Synthesis, characterization, and biological stabilities of gold(III) di-2-pyridyl and sec-butyl-phenanthroline complexes Público

Abstract

Abstract
Synthesis, characterization, and biological stabilities of gold(III) di-2-pyridyl and sec-butyl-phenanthroline complexes

In an effort to develop novel gold-based chemotherapies, gold(III) coordination complexes possessing a series of dipyridyl ligands were targeted as synthetic products. It was found that dipyridyl ligands linked by different groups exhibited varying coordination to gold(III). Dipyridyl sulfide (DPS) exhibited bidentate binding to gold(III), and formed a complex ion with a gold tetrachloride counter ion {[(DPS)AuCl2]AuCl4; compound 3}; dipyridyl oxide (DPO) formed a neutral monodentate coordination complex with gold(III) {[(DPO)(AuCl3)]; compound 4}; and attempts to make gold(III) complexes with dipyridyl ketone (DPK) were unsuccessful, as a complex ion possessing the protonated ligand and a gold tetrachloride anion was isolated {[DPK-H]AuCl4; compound 5}. Compounds 3-5 were structurally characterized using X-ray crystallography, which confirmed the different coordination environments about the gold(III) metal centers. Compound 4 was further characterized by ¹H NMR and UV-vis spectroscopy, and its DNA binding and buffer stability were determined. Compound 4 displayed minimal DNA binding, but was found to have poor stability in the presence of the biological reductant reduced glutathione (GSH).

After completing studies of the dipyridyl ligands, differentially alkylated phenanthroline ligands were synthesized and complexed with gold. These ligands included 5,6-dimethyl-2,9-disecbutyl-1,10-phenanthroline, 4-methyl-2,9-disecbutyl-1,10-phenanthroline, 4,5,6,7-tetramethyl-2,9-disecbutyl-1,10-phenanthroline, and 5-methyl-2,9-disecbutyl-1,10-phenanthroline. The gold complexes of 5,6-dimethyl-2,9-disecbutyl-1,10-phenanthroline and 4-methyl-2,9-disecbutyl-1,10-phenanthroline were chosen for biological stability studies, including buffer stability, glutathione buffer stability, and ascorbic acid stability. Their in vitro DNA binding was also probed. Both of these complexes demonstrated stability in slightly basic buffer and GSH buffer. They did not appear as stable in the presence of ascorbic acid, and also exhibited in vitro DNA binding. Despite the DNA binding and the lack of stability in ascorbic acid, these compounds appear promising for potential use in biological systems.

Table of Contents

Table of Contents
Introduction...5

Experimental...13

General Experimental Procedures...13
Synthesis of dipyridyl sulfide (1)...13
Synthesis of dipyridyl oxide (2)...13
Synthesis of gold(III) dipyridyl sulfide (3)...14
Synthesis of gold(III) dipyridyl oxide (4)...14
Synthesis of gold(III) dipyridyl ketone (5)...15
Synthesis of 5,6-dimethyl-2,9-disecbutyl-1,10-phenanthroline ligand (6)...15
Synthesis of 5,6-dimethyl-2,9-disecbutyl-1,10-phenanthroline gold (III) complex (7)...16
Synthesis of 4-dimethyl-2,9-disecbutyl-1,10-phenanthroline ligand (8)...16
Synthesis of 4-methyl-2,9-disecbutyl-1,10-phenanthroline gold (III) complex (9)...17
Synthesis of 4,5,6,7-tetramethyl-2,9-disecbutyl-1,10-phenanthroline ligand (10)...17
Synthesis of 4,5,6,7-tetramethyl-2,9-disecbutyl-1,10-phenanthroline gold (III) (11)...18
Synthesis of 5-methyl-2,9-disecbutyl-1,10-phenanthroline ligand (12)...18
Synthesis of 5-methyl-2,9-disecbutyl-1,10-phenanthroline gold (III) complex (13)...19
X-ray crystallographic studies...19
Buffer Stability studies...20
GSH Buffer stability studies - Dipyridyl Ligands...20
DNA binding studies- Dipyridyl Ligands...20
DNA Binding Studies- Phenanthroline Ligands...21

Results and Discussion...22

Synthesis...22
¹H NMR and UV-vis Spectroscopy...23
X-Ray Crystal Structures...28
Buffer Stability...34
GSH Buffer Stability...37
Ascorbic Acid Stability...39
DNA Binding...41

Conclusion...44

References...46

Figures, Tables, and Schemes

Compound Numbering Legend...1
Scheme 1...7
Scheme 2...9
Scheme 3...9
Scheme 4...10
Scheme 5...10
Scheme 6...11
Scheme 7...11
Scheme 8...12
Scheme 9...12
Figure 1...25
Figure 2...26
Figure 3...27
Figure 4...30
Figure 5...30
Figure 6...31
Figure 7...32
Figure 8...36
Figure 9...36
Figure 10...38
Figure 11...38
Figure 12...39
Figure 13...40
Figure 14...41
Figure 15...42
Figure 16...43
Figure 17...43
Table 1...8
Table 2...22
Table 3...23
Table 4...32
Table 5...33
Table 6...34

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	BA
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic Chemistry, Inorganic Chemistry, Analytical
Palabra Clave	phenanthroline gold(III) anti-cancer
Committee Chair / Thesis Advisor	MacBeth, Cora, Emory University
Committee Members	Marsteller, Pat, Emory University Weaver, Jeremy, Emory University

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