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Springer Theses
Recognizing Outstanding Ph.D. Research

Raphael Enoque Ferraz de Paiva

Gold(I,III) Complexes
Designed for
Selective Targeting
and Inhibition of
Zinc Finger Proteins
Springer Theses

Recognizing Outstanding Ph.D. Research

Aims and Scope

The series “Springer Theses” brings together a selection of the very best Ph.D.
theses from around the world and across the physical sciences. Nominated and
endorsed by two recognized specialists, each published volume has been selected
for its scientific excellence and the high impact of its contents for the pertinent field
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include an extended introduction, as well as a foreword by the student’s supervisor
explaining the special relevance of the work for the field. As a whole, the series will
provide a valuable resource both for newcomers to the research fields described,
and for other scientists seeking detailed background information on special
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contributions made by today’s younger generation of scientists.

Theses are accepted into the series by invited nomination only

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• The theses should have a clearly defined structure including an introduction
accessible to scientists not expert in that particular field.

More information about this series at http://www.springer.com/series/8790

Raphael Enoque Ferraz de Paiva

Gold(I,III) Complexes
Designed for Selective
Targeting and Inhibition
of Zinc Finger Proteins
Doctoral Thesis accepted by
the University of Campinas, Campinas, Brazil

123
Author Supervisor
Dr. Raphael Enoque Ferraz de Paiva Prof. Pedro Paulo Corbi
Institute of Chemistry Institute of Chemistry
University of Campinas University of Campinas
Campinas, Brazil Campinas, Brazil

ISSN 2190-5053 ISSN 2190-5061 (electronic)

Springer Theses
ISBN 978-3-030-00852-9 ISBN 978-3-030-00853-6 (eBook)
https://doi.org/10.1007/978-3-030-00853-6

Library of Congress Control Number: 2018955155

© Springer Nature Switzerland AG 2018

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part
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The most exciting phrase to hear in science,
the one that heralds the most discoveries, is
not “Eureka!” (I found it!) but “That’s
funny…”
—Isaac Asimov
The mediocre teacher tells. The good teacher
explains. The superior teacher demonstrates.
The great teacher inspires
—William Arthur Ward

I dedicate this thesis to every teacher (in the

most fundamental sense of the word) I had
during my life. Luckily, I’ve had many great
teachers.
Supervisor’s Foreword

Raphael joined my group as an undergraduate student at the Institute of Chemistry

of the Campinas State University (UNICAMP), Brazil, in 2010. He obtained his
master’s degree working in the synthesis and biological evaluation of silver and
platinum complexes with anti-inflammatory agents. Raphael developed his Ph.D.
project focusing on the development of gold(I,III) compounds for the inhibition of
zinc finger proteins. This project was developed at UNICAMP with a one year
exchange at VCU under the supervision of Prof. Nicholas Farrell.
The zinc finger family of proteins was explored as target in this work, in par-
ticular, the nucleocapsid protein (NCp7) from the human immunodeficiency virus
(HIV-1). One of the most remarkable structural and functional characteristics NCp7
is the presence of two -Cys-X2-Cys-X4-His-X4-Cys- zinc finger (ZnF) domains.
Inhibition of this proteins leads to the loss of viral infectivity, suggesting that NCp7
inhibitors could be developed as alternatives to the typical anti-retroviral therapies
available today.
The broad contribution of this thesis was on the development of gold-based com-
pounds for the inhibition of zinc finger proteins. Gold(I) compounds were developed
using phosphine ligands as “carriers” and labile pyridine derivatives or chloride as
co-ligands. Innovative approaches were used for evaluating the interaction of gold(I)
compounds with zinc fingers. Travelling-wave ion mobility mass spectrometry
(TWIM-MS) coupled with tandem MS proved to be an extremely powerful technique
for detecting metallation sites in zinc fingers, as well as for identifying and separating
conformers. X-ray absorption spectroscopy (XAS) was used for identifying changes in
the coordination sphere and geometry of gold. In addition, gold(III) compounds were
also developed. Stabilizing gold(III) represents an interesting challenge, as it is prone to
reduction in the biological media. The organometallic compounds [Au(2-benzylpy-
ridine)Cl2] is particularly noteworthy. It was able to inhibit NCp7 through a sui generis
mechanism based on a gold-catalyzed C-S bond formation.

ix
x Supervisor’s Foreword

Finally, the dedication and motivation of Dr. Raphael de Paiva are noteworthy. He
was always willing to help his colleagues and ready for new challenges. His
published works and conferences awards confirm his wonderful work and his
dedication to science. It was a great honor to me to write about Dr. Raphael Enoque
Ferraz de Paiva and I wish him success in his career.

Campinas, Brazil Prof. Pedro Paulo Corbi

July 2018
Abstract

Many complementary approaches have been used to inactivate the HIV-1 nucleocapsid
protein (NCp7) zinc finger for therapeutic use. The cysteine residues of NCp7 are some
of the most nucleophilic of all zinc-bound thiolates found in proteins. Although it is
considered a noble metal, gold has a very rich chemistry under the right conditions. It is
capable of forming coordination compounds in both of its typical oxidation states (1+
and 3+). Gold(I) forms linear compounds, with coordination number 2, while gold(III)
forms square planar compounds with coordination number 4. Electron-rich metals such
as gold are particularly suitable for designing metal-based zinc ejectors because, as soft
Lewis acid electrophiles, they have high affinity for Cys residues. Without the proper
tridimensional folding granted by Zn coordination, NCp7 is inactivated and unable to
further recognize specific nucleic acid sequences.
A series of Au(I) complexes with the general structure [Au(L)(PR3)] (R = Et or Cy)
was designed. The two aromatic residues in the structure of NCp7 (Phe16 and Trp37)
are responsible for p-stacking with purine and pyrimidine bases found on RNA and
DNA. The presence of these residues can be used for introducing an extra selectivity
component in the designed compounds, as an aromatic L ligand can be used. We also
examined for comparison the “standard” gold-phosphine compound auranofin which
contains a thiosugar ligand coordinated to {Au(Et3P)}. The nature of the phosphine
and the nature of L affect both the reactivity with the C-terminal NCp7 ZnF2 and the
“full” NCp7 as well as the final coordination sphere of Au once incorporated into the
protein. In this reaction, the first step is the electrophilic attack of the Au(I)-phosphine
compounds on the Zn-coordinated residues, forming a heterobimetallic {R3PAu}-
ZnF species. Two alternative pathways open up from here on. In the most typical
pathway, after Zn displacement, the {R3PAu} moiety can remain coordinated to a Cys
residue. Afterwards, the phosphine is lost and a Cys-Au-Cys gold finger (AuF) is
obtained. In this mechanism, compounds with slower reactivity such as [Au(dmap)
(Et3P)] allow us to probe the initial auration steps, with species such as {Et3PAu}-
apoNCp7 still being present. Longer incubation times or more reactive compounds
such as the chloride precursors provide information on the final species, the gold finger
itself. In an alternative pathway, observed for the model compound auranofin, the
{R3PAu} moiety coordinates to a His residue, and the final hypothetical AuF obtained

xi
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