis. Since the DNA binding and antiproliferative mechanisms of these complexes are found to initiate tumor cell death via a different mechanism than cis-platin, they may have utility in treating cis-platin-resistant tumor cell lines and alleviating some of the mutagenic side effects associated with cis-platin.

Table of Contents

Table of Contents
Introduction

....................................................................................................................................1
Experimental ..................................................................................................................................7
General .......................................................................................................................................7
Synthesis of [(methylbipy)AuCl3] .................................................................................................7
X-Ray Studies ............................................................................................................................8
Stability Experiments .................................................................................................................9
Stability Experiments in the Presence of Biological Reductants ..............................................9
DNA Binding- Ultrafiltration Experiments ............................................................................10
DNA Binding- Circular Dichroism .........................................................................................10
Cellular Cytotoxicity Tests .....................................................................................................11
Western Blot Analysis ............................................................................................................12
Results and Discussion .................................................................................................................12
Synthesis and Spectroscopic Characterization of [(methylbipy)AuCl3] ....................................12
X-Ray Crystal Structure of [(methybipy)AuCl3] ......................................................................15
Stability Studies ......................................................................................................................17
DNA Binding Studies .............................................................................................................21
Cellular Cytotoxicity ...............................................................................................................24
Cell Death Pathway/Cell Cycle Arrest ...................................................................................26
Conclusion ....................................................................................................................................28
References .....................................................................................................................................31
Appendix .......................................................................................................................................33
Figures, Tables, and Schemes
Figure 1 .......................................................................................................................................1
Figure 2 .......................................................................................................................................2
Figure 3 .......................................................................................................................................4
Figure 4 .....................................................................................................................................14
Figure 5 .....................................................................................................................................15

Figure 6 .....................................................................................................................................16
Figure 7 .....................................................................................................................................18
Figure 8 .....................................................................................................................................20
Figure 9 .....................................................................................................................................20
Figure 10 ...................................................................................................................................21
Figure 11 ....................................................................................................................................22
Figure 12 ...................................................................................................................................23
Figure 13 ...................................................................................................................................25
Figure 14 ...................................................................................................................................28
Table 1 ......................................................................................................................................11
Table 2 ......................................................................................................................................17
Table 3 ......................................................................................................................................24
Scheme 1 ....................................................................................................................................6
Scheme 2 ....................................................................................................................................8
Scheme 3 ..................................................................................................................................18

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School	Emory College
Department	Chemistry
Degree	BS
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Inorganic
关键词	Cell Death Mechanism anti-cancer Physiological Stability Gold(III) coordination complex Ascorbic Acid DNA Binding Glutathione
Committee Chair / Thesis Advisor	MacBeth, Cora, Emory University
Committee Members	Dyer, Brian, Emory University Jacob, Nitya P, Emory University

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