Molecular Design of 2,9-disubstituted-1,10-phenanthroline Gold(III) Complexes: Inhibiting Thioredoxin Reductase and InvestigatingCytotoxicity Pubblico

Rhine, Melody Anna Jessica (2009)

Permanent URL: https://etd.library.emory.edu/concern/etds/2z10wq53z?locale=it
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Abstract

Cancer is one of the leading medical concerns of modern times. Cisplatin has proven to be one of the most potent drugs available for anti-cancer chemotherapy. As a direct result of the success of the metallopharmaceutical cisplatin, this paper investigates the antitumor properties of various gold (III) complexes, which in recent years have been investigated as potential alternatives to platinum-based drugs. These compounds reported here, which are complex ions of protonated phenanthroline ligands and AuCl4 - anions [2,9-di-n-butyl-1,10-phenanthrolineH+ AuCl4 - (1), 2,9-di-sec-butyl-1,10-phenanthrolineH+ AuCl4 - (2), 2,9-dimethyl-1,10-phenanthrolineH+ AuCl4 - (3)] were synthesized and then characterized with 1H NMR, IR, and UV-vis spectroscopy. The biological activity of these compounds was examined by a variety of methods, including reduction by Glutathione (GSH), thioredoxin reductase (TrxR) enzyme inhibition, and cancer cell cytotoxity. Initial data indicates that complexes 1, 2 and 3 are not easily reduced by Glutathione, a reductant that is naturally occurring in most biological systems. In addition, these compounds exhibit significant activity for TrxR inhibition and are highly cytotoxic to the studied cancer cell lines.

Table of Contents

1. Introduction, 1

2. Experimental, 6 2.1 General Procedures, 6 2.2 Ligand Synthesis, 7 2.3 Synthesis of RphenH+ [AuCl4]-, 8 2.3.1 Synthesis of Compound 1, 8 2.3.2 Synthesis of Compound 2, 9 2.3.3 Synthesis of Compound 3, 10 2.4 X-Ray Crystallography for Compounds 1 and 2, 11 2.5 Cytotoxicity Testing: Cell lines and Culture, 11 2.6 Thioredoxin Reductase Assay, 12

3. Results and Discussion, 13 3.1 Synthesis of Compounds and Spectroscopic Characterization, 13 3.2 X-Ray Crystallography, 14 3.3 Biological Activity, 17 3.3.1 Stability in Buffer, 17 3.3.2 Glutathione Reduction, 19 3.3.3 Thioredoxin Reductase Inhibition and Cytotoxicity, 20

4. Conclusions and Future Research, 23

Figures and Tables Figure 1, 1 Figure 2, 5 Figure 3, 6 Figure 4, 9 Figure 5, 10 Figure 6, 10 Figure 7, 15 Figure 8, 15 Table 1, 16

Figure 9, 18 Figure 10, 19 Figure 11, 21

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