Investigation of 1-Methylcytosine as a Ligand in Gold(III) Complexes: Synthesis and Protein Interactions

James Beaton,Nicholas Farrell

doi:10.3390/inorganics7010001

Abstract

The HIV nucleocapsid protein NCp7 was previously shown to play a number of roles in the viral life cycle and was previously identified as a potential target for small molecule intervention. In this work, the synthesis of the previously unreported complexes [Au(dien)(1MeCyt)]3+, [Au(N-Medien)(1MeCyt)]3+, and [Au(dien)(Cyt)]3+ is detailed, and the interactions of these complexes with the models for NCp7 are described. The affinity for these complexes with the target interaction site, the “essential” tryptophan of the C-terminal zinc finger motif of NCp7, was investigated through the use of a fluorescence quenching assay and by 1H-NMR spectroscopy. The association of [Au(dien)(1MeCyt)]3+ as determined through fluorescence quenching is intermediate between the previously reported DMAP and 9-EtGua analogs, while the associations of [Au(N-Medien)(1MeCyt)]3+ and [Au(dien)(Cyt)]3+ are lower than the previously reported complexes. Additionally, NMR investigation shows that the self-association of relevant compounds is negligible. The specifics of the interaction with the C-terminal zinc finger were investigated by circular dichroism spectroscopy and electrospray-ionization mass spectrometry. The interaction is complete nearly immediately upon mixing, and the formation of AuxFn+ (x = 1, 2, or 4; F = apopeptide) concomitant with the loss of all ligands is observed. Additionally, oxidized dimerized peptide was observed for the first time as a product, indicating a reaction via a charge transfer mechanism.

Highlights

Gold compounds have a long history in medicinal chemistry
We suggested that highly nucleophilic cysteines of biomolecules can be targeted using weak nucleophiles, such as platinum-nucleobase PtN4 complexes for selective peptide reactions [2]
The previously unreported 1-methylcytosine complexes based on the [Au(dien)

Summary

Introduction

Gold compounds have a long history in medicinal chemistry. The thiophilic nature of gold suggests sulfur-rich proteins, such as thioredoxin, as reasonable cellular targets for gold action [1].Au(III) is quite labile in its chemistry and is susceptible to reduction to Au(I) [1]. Gold compounds have a long history in medicinal chemistry. The thiophilic nature of gold suggests sulfur-rich proteins, such as thioredoxin, as reasonable cellular targets for gold action [1]. Au(III) is quite labile in its chemistry and is susceptible to reduction to Au(I) [1]. Apart from the inherent difficulty in understanding speciation of an Au(III) complex in a biological medium, nonselective interactions are highly likely. This is especially true when highly nucleophilic sulfur sites in proteins are considered as viable targets. We suggested that highly nucleophilic cysteines of biomolecules can be targeted using weak nucleophiles, such as platinum-nucleobase PtN4 complexes for selective peptide reactions [2]. Au(III) is more chemically reactive than Pt(II), the same principle applies [3]

Results

Discussion

Conclusion