Defense Date

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Nicholas Farrell

Abstract

The medicinal uses of gold date as far back as 2500 B.C. in China. In modern times, gold has been used in the treatment of a number of different human diseases including rheumatoid arthritis, cancer, and viral infections. This dissertation will focus on the development of gold complexes for the purpose of selective inhibition of HIV NCp7, a 55 amino acid zinc finger protein with two Cys3His zinc binding domains.

NCp7 is involved in a number of viral life cycle processes including activation of reverse transcription, integration, DNA recognition, RNA packaging, and formation of the viral envelope. The diversity in the roles of NCp7 across the viral life cycle make it a highly attractive target for chemical intervention. Ejection of the tetrahedrally coordinated zinc atoms, modification or deletion of the zinc coordinating amino acids, or modification or deletion of the “essential” tryptophan residue can result in the loss of viral infectivity. This is due to the inability of NCp7 to recognize its “natural” substrate – polynucleic acids. Previous studies have investigated the differences in the manner in which platinum(II), gold(I), and gold(III) complexes interact with NCp7. The platinum(II) complex [Pt(dien)(9-EtGua)]2+ interacts with the C-terminal zinc finger of NCp7 in a non-covalent manner, through a π-π stacking interaction between the platinated 9-EtGua and the “essential” tryptophan residue. The isostructural and isoelectronic complex [Au(dien)(9-EtGua)]3+ ejects the tetrahedrally coordinated zinc atom and replaces it with a gold atom, forming “gold fingers”. This result is consistent with the interactions of the gold(I) complex [(PPh3)Au(9-EtGua)]+.

In order to complete the series of isoelectronic and isostructural platinum(II), palladium(II), and gold(III) complexes with N-heterocyclic ligands and diethylenetriamine chelates, the complexes [Au(dien)(1-MeCyt)]3+ and [Au(N-Medien)(1-MeCyt)]3+ were synthesized. These complexes were found to dimerize the C-terminal zinc finger once the central zinc atom is ejected. This is likely the result of a charge transfer from the 1-methylcytosine ligand to the tryptophan residue, and is a product that was not seen as a result of interaction with the previously published 4-dimethylaminopyridine and 9-ethylguanine analogs. The 1-methylcytosine complexes also stabilize the gold(III) oxidation state and associate with N-acetyltryptophan in a manner consistent with the previously studied gold(III) analogs. Finally, in order to address concerns arising from the inner filter effect, a proof of concept study using 1H-NMR spectroscopy was utilized to show that the complex [Au(dien)(1-MeCyt)]3+ likely has a lower association constant with N-acetyltryptophan than the value determined by fluorescence quenching.

The impact of the incorporation of additional steric hindrance on the gold(III) chelate was studied using the di-(2-picolyl)amine ligand. The gold(III) chlorides incorporating this ligand and the centrally methylated analog were found to eject zinc from the C-terminal zinc finger of NCp7, and the electronegativity differences between the gold(III) and platinum(II) metal centers were highlighted. The attempts to incorporate an N-heterocyclic ligand into these complexes were unsuccessful due to the steric and electronic demands of the chelate.

The use of an organometallic chelating ligand led to the investigation of the ability of gold(III) complexes to catalyze the arylation of zinc-coordinating cysteine residues. The complex [AuCl2(dampa)], which had been formerly investigated as a chemotherapeutic agent due to its structural similarities to cisplatin, was found to arylate N-acetylcysteine, glutathione, and NCp7. The arylation was not found to be dependent on the cis- chloride ligand, as blocking that site with the ligand triphenylphosphine did not prevent the arylation of NCp7. The X-Ray crystal structure of the complex [AuCl(dampa)(PPh3)](PF6) was also solved. Using the advancement of the knowledge of how the electronic and structural properties of gold(III) complexes described herein impact interactions with NCp7, it is possible that a coordination complex that is a selective inhibitor of NCp7 may eventually be developed.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-13-2018

Available for download on Friday, December 13, 2019

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