Metals in Medicine

By James C. Dabrowiak

Working from basic chemical principles, Metals in Medicine 2nd Edition describes a wide range of metal-based agents for treating and diagnosing disease. Thoroughly revised and restructured to reflect significant research activity and advances, this new edition contains extensive updates and new pedagogical features while retaining the popular feature boxes and end-of-chapter problems of the first edition.
Topics include:

• Metallo-Drugs and their action
• Platinum drugs for treating cancer 
• Anticancer agents beyond cisplatin including ruthenium, gold, titanium and gallium
• Responsive Metal Complexes
• Treating arthritis and diabetes with metal complexes
• Metal complexes for killing bacteria, parasites and viruses
• Metal ion imbalance and its links to diseases including Alzheimer’s, Wilson’s and Menkes disease 
• Metal complexes for detecting disease
• Nanotechnology in medicine

Now in full colour, Metals in Medicine 2nd Edition employs real-life applications and chapter-end summaries alongside feature boxes and problems. It provides a complete and methodical examination of the use of metal complexes in medicine for advanced undergraduate and postgraduate students in medicinal inorganic chemistry, bioinorganic chemistry, biochemistry, pharmacology, biophysics, biology and bioengineering. It is also an invaluable resource for academic researchers and industrial scientists in inorganic chemistry, medicinal chemistry and drug development.

• Language: English
• Publisher: Wiley
• Release date: May 2, 2017
• ISBN: 9781119191346

Book preview

Inorganic Chemistry

A Wiley Series of Advanced Textbooks

ISSN: 1939-5175

Editorial Board

David Atwood, University of Kentucky, USA

Bob Crabtree, Yale University, USA

Gerd Meyer, Iowa State University, USA

Derek Woollins, University of St. Andrews, UK

Previously Published Books in this Series

The Organometallic Chemistry of N-heterocyclic Carbenes

Han Vinh Huynh; ISBN: 978-1-118-59377-6

Bioinorganic Chemistry: Inorganic Elements in the Chemistry of Life, An Introduction and Guide, 2nd Edition

Wolfgang Kaim, Brigitte Schwederski, Axel Klein; ISBN: 978-0-470-97523-7

Structural Methods in Molecular Inorganic Chemistry

David Rankin, Norbert Mitzel and Carole Morrison; ISBN: 978-0-470-97278-6

Introduction to Coordination Chemistry

Geoffrey Alan Lawrance; ISBN: 978-0-470-51931-8

Chirality in Transition Metal Chemistry

Hani Amouri & Michel Gruselle; ISBN: 978-0-470-06054-4

Bioinorganic Vanadium Chemistry

Dieter Rehder; ISBN: 978-0-470-06516-7

Inorganic Structural Chemistry 2nd Edition

Ulrich Muller; ISBN: 978-0-470-01865-1

Lanthanide and Actinide Chemistry

Simon Cotton; ISBN: 978-0-470-01006-8

Mass Spectrometry of Inorganic and Organometallic Compounds: Tools-Techniques-Tips

William Henderson & J. Scott McIndoe; ISBN: 978-0-470-85016-9

Main Group Chemistry, Second Edition

A.G. Massey; ISBN: 978-0-471-19039-5

Synthesis of Organometallic Compounds: A Practical Guide

Sanshiro Komiya; ISBN: 978-0-471-97195-5

Chemical Bonds: A Dialog

Jeremy Burdett; ISBN: 978-0-471-97130-6

The Molecular Chemistry of the Transition Elements: An Introductory Course

Francois Mathey & Alain Sevin; ISBN: 978-0-471-95687-7

Stereochemistry of Coordination Compounds

Alexander von Zelewsky; ISBN: 978-0-471-95599-3

For more information on this series see: www.wiley.com/go/inorganic

Metals in Medicine

Second Edition

James C. Dabrowiak

Department of Chemistry, Syracuse University, New York, USA

Wiley Logo

This edition first published 2017

© 2017 by John Wiley & Sons Ltd

Edition History

Metals in Medicine, John Wiley & Sons Ltd, Nov 2009, 9780470681961 / 9780470681978

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of James C. Dabrowiak to be identified as the author of this work has been asserted in accordance with law.

Registered Office(s)

John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA

John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK

Editorial Office

9600 Garsington Road, Oxford, OX4 2DQ, UK

For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.

Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats.

Limit of Liability/Disclaimer of Warranty:

In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging-in-Publication Data:

Names: Dabrowiak, James C., author.

Title: Metals in medicine / James C. Dabrowiak.

Other titles: Inorganic chemistry (John Wiley & Sons)

Description: Second edition. | Hoboken, NJ : John Wiley & Sons, Inc., 2017. | Series: Inorganic chemistry: a textbook series | Includes

bibliographical references and index.

Identifiers: LCCN 2016058034 (print) | LCCN 2016059475 (ebook) | ISBN 9781119191308 (pbk.) | ISBN 9781119191315 (pdf) |

ISBN 9781119191346 (epub)

Subjects: | MESH: Metals--therapeutic use | Metals--pharmacokinetics | Drug Discovery

Classification: LCC RM666.M513 (print) | LCC RM666.M513 (ebook) | NLM QV 290 | DDC 615/.231--dc23

LC record available at https://lccn.loc.gov/2016058034

Cover Design: Wiley

Cover Image: (Gold Rod of Asclepius) © ChrisGorgio/iStockphoto; (Cisplatin HAS, Gold Nano Particle, and Protein Data Bank)

Courtesy of James C. Dabrowiak

To Tatiana

CONTENTS

Feature Boxes

Preface to the Second Edition

Preface to the First Edition

Web Site

Acknowledgments

About the Companion Website

1 Inorganic Chemistry Basics

1.1 Introduction

1.2 Crystal Field Theory

1.3 Molecular Orbital Theory

1.4 Absorption Spectra of Metal Complexes

1.5 Magnetic Properties of Metal Complexes

1.6 Structure and Reactivity of Metal Complexes

1.7 Summary

Discussion Questions

Problems

References

Further Reading

2 Metallo-Drugs and Their Action

2.1 Introduction

2.2 Proteins as Targets for Metallo-Drugs

2.3 DNA as a Target for Metallo-Drugs

2.4 Reaction of Metal Complexes in the Biological Milieu

2.5 Evaluating the Pharmacological Effects of Agents

2.6 From Discovery to the Clinic

2.7 Summary

Discussion Questions

Problems

References

Further Reading

3 Platinum Drugs for Treating Cancer

3.1 Introduction

3.2 Cisplatin

3.3 Carboplatin

3.4 Oxaliplatin

3.5 Regionally Used Platinum Drugs

3.6 Platinum Agents in Preclinical Development

3.7 Summary

Discussion Questions

Problems

References

4 Anticancer Agents Beyond Cisplatin

4.1 Introduction

4.2 Ruthenium Anticancer Agents

4.3 Gold Anticancer Agents

4.4 Titanium Compounds for Treating Cancer

4.5 Gallium for Treating Cancer

4.6 Other Anticancer Active Metal Complexes

4.7 Summary

Discussion Questions

Problems

References

Further Reading

5 Responsive Metal Complexes

5.1 Introduction

5.2 Prodrug Activation by Redox

5.3 Prodrug Activation by pH

5.4 Prodrug Activation by Enzymes

5.5 Prodrug Activation by Light

5.6 Photodynamic Therapy

5.7 Summary

Discussion Questions

Problems

References

Further Reading

6 Metal Complexes for Treating Arthritis and Diabetes

6.1 Introduction

6.2 Chemistry of Gold in Biological Media

6.3 Gold Compounds for Treating Arthritis

6.4 Vanadium Compounds for Treating Diabetes

6.5 Summary

Discussion Questions

Problems

References

Further Reading

7 Metal Complexes for Killing Parasites, Bacteria and Viruses

7.1 Introduction

7.2 Malaria

7.3 Leishmaniasis

7.4 American Trypanosomiasis (Chagas Disease)

7.5 Human African Trypanosomiasis

7.6 Tuberculosis

7.7 Peptic Ulcer Disease

7.8 Syphilis

7.9 Bacterial Infections

7.10 Acquired Immunodeficiency Syndrome (AIDS)

7.11 Summary

Discussion Questions

Problems

References

8 Metal Ion Imbalance in the Body

8.1 Introduction

8.2 Alzheimer's Disease

8.3 Lithium and the Brain

8.4 Wilson's Disease: Copper Overload

8.5 Menkes Disease: Copper Deficiency

8.6 Beta-Thalassemia: Iron Overload

8.7 Iron-Deficiency Anemia

8.8 Calcium Imbalance

8.9 Chelation Therapy

8.10 Summary

Discussion Questions

Problems

References

Further Reading

9 Metal Complexes for Detecting Disease

9.1 Introduction

9.2 Technetium in Diagnostic Nuclear Medicine

9.3 Metal Compounds as Contrast Agents for MRI

9.4 Radiotherapy

9.5 Summary

Discussion Questions

Problems

References

Further Reading

10 Nanomedicine

10.1 Introduction

10.2 Circulation, Uptake, and Elimination of Nanoparticles

10.3 Nanoscience for Treating Cancer

10.4 Nanoparticles for Detecting Disease

10.5 Theranostic Nanoparticles

10.6 Cytotoxicity of Nanoparticles

10.7 Summary

Discussion Questions

Problems

References

Eula

List of Tables

Chapter 1

Table 1.1

Table 1.2

Table 1.3

Table 1.4

Table 1.5

Table 1.6

Chapter 3

Table 3.1

List of Illustrations

Chapter 1

Figure 1.1 Common geometries of metal complexes and intermediates found in inorganic chemistry.

Figure 1.2 Transition metal ions and their electronic configurations for various oxidation states.

Figure 1.3 Boundary surfaces of the five d-orbitals.

Figure 1.4 Generation of the octahedral crystal field from the free ion.

Figure 1.5 Octahedral, tetragonal and square planar crystal field.

Figure 1.6 Tetrahedral crystal field.

Figure 1.7 Some possible electronic configurations for the d⁴ free ion and their respective values of S.

Figure 1.8 High- and low-spin possibilities for d⁴ in an octahedral crystal field.

Figure 1.9 Molecular orbital diagram for molecular hydrogen, H2. The black dots represent the hydrogen nucleus, a proton.

Figure 1.10 Molecular orbital diagram for [Co(NH3)6]³+, σ bonding only.

Figure 1.11 Partial molecular orbital diagram for Cr(CO)6. The energies of levels are only approximate. Antibonding MOs at high energy (less stable) are not shown in the diagram. While there are a total of 12 π* MOs on the six carbon monoxide molecules, for reasons pertaining to symmetry, only three π* MOs on the COs are used in interacting with the t2g orbitals (dxz, dyz, dxy) on the metal to produce bonding, t2g, and antibonding, t2g*, MOs. The lowest unoccupied molecular orbital, LUMO, and highest occupied, HOMO, are also shown on the diagram.

Figure 1.12 Bonding between carbon monoxide and a metal to form a metal carbonyl bond. For clarity, only portions of the and dxy orbitals on the metal are shown. The metal carbonyl bond is formed using the σ (2p) MO on CO and the atomic orbital on M, while the π-bond between M and CO is formed using a π* (2p) MO on CO and the dxy atomic orbital on M. The shaded and unshaded orbitals indicate that the sign of the wavefunction is positive and negative, respectively.

Figure 1.13 Synthesis of ferrocene.

Figure 1.14 Approximate shape of the a1g (σ) bonding molecular orbital for [Co(NH3)6]³+.

Figure 1.15 Absorption spectrum of [Ti(H2O)6]³+ in water. Adapted from Lever, A.B.P., Inorganic Electronic Spectroscopy, 1968, Elsevier. Reproduced with permission of Elsevier.

Figure 1.16 Jahn–Teller (tetragonal) distortion, ‘ -in’, for [Ti(H2O)6]³+, 3d¹.

Figure 1.17 Absorption spectrum of [Co(NH3)6]³+ in water. High-energy part adapted from Riordan, A.R., et al., (2005) Spectrochemical Series of Cobalt(III). An Experiment for High School Through College. Chem. Educator, 10, 115–119; low-energy part adapted from Lever, A.B.P., Inorganic Electronic Spectroscopy, 1968, Elsevier.

Figure 1.18 (a) Measurement of the rotation of linearly polarized light. The electric vector of light, indicated by an arrow, changes in magnitude with time (distance) in the manner shown. The angle of rotation of the plane of polarization, α, is positive if the plane of light after passing through the optically active sample is rotated to the left as viewed by an observer facing the light; that is, if the light is moving toward the observer. The angle of rotation is measured by an analyzer/detector. (b) Schematic of the circular dichroism measurement. Left and right circularly polarized light (cpl), indicated as left cpl and right cpl, pass through an optically active sample, with one form being absorbed by the sample to a greater extent than the other form. The absorbance of each form is measured by a detector which is ‘locked into’ the form of light being generated.

Figure 1.19 (a) Absorption curve, (b) optical rotatory dispersion (ORD) and circular dichroism (CD) curves for an enantiomer exhibiting a positive Cotton effect. (c) ORD and CD curves for the mirror-image enantiomer exhibiting a negative Cotton effect.

Figure 1.20 Rate curves, concentration versus time, for the reaction of MLxX, starting concentration [MLxX]0, with nucleophile Y to form product MLxY.

Figure 1.21 Water exchange rate constants and half-lives for some metal ions at 25 °C. Adapted from Helm, L. and Merbach, A.E. (1999) Water Exchange on Metal Ions: Experiments and Simulations. Coord. Chem. Rev., 187, 151–181. Copyright 1999, with permission from Elsevier. Reproduced with permission of Elsevier.

Figure 1.22 Reaction coordinate based on transition state theory for a reaction with –ΔGrxn.

Figure 1.23 Structures of cisplatin and transplatin.

Figure 1.24 Dhara synthesis of cisplatin.

Figure 1.25 Equilibria involving the iodo complexes in the synthesis of cisplatin.

Figure 1.26 Synthesis of transplatin.

Figure 1.27 Structure of an octahedral complex with ethylenediaminetetraacetic acid, EDTA, which binds to the metal ion as a tetravalent anion.

Figure 1.28 Optical isomers and absolute configuration for an octahedral tris-bidentate chelate complex with three identical symmetrical, bidentate, A–A-type ligands. Examples of commonly found A–A-type ligands are ethylenediamine, NH2CH2CH2NH2, A = N, oxalate, O2CCO2²−, A = O, and so on.

Figure 1.29 Geometric and optical isomers for octahedral tris-bidentate chelate complexes with three identical, unsymmetrical, A–B-type ligands. Examples of commonly found ligands of this type are glycinate, NH2CHCO2−, where A = N and B = O, di-deprotonated glycolic acid, −OCH2CO2−, A = O(OH), B = O(CO2H), and so on. The front unique face for the fac isomer and the edge, meridian, for the mer isomer are shown with dashed lines.

Figure 1.30 Structures of [Cu(232 tet)]²+, [Cu(cyclam)]²+ and [Cu(TPP)], where TPP is the di-deprotonated porphyrin core of meso-tetra-(p-sulfonatophenyl)porphyrin.

Chapter 2

Figure 2.1 Structures, three-letter and single-letter amino acid codes for the common amino acids found in proteins. Metal-binding function groups on the side chains are indicated in yellow and green.

Figure 2.2 Connectivity in a peptide or protein, showing the peptide (amide) bond and the sequence, using three- and one-letter amino acid codes written from the N-terminal to the C-terminal residue of the peptide/polymer.

Figure 2.3 Complexation of donor atoms located in the side chains of various amino acids to a metal ion (M) to form a 1:1 complex. The pKa values given are the approximate values for the free amino acid. (a) The carboxylic acid group of aspartic or glutamic acid, showing mono- and bidentate coordination to the metal ion. Due to resonance, the negative charge in the bidentate complex can be exchanged between the two oxygen atoms. (b) The imidazole group of histidine. The imidazolium ion of histidine has two resonance forms and the imidazole two tautomeric forms. A metal ion can bind to either of the tautomeric forms of imidazole, to form a M–Nϵ or M–Nδ complex. (c) The primary amine group of lysine. (d) The thioether group of methionine. (e) The thiol group of cysteine. (f) The phenol group of tyrosine.

Figure 2.4 (a) Resonance stabilization of the trans amide linkage. (b) Deprotonation of the amide nitrogen atom and binding of a metal ion to the deprotonated amide. All atoms shown lie in the same plane.

Figure 2.5 (a) Structure of the fully protonated form of the tripeptide, glutathione, γ-glutamylcysteinylglycine, GSH, showing the pKa values (in parentheses) of the functional groups. (b) Redox reaction, that is, reduction/oxidation reaction, of glutathione; reduced form, GSH, oxidized form, GSSG. (c) Reaction of GSH with a disulfide functional group on a protein, reducing it to the di-thiol form with the formation of GSSG.

Figure 2.6 (a) Amino acid sequence and Zn²+-S-Cys connectivities of zinc human metallothionein-2, Zn7MT-2. (b) Structures of the Zn4(Cys)11 cluster (α-domain) and the Zn3(Cys)9 cluster (β-domain) in Zn7MT-2. Adapted with permission from Knipp, M., et al., Reaction of Zn7Metallothionein with cis- and trans-[Pt(N-donor)2Cl2] anticancer complexes: trans-PtII complexes retain their N-donor ligands. J. Med. Chem., 50, 4075–4086. Copyright 2007, American Chemical Society; Scheme 2. Reproduced with permission of American Chemical Society.

Figure 2.7 Structure of p53 tumor repressor protein bound to a consensus response element DNA 20 mer. The DNA sequences recognized by the individual p53 monomers are shown on the right. Adapted with permission from Vainer, R., Cohen, S., Shahar, A., et al. (2016) Structural basis for p53 Lys120-acetylation-dependent DNA-binding mode. J. Mol. Biol., 428, 3013–3025; Figure 1. Reproduced with permission of Elsevier.

Figure 2.8 The 5′-phosphate nucleotides of DNA and RNA. For simplicity, only 5′-UMP of RNA is shown.

Figure 2.9 (a) Reaction of a 5′-monophosphate group with a 3′-hydroxyl group with the loss of a water molecule to form a phosphodiester bond in DNA or RNA. (b) Connectivity of a strand of DNA. The sequence, in the 5′ to 3′ direction, which is convention, is 5′-d(ATG). Also shown are the hydrogen bond sites (arrows) between a heterocyclic base and its complement in a Watson–Crick double helix.

Figure 2.10 Watson–Crick base pairs (bp) of DNA showing adenine (A) paired with thymine (T) and guanine (G) paired with cytosine (C), with the approximate location of the helix axis (viewed down the axis) and the locations of the major and minor grooves indicated for B-DNA. The locations of hydrogen bond sites between the bases and main metal-binding sites on G and A are shown in yellow and green highlights, respectively.

Figure 2.11 Structure of B-DNA, showing the sequence and locations of the major and minor grooves. The sugar-phosphate backbones of both strands are depicted as orange bands. Created from PBD file 1BNA using PyMol v. 1.8.0.3.

Figure 2.12 (a) Diagram showing some of the possible adducts that can form between a metal ion (red sphere) and the bases of double-stranded DNA. (b) Intercalation of a drug molecule between the base pairs of DNA.

Figure 2.13 Equilibria and pKa values of (a) phosphate and (b) carbonate at 37 °C.

Figure 2.14 Reaction of carbonate with metal complexes. (a) Reaction of a metal hydroxo complex with carbon dioxide to produce a hydrogencarbonato complex. The latter can deprotonate to form a monodentate carbonato complex which, if there is a displaceable ligand in the position cis to the carbonate, can form a bidentate carbonato complex. The charge on the ligand bound to the metal ion is given in parenthesis. (b) Formation of hydrogencarbonato/carbonato complexes by a ligand substitution reaction. The group X is any displaceable monodentate ligand.

Figure 2.15 Plot of percent viability versus drug concentration, showing the IC50 value.

Figure 2.16 Drug approval process used by the US Food and Drug Administration (FDA). The length of the arrows and rectangles are approximately proportional to the length of time for each step in the approval process.

Chapter 3

Figure 3.1 Structures of the major platinum anticancer drugs.

Figure 3.2 Speciation of cisplatin in aqueous solution. Redrawn from Scheme 1.1, p. 73 of Berners-Price, S.J., Ronconi, L., and Sadler, P.J. (2006) Insights into the mechanism of action of platinum anticancer drugs from multinuclear NMR spectroscopy. Prog. Nucl. Mag. Res. Sp., 49, 65–98. Reproduced with permission of Elsevier.

Figure 3.3 Speciation of cisplatin in physiological carbonate.

Figure 3.4 Structure of human serum albumin (HSA), showing the locations of cisplatin-binding sites with enlargement of the His105 and Met329 sites. The cartoon image of HSA was created from PDB file 4S1Y using PyMol v.1.8.0.3. The enlargements of two sites were adapted with permission from Ferraro, G. Massai, L., Messori, L., et al. (2015) Cisplatin binding to human serum albumin a structural study. Chem. Commun., 51, 9436–9439 (Figure 2). Reproduced with permission of Royal Society of Chemistry.

Figure 3.5 Types of cisplatin adducts at nitrogen sites on the heterocyclic bases of DNA.

Figure 3.6 The reaction mechanism of cisplatin with DNA to form a 1,2 intrastrand crosslink at GG of the indicated DNA duplex. Adapted from Scheme 2.2, p. 5610 of Davies, M.S., Berners-Price, S.J., and Hambley, T.W. (2000) Slowing of cisplatin aquation in the presence of DNA but not in the presence of phosphate: improved understanding of sequence selectivity and the roles of monoaquated and diaquated species in the binding of cisplatin to DNA. Inorg. Chem., 39, 5603–5613. Reproduced with permission of American Chemical Society.

Figure 3.7 Cisplatin binding to the closed circular DNA plasmid pUC19, as studied using agarose gel electrophoresis. Lane 1 is the control having no added cisplatin, while lanes 2–14 have an increasing fraction of platinum bound to DNA. Adapted from Keck, M.V. and Lippard, S.J. (1992) Unwinding of supercoiled DNA by platinum-ethidium and related complexes. J. Am. Chem. Soc., 114, 3386–3390 (Figure 2). Copyright 1992, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 3.8 Cisplatin (cis-[Pt(NH3)2]²+) binding to a closed circular DNA molecule to form a 1,2 intrastrand crosslink, which makes the writhe of the DNA less negative.

Figure 3.9 Supercoiled DNA (Form I) cleaved by a cutting agent into Form II and Form III DNA. The solid cyan line represents double-stranded DNA.

Figure 3.10 Magnetic tweezer experiment involving double-stranded DNA molecules with an end-attached 1 μm superparamagnetic iron oxide (FeO) nanoparticle affixed to a glass surface. The experiment measures the effects of the binding of cisplatin (blue dots) on the measured force versus DNA extension curve under different physiological ionic conditions. Adapted from Park, J.-S., Kim, S.H., Lee, N.-K., et al. (2012) In situ analysis of cisplatin binding to DNA: the effects of physiological ionic conditions. Phys. Chem. Chem. Phys., 14, 3128–3133 (Figure 1). Reproduced with permission of Royal Society of Chemistry.

Figure 3.11 Crystal structure of cisplatin bound to the DNA 12-mer duplex, CCTCTGGTCTCC/GGAGACCAGAGG, with the site of binding of cis-[Pt(NH3)2]²+ indicated in boldface type. (a) The binding of cis-[Pt(NH3)2]²+ to the GG sequence on one strand bends the helix axis of the double-stranded DNA toward the major groove of DNA by ∼40°. (b) View showing cis-[Pt(NH3)2]²+ bound to N7 of the guanine bases in the GG sequence. Reprinted with permission from Takahara, P.M., et al. (1995) Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin. Nature, 377, 649–652 (Figure 1). Copyright 1995, Nature Publishing Group. Reproduced with permission of Nature Publishing Group.

Figure 3.12 (a) Average ribbon diagram of Zn²+ bound to the peptide sequence ICEEPTCRNRTRHLP-LQFSRTGPLCPACMKA, zpp. The Zn²+ ion is bound to four thiolate sulfur atoms of the four cysteine residues of the peptide in a tetrahedral coordination geometry. (b) Qualitative representation of the 1:1 zinc, cisplatin–zpp intermediate complex with the Zn²+ bound to the amino terminus and the Pt²+ bound to the carboxyl terminus of the peptide. Adapted from Bose, R.N., et al. (2005) Structural perturbation of a C4 zinc-finger module by cis-diamminedi-chloroplatinum(II): Insights into the inhibition of transcription process by the antitumor drug. Inorg. Chim. Acta, 358, 2844–2854 (Figure 8). Copyright 2005, Elsevier. Reproduced with permission of Elsevier.

Figure 3.13 Electron microscopy images of platinum-free (a) and platinum-added (b) microtubules. The microtubules in (a) were allowed to form and were stabilized by the addition of the anticancer drug taxol. In (b) the tubulin monomers (27 μM) were allowed to oligomerize in the presence of the diaqua form of cisplatin (27 μM) for 17 minutes prior to image capture. Adapted from Tulub, A.A. and Stefanov, V.E. (2001) Cisplatin stops tubulin assembly into microtubules. A new insight into the mechanism of antitumor activity of platinum complexes. Int. J. Biol. Macromol., 28, 191–198 (Figure 2a and c; p. 194). Reproduced with permission of Elsevier.

Figure 3.14 Proposed structure of the cisplatin adduct with the pyrophosphohydrolase enzyme MazG (Pt2MazG) produced when E. coli bacteria are stressed with cisplatin. Adapted from Stefanopoulou, M., Kokoschka, M., Sheldrick, W.S., et al. (2011) Cell response of Escherichia coli to cisplatin-induced stress. Proteomics, 11, 4174–4188 (Figure 4). Reproduced with permission of John Wiley & Sons.

Figure 3.15 Helix 18 of 18S rRNA. (a) Structure of helix 18 with cisplatin binding sites at A790 and A792, and a possible interstrand crosslink between C786 and G797. The number of asterisks is a measure of the likelihood that the site has a bound Pt ion. (b) Stem-loop structures of helix 18 for S. cerevisiae, H. sapiens and E. coli. Adapted from Hostetter, A.A., Osborn, M.F. and DeRose, V.J. (2012) RNA-Pt adducts following cisplatin treatment of Saccharomyces cerevisiae. ACS Chem. Biol., 7, 218−225 (Figure 5). Copyright 2012, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 3.16 Synthesis of carboplatin.

Figure 3.17 Structure of carboplatin viewed in the donor atom plane. The cyclobutane-1,1-dicarboxylate ligand (cbdca) has conformational flexibility that allows it to block nucleophiles (Nu) from attacking the Pt²+ ion of carboplatin in a ligand substitution reaction. Adapted from Neidle, S., Ismail, I.M., and Sadler, P.J. (1980) The structure of the antitumor complex cis-(diammino) (1, 1-cyclobutanedicarboxylato)-Pt(II): X-ray and NMR studies. J. Inorg. Biochem., 13, 205–212. Reproduced with permission of Elsevier.

Figure 3.18 Hydrolysis of carboplatin in 0.2 M perchloric acid (HClO4).

Figure 3.19 Reaction of carboplatin with L-(S)-methionine in water at pH = 7.

Figure 3.20 Reaction of carboplatin with carbonate. Adapted from Di Pasqua, A.J., Centerwall, C.R., Kerwood, D.J., and Dabrowiak, J.C. (2009) Formation of carbonato and hydroxo complexes in the reaction of platinum anticancer drugs with carbonate. Inorg. Chem., 48, 1192–1197 (Figure 3; p. 1194). Reproduced with permission of American Chemical Society.

Figure 3.21 Platinum concentration inside MCM-7 breast cancer cells after a 24-hour incubation with the indicated concentrations of the platinum drugs. Adapted from A. Ghezzi, et al. (2004) Uptake of antitumor platinum(II)-complexes by cancer cells, assayed by inductively coupled plasma mass spectrometry (ICP-MS). J. Inorg. Biochem., 98, 73–78 (Figure 4). Copyright 2004, Elsevier. Reproduced with permission of Elsevier.

Figure 3.22 IC50 values of carboplatin and carboplatin aged in carbonate solutions for various times against different cell lines. Blue is carboplatin aged in 23.8 mM carbonate toward SK-N-SH neuroblastoma cells, yellow is carboplatin aged in 0.5 M carbonate toward SK-N-SH cells, red is carboplatin aged in 23.8 mM carbonate toward HK-2 proximal renal tubule cells, and green is carboplatin aged in 0.5 M carbonate toward BL Burkitt's lymphoma cells. Adapted from Di Pasqua, A.J., Goodisman, J., Kerwood, D.J., et al. (2007) Role of carbonate in the cytotoxicity of carboplatin. Chem. Res. Toxicol., 20, 896–904 (Figure 4). Copyright 2007, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 3.23 Solution NMR structure of the 1,3 intrastrand crosslink formed by carboplatin. Adapted from Teuben, J.-M., Bauer, C., Wang, A.H.-J., et al. (1999) Solution structure of a DNA duplex containing a cis-diammineplatinum(II) 1,3-d(GTG) intrastrand cross-link, a major adduct in cells treated with the anticancer drug carboplatin. Biochemistry, 38, 12305–12312 (Figure 6). Copyright 1999, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 3.24 Cartoon of the X-ray structure of carboplatin bound to ribonuclease A (RNase-A), showing two protein molecules in the asymmetry unit (magenta and cyan), and the location of the carboplatin fragment at Met29 on both proteins. Adapted from Messori, L., Marzo, T., and Merlino, A. (2015) Interactions of carboplatin and oxaliplatin with proteins: Insights from X-ray structures and mass spectrometry studies of their ribonuclease A adducts. J. Inorg. Biochem., 153, 136–142 (Figure 2). Reproduced with permission of Elsevier.

Figure 3.25 Structure and stereochemistry of 1,2-diaminocyclohexane, dach.

Figure 3.26 Synthesis of oxaliplatin.

Figure 3.27 Model of oxaliplatin based on the crystal structure of the drug. Public domain image.

Figure 3.28 Proposed structures for the products of the reactions of oxaliplatin with GSH and GSSG. Adapted from Fakih, S., Munk, V.P., Shipman, M.A., del Socorro Murdoch, P., Parkinson, J.A., and Sadler, P.J. (2003) Novel adducts of the anticancer drug oxaliplatin with glutathione and redox reactions with glutathione disulfide. Eur. J. Inorg. Chem., 1206–1214 (Figure 6b; p. 1210). Reproduced with permission of John Wiley & Sons.

Figure 3.29 (a) Average solution structure of [Pt(1R,2R-dach)]²+ from oxaliplatin bound to the duplex 5′-CCTCAGGCCTCC/GGAGGCCTGAGG (PDB 1PG9). (b) Average solution structure of cis-[Pt(NH3)2]²+ from cisplatin bound to the duplex 5′-CCTCTGGTCTCC/GGAGACCAGAGG (PDB 1A84). The bold and underlined bases are the sites of platinum binding. Images created with PyMol v.1.8.0.3.

Figure 3.30 Platination site of [Pt(dach)]²+ on the DNA duplex, 5′-CCTCTGGTCTCTCC/GGAGACCAGAGG. The pseudo-equatorial hydrogen atom on the nitrogen atom of 1R,2R-dach, which is cis to N7 of G7, forms a hydrogen bond to O6 of G7 of the DNA duplex. Adapted from Spingler, B., et al. (2001) 2.4 Å crystal structure of an oxaliplatin 1,2-d(GpG) intrastrand crosslink in a DNA dodecamer duplex. Inorg. Chem., 40, 5596–5602. Copyright 2001, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 3.31 A nucleosome core particle (NCP) which has been treated with cisplatin (CisPt) and in a separate experiment with oxaliplatin (OXPt), and their respective binding sequences under the abbreviation. Bases at which binding occurs are shown in black or gray. The view shown is a ‘slice’ through the C2 symmetry axis of the entire NCP, so only half of the entire NCP is shown. The ribbon structures in the center are four of the eight histone proteins, around which is wrapped a DNA duplex 78 bp in length. Both drugs bind to methionine residues of the histone proteins, the locations of which are indicated by ‘Pt-Met’. Adapted from Wu, B., et al. (2008) Site selectivity of platinum anticancer therapeutics. Nat. Chem. Biol., 4, 110–112. Copyright 2008, Nature Publishing Group. Reproduced with permission of Nature Publishing Group.

Figure 3.32 (a) Cartoon structure of hen egg-white lysozyme (HEWL), showing bound [Pt(dach]²+ at Asp119 (PDB 4PPO). (b) Stick representation of the Pt binding site. Pt is bound to the Asp119 side chain (cyan). The dach ligand is inserted into a cavity formed by Trp62, Trp63, Asp101, and Asn103 residues of a symmetry-related (neighboring) molecule (yellow). Adapted from Messori, L., Marzoa, T., and Merlino, A. (2014) The X-ray structure of the complex formed in the reaction between oxaliplatin and lysozyme. Chem. Commun., 50, 8360–8362 (Figures 2 and 4). Reproduced with permission of Royal Society of Chemistry.

Figure 3.33 Structures of platinum antitumor agents that have gained regional approval for use as anticancer drugs.

Figure 3.34 Structures of some platinum compounds in preclinical development.

Figure 3.35 Structures of platinum compounds in preclinical studies.

Figure 3.36 Cartoon of lipoplatin showing a cut-away (hemisphere) of the liposome containing cisplatin. Adapted from Wang, X. and Guo, Z. (2013) Targeting and delivery of platinum-based anticancer drugs. Chem. Soc. Rev., 42, 202–224 (Figure 4). Reproduced with permission of Royal Society of Chemistry.

Chapter 4

Figure 4.1 Structures of some anticancer ruthenium complexes.

Figure 4.2 Structures of antitumor active ruthenium compounds. One of the optically active forms – the R enantiomer – of DW12 is shown.

Figure 4.3 Synthesis of some antitumor-active ruthenium compounds.

Figure 4.4 Hydrolysis of NAMI-A in physiological media.

Figure 4.5 UV–visible absorption spectra of NAMI-A before (absorbance divided by 10) and after addition of excess ascorbic acid. The spectra in red are of the Ru²+ complex, from 12 s to 10 min after its formation by adding ascorbic acid to NAMI-A. The inset shows the change in absorbance at 402 nm with time of the Ru²+ complex in the presence of NaCl and NaClO4. The chemical changes occurring in the experiment are shown in the highlighted area. Adapted from Brindell, M., et al. (2007) Kinetics and mechanism of the reduction of (ImH)[trans-RuCl4(dmso)(Im)] by ascorbic acid in acidic aqueous solution. J. Biol. Inorg. Chem., 12, 809–818 (Figure 1). Copyright 2007, Springer. Reproduced with permission of Springer.

Figure 4.6 Structure of the reaction product of NAMI-A with human carbonic anhydrase II (hCAII). The Ru³+ ion is shown in purple, water molecules are shown as small red spheres, and the imidazole molecule bound to Zn²+ (donated by NAMI-A) is blue. Adapted from Casini, A., Temperini, C., Gabbiani, C., et al. (2010) The X-ray structure of the adduct between NAMI-A and carbonic anhydrase provides insights into the reactivity of this metallodrug with proteins. ChemMedChem, 5, 1989–1994. Reproduced with permission of John Wiley & Sons.

Figure 4.7 Product of reaction of KP1019 with human serum albumin (HSA), showing binding sites IB and IIA for Ru³+ (gold sphere). The image of HSA having bound myristate molecules was created from PDB file 5IFO using PyMol v.1.8.0.5. Images for sites IB and IIA were adapted from Bijelic, A., Theiner, S., Keppler, B.K., et al. (2016) X-ray structure analysis of indazolium trans-[tetrachlorobis(1H-indazole) ruthenate(III)] (KP1019) bound to human serum albumin reveals two ruthenium binding sites and provides insights into the drug binding mechanism. J. Med. Chem., 59, 5894–5903.

Figure 4.8 Binding of the ruthenium arene compounds RAED-C and RAPTA-C to the nucleosome core particle (NCP). (a) Cartoon of the NCP showing 145 bp of double-stranded DNA (cyan and orange) and four histone proteins H3 (blue), H4 (green), H2A (yellow), and H2B (red), with RAED-C shown as a space-filling model. The details of one of the DNA binding sites for RAED-C (site +1.5) are shown. (b) Cartoon of NCP as indicated above, showing the locations of RAPTA-C binding sites (1–3) on the histone proteins H4, H2A, and H2B. The details of Site 2, showing ruthenium binding to the amino acids, E61 and E64 of H2A, NCPs and Site +1.5 for RAED-C can be seen. Adapted from Adhireksan, Z., Davey, G.E., Campomanes, P., et al. (2014) Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity. Nat. Commun., 5, 3462. doi: 10.1038/ncomms4462. Site 2 RAPTA-C, adapted from Wu, B., Ong, M.S., Groessl, M., et al. (2011) A ruthenium antimetastasis agent forms specific histone protein adducts in the nucleosome core. Chem. Eur. J., 17, 3562–3566. Reproduced with permission of John Wiley & Sons.

Figure 4.9 Proposed general scheme for the catalytic oxidation of GSH to its corresponding disulfide GSSG by ruthenium(II) arene phenylazopyridine complexes with the production of hydrogen peroxide.

Figure 4.10 Cocrystal structure at 2.35 Å of (R)-DW12 with PAK1, p21-activated kinase-1 (residues 249–545, with a mutation, Lys replaced by Arg at position 299). The hydrogen bonding between pyridocarbazole ligands of DW12 and specific residue on the protein are shown. Adapted from Maksimoska, J., et al. (2008) Targeting large kinase active site with rigid, bulkey octahedral ruthenium complexes. J. Am. Chem. Soc., 130, 15764–15765 (Figure 2a). Copyright 2008, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 4.11 Synthesis of some gold complexes that exhibit anticancer properties.

Figure 4.12 Structure of [Au(TPP)]Cl, which has anticancer properties.

Figure 4.13 Structures of some Au³+ compounds studied in connection with binding to DNA.

Figure 4.14 Inhibition of DNA cleavage at guanine bases on a DNA restriction fragment by [AuBr3PEt3].

Figure 4.15 MDA-MB-231 human breast cancer cells treated with increasing concentrations of [((i-Pr)2Im)2Au]Cl for 24 hours, followed by cell lysis and determination of the enzymatic activity (% of control) of thioredoxin reductase (TrxR) and glutathione reductase (GR). Adapted from Hickey, J.L., Ruhayel, R.A., Barnard, P.J., et al. (2008) Mitochondria-targeted chemotherapeutics: The rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols. J. Am. Chem. Soc., 130, 12570–12571. Copyright 2008, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 4.16 Gold-N-heterocyclic carbene anticancer complex [Au(BPB)((CH3)2Im)]+ with a thiol switch. (a) Structure of the Au³+ complex. (b) Fluorescence intensity spectrum before (red) and after (blue) adding GSH to a solution of the complex. (c–e) Fluorescence microscopy images of HeLa cells. (c) Image of the cells (365 nm excitation) following a 10-min exposure to [Au(BPB)((CH3)2Im)]+. (d) Location of mitochondria in the cells detected with Mito-tracker Red stain (546 nm excitation). (e) The merged images (c) + (d). Adapted from Zou, T., Lum, C.T., Chui, S.S.Y., et al. (2013) Gold(III) complexes containing N-heterocyclic carbene ligands: thiol ‘switch-on’ fluorescent probes and anti-cancer agents. Angew. Chem. Int. Ed., 52, 2930–2933. Reproduced with permission of John Wiley & Sons.

Figure 4.17 Structures of titanocene dichloride and the cis,cis,cis-Δ- isomer of budotitane.

Figure 4.18 (a) Synthesis of titanocene dichloride, [(Cp)2TiCl2]. (b) Synthesis of budotitane. (c) Tautomerization and deprotonation of 1-phenylbutane-1,3-dione, Hbzac, the ligand in budotitane.

Figure 4.19 Structures of titanium complexes which exhibit anticancer properties.

Figure 4.20 Species distribution as a function of pH for [Ga³+] = 10 μM in water. The species are: [Ga(H2O)6]³+, 1,0; [Ga(OH)-(H2O)5]²+, 1,1; [Ga(OH)2(H2O)4]+, 1,2; [Ga(OH)3(H2O)3], 1,3; [Ga(OH)4(H2O)2], 1,4. Reprinted from Baes, C.F. and Mesmer, R.E. (1976) The Hydrolysis of Cations. Reproduced with permission of John Wiley & Sons.

Figure 4.21 Structures of octahedral, fac-Δ-[Ga(ma)3], fac-Δ-tris(3-hydroxy-2-methyl-4H-pyranonato)gallium(III), gallium maltolate, and mer-Δ-[GaQ3], mer-Δ-tris-(8-hydroxyquiolinato)gallium(III), KP46.

Figure 4.22 Proposed binding site of mer-Λ-KP46 at site IB of human serum albumin (HAS) determined using molecular docking techniques. Chelate rings of KP46 bound to hydrophilic residues on the protein are green; the chelate ring exposed to solvent is yellow. The image of HSA was created from PDB file 5IFO using PyMol v.1.8.0.5. The image of the binding site was adapted from Enyedy, E.A., Dömötör, O., Bali, K., et al. (2015) Interaction of the anticancer gallium(III) complexes of 8-hydroxyquinoline and maltol with human serum proteins. J. Biol. Inorg. Chem., 20, 77–88 (Figure 4b). Reproduced with permission of Springer.

Figure 4.23 Concentration distribution curves for the GaM-apoTf (a) and KP46-apoTf (b) systems as a function of the total concentrations of the complexes. Dashed lines denote KP46 concentrations over the solubility limit. CapoTf = [apoTf] = 37 μM considering that 30% of the binding sites on apoTf are saturated with Fe(III), pH 7.4. Adapted from Enyedy, E.A., Dömötör, O., Bali, K., et al. (2015) Interaction of the anticancer gallium(III) complexes of 8-hydroxyquinoline and maltol with human serum proteins. J. Biol. Inorg. Chem., 20, 77–88 (Figure 8). Reproduced with permission of Springer.

Figure 4.24 (a) The active site of oxidized diferric RNR-R2 from E. coli, PDB code 1RIB. (b) The active site of reduced diferrous RNR-R2 from E. coli, PDB code, 1XIK. Adapted from Han, W.-G. and Noodleman, L. (2009) DFT calculations of comparative energetics and ENDOR/Mössbauer properties for two protonation states of the iron dimer cluster of ribonucleotide reductase intermediate X. Dalton Trans., 6045–6057. Reproduced with permission of Royal Society of Chemistry.

Figure 4.25 (a) Structure of cis,cis,cis-[GaL2]ClO4, one of a series of Ga³+ complexes that target the proteasome. (b) Structure of GaLCl2, containing a pyridine-dimethylthiosemicarbazone ligand. (c) Structure of [Ga(3-AP)2] NO3 containing the 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, triapine (3-AP) ligand.

Figure 4.26 Examples of Pd+2 complexes with anticancer activity.

Figure 4.27 Structures of some osmium compounds with anticancer activity.

Figure 4.28 Atomic force microscopy (AFM) images of pBR322 plasmid DNA in the absence (a,b) and presence (c,d) of [Os4(η⁶-p-cym)4(μ²-OH)4(prz)2][PF6]4 in a DNA base:tetramer ratio of 5:1. Images were recorded 30 min after preparing the samples (a,c), and 24 h after incubation at 310 K (b,d). OC, Open-circular DNA; L, Linear plasmid DNA. Adapted from Fu, Y., Romero, M.J., Salassa, L., et al. (2016) Os2–Os4 switch controls DNA knotting and anticancer activity. Angew. Chem. Int. Ed., 55, 8909–8912. Reproduced with permission of John Wiley & Sons.

Figure 4.29 Structures of some rhodium and iridium complexes exhibiting anticancer activity.

Chapter 5

Figure 5.1 Metallo-prodrugs activated by redox reactions.

Figure 5.2 Disposition of cells relative to their proximity to a blood vessel (oxygen source) within a solid tumor. Adapted from Denny, W. A. (2000) The role of hypoxia-activated prodrugs in cancer therapy. Lancet Oncol., 1, 25–29. Reproduced with permission of Elsevier.

Figure 5.3 Mechanism of a bifunctional nitrogen mustard inducing an interstrand crosslink in double-stranded DNA.

Figure 5.4 Image of Fc-OH-TAM (n = 4) docked in the ligand binding domain (LBD) of ERα with an antagonist conformation. The locations of the ferrocene (FeCp2) and tertiary amine groups of Fe-OH-TAM are also shown. Adapted from Jaouen, G., Vessières, A., and Top, S. (2015) Ferrocifen-type anticancer drugs. Chem. Soc. Rev., 44, 8802–8817. Reproduced with permission from the Royal Society of Chemistry.

Figure 5.5 Mechanism of quinone methide (QM) formation.

Figure 5.6 pH-dependent ring-opening and -closing reactions of [Pt(L)2], a Pt²+ prodrug containing the racemic form of the 2-amino-4-methyl-1-pentanolato ligand.

Figure 5.7 Concentration–effect curves, showing the antiproliferative effects of cis-[Pt(L)2] in non-small cell lung cancer cells (A549) and colon carcinoma cells (HT-29) at pH 7.4 and 6.0. The percentage of viable cells (T/C) is the number of live cells treated divided by the number of live cells untreated × 100, following a 24-h exposure to cis-[Pt(L)2]. Adapted from Valiahdi, S.M., Egger, A.E., Miklos, W., et al. (2013) Influence of extracellular pH on the cytotoxicity, cellular accumulation, and DNA interaction of novel pH-sensitive 2-aminoalcoholatoplatinum(II) complexes. J. Biol. Inorg. Chem., 18, 249–260. Reproduced with permission of Springer.

Figure 5.8 Structure of vitamin B12, select β-ligand conjugates and the enzymatic reductive activation mechanism by which drugs are released from the β-ligand site.

Figure 5.9 Structure of select compounds with potential application in photoactivated therapy (PACT).

Figure 5.10 Confocal fluorescence microscopy images of human prostate carcinoma PPC-1 cells that were incubated for 60 min with 50 μM fac-[Re(bpy)(CO)3(thp)]CF3SO3. (a) This image (in blue, λem = 465−495 nm) was collected with minimal photolysis from the 405-nm excitation source, and indicates the incorporation of compound into the cytosol. (b) This image (in green, λem > 660 nm) was collected after 405-nm photolysis for 15 min and indicates the transformation of fac-[Re(bpy)(CO)3(thp)]CF3SO3 to its monoaquated form. Adapted from Pierri, A.E., Pallaoro, A., and Wu, G. (2012) A luminescent and biocompatible photoCORM. J. Am. Chem. Soc., 134, 18197–18200. Copyright 2012, American Chemical Society. Reproduced with permission of Royal Society of Chemistry.

Figure 5.11 Structures of Photofrin and metallo-sensitizers for use in photodynamic therapy (PDT).

Figure 5.12 Jablonski diagram for photodynamic therapy (PDT), highlighting Type I and II mechanisms.

Chapter 6

Figure 6.1 Structures of gold drugs used for treating arthritis. The connectivity in the polymeric compounds, sodium aurothiomalate (myochrysine), and aurothioglucose (solganol), is also shown.

Figure 6.2 Synthesis of gold drugs that exhibit anti-arthritic properties.

Figure 6.3 (a) View approximately down the fourfold helical symmetry axis of gold(I) thiomalate (myochrysine). A fourfold symmetry axis is one in which the structure can be rotated by 90° (one-quarter of a circle; 360°) to obtain a structure that is equivalent to the original orientation. (b) Side view, approximately perpendicular to the fourfold symmetry axis. This view shows two left-hand (left-hand screw) intertwined helices produced by the S–Au–S network when S-thiomalate is used as the bridging ligand. Adapted from Bau, R. (1998) Crystal structure of the antiarthritic drug gold thiomalate (myochrysine): a double-helical geometry in the solid state. J. Am. Chem. Soc., 120, 9380–9381 (Figures 1 and 2). Copyright 1998, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 6.4 Hydrolysis of auranofin in aqueous HCl. (a) Nucleophilic attack of chloride ion on Au+ to produce a three-coordinate intermediate. (b) Acid-catalyzed cleavage of the gold thiolate bond.

Figure 6.5 Structures of cysteine and histidine in a peptide chain.

Figure 6.6 600 MHz ¹H NMR spectrum of the region of Hϵ1of His3 of human serum albumin (n and n′) in human blood plasma at pH 7.4. (a) Normal plasma in D2O. (b) Plasma plus 0.4 mol equivalents (with respect to albumin) of the oral anti-arthritic drug, auranofin. ‘Free His’ is the free amino acid histidine in plasma. Adapted from Christodoulou, J., et al. (1995) 1H NMR of albumin in human blood plasma: drug binding and redox reactions at Cys34. FEBS Lett., 376, 1–5 (Figure 3). Copyright 1995, Elsevier. Reproduced with permission of Elsevier.

Figure 6.7 (a) Human serum albumin (HSA) with helices h1–h3 shown in red. (b) Diagram of the His3-Cys34 ‘switch’ of albumin. Binding of Au-PEt3 to Cys34 causes a structural change in the albumin protein that changes the chemical environment of His3 near the N terminus of the protein from n′ (Cys34 buried) to n (Cys34 exposed). Image of HSA (a) created from PDB file 1HA2 using PyMol v.1.8.0.5. Adapted from Christodoulou, J., et al. (1995) 1H NMR of albumin in human blood plasma: drug binding and redox reactions at Cys34. FEBS Lett., 376, 1–5 (Figure 5). Copyright 1995, Elsevier. Reproduced with permission of Elsevier.

Figure 6.8 Binding region of the myochrysine–cathepsin K adduct. The coordination geometry about the Au+ ion is linear (S-Au-S angle = 173.1°), with the thiolate from S-thiomalate and the thiolate from Cys25 of the protein as donor atoms to the gold ion. The carboxylates of the thiomalate are involved in electrostatic interactions with nearby residues on the protein. PDB ID: 2ATO. Adapted from Bhabak, K.P., Bhuyan, B.J., and Mugesh, G. (2011) Bioinorganic and medicinal chemistry: aspects of gold(I)–protein complexes. Dalton Trans., 40, 2099–2111 (Figure 7). Reproduced with permission of Royal Society of Chemistry.

Figure 6.9 Structure of recombinant rat thioredoxin reductase 1 with oxidized C-terminal tail and highlighted selenocysteine (Sec498), PDB ID: 3EAO. Adapted from Bhabak, K.P., Bhuyan, B.J., and Mugesh, G. (2011) Bioinorganic and medicinal chemistry: aspects of gold(I)–protein complexes. Dalton Trans., 40, 2099–2111 (Figure 10). Reproduced with permission of Royal Society of Chemistry.

Figure 6.10 Active site of glutathione reductase with Au+ bound to Cys58 and Cys63 with glycerol, phosphate, and K+ as products of crystallization. Adapted from Urig, S., Fritz-Wolf, K., Réau, R., et al. (2006) Undressing of phosphine gold(I) complexes as irreversible inhibitors of human disulfide reductases. Angew. Chem. Int. Ed., 45, 1881–1886 (Figure 3). Reproduced with permission of John Wiley & Sons.

Figure 6.11 Circular dichroism (CD) spectra of a titration of the zinc finger peptide Zn-Sp1-3 with myochrysine, showing displacement of the Zn²+ ion by Au+. The arrows indicate the direction of the shift in the CD spectrum as the concentration of myochrysine was increased. The inset shows a model of the Au+-Sp1-3 complex. Adapted from Larabee, J.L., et al. (2005) Mechanisms of Aurothiomalate-Cys2His2 Zinc Finger Interactions. Chem. Res. Toxicol., 18, 1943–1954 (Figure 8D and TOC graphic). Copyright 2005, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 6.12 Sequences of the three zinc finger model peptides CCHH, CCCC, and CCHC, along with a schematic that indicates the secondary structure in the canonical zinc fingers. Adapted from Franzman, M.A. and Barrios, A.M. (2008) Spectroscopic evidence for the formation of goldfingers. Inorg. Chem., 47, 3928–3230 (Scheme 1). Copyright 2008, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 6.13 Titrations of zinc finger peptides with [AuCl(PEt3)] monitored by UV–visible absorption spectroscopy. The insets show increases in A310 as a function of added [AuCl(PEt3)] with the stoichiometry as a red line. Adapted from Franzman, M.A. and Barrios, A.M. (2008) Spectroscopic evidence for the formation of goldfingers. Inorg. Chem., 47, 3928–3230 (Figure 1). Copyright 2008, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 6.14 Cartoon showing six of the nine zinc fingers of the transcription factor TFIIIA bound to a 31-base-pair segment of DNA. Each finger consists of a Zn²+ ion (gray sphere), about which are arranged an α-helix, with two-coordinated histidines and a β-sheet with two-coordinated cysteines. The 3′ and 5′ ends of the two strands of the DNA double helix and the N and C termini of the protein are also indicated. Image created from PDB file 1TF6 using PyMol v.1.8.0.5.

Figure 6.15 Structure of finger 6 of TFIIIA. The Zn²+ ion is in a tetrahedral environment coordinated by N-1 of the imidazole residues of two histidines and the thiolate ions of two cysteine residues to produce a Cys2His2-type coordination environment. For this finger of TFIIIA there is a stacking interaction between one of the histidine donors and a phenylalanine residue (F173) which, in addition to the coordinated Zn²+ ion, stabilizes the finger. The α-helix and β-sheet structures and other amino acid residues are also indicated. Adapted from Lu, D. and Klug, A. (2007) Invariance of the Zinc Finger Model: A Comparison of the Free Structure with Those in Nucleic-Acid Complexes. Proteins: Structure, Function and Bioinformatics, 67, 508–512 (Figure 3). Reproduced with permission of John Wiley & Sons.

Figure 6.16 Structures of some vanadium complexes with insulin-mimetic properties. Since the vanadate and vanadyl complexes are subject to association, change in coordination number and protonation, the mononuclear forms that would be present in dilute solution are shown.

Figure 6.17 Concentration of glucose in plasma of STZ-diabetic rats 20 hours after feeding the rats with a single dose of either BMOV or BEOV. Adapted from Thompson, K.H., et al. (2003) Preparation and characterization of vanadyl complexes with bidentate maltol-type ligands; in vivo comparison of anti-diabetic therapeutic potential. J. Biol. Inorg. Chem., 8, 66–74 (Figure 2). Copyright 2003, Springer. Reproduced with permission of Springer.

Figure 6.18 Species distribution plot of bis(maltolato)oxovanadium(IV), BMOV. Adapted from Kiss, T., Jakusch, T., Hollender, D., et al. (2008) Biospeciation of antidiabetic VO(IV) complexes. Coord. Chem. Rev., 252, 1153–1162 (Figure 2). Reproduced with permission of Elsevier.

Figure 6.19 Cartoon of human transferrin (hTf) having only the C-terminal site occupied by Fe³+. The protein donor ligands that are common to both binding sites are also shown. Image created from PDB file 4X1B using PyMol v.1.8.0.5.

Figure 6.20 Fasting plasma glucose following 28 days' oral administration of bis(ethylmaltolato)oxovanadium(IV), BEOV (20 mg per day) to seven type 2 diabetic human subjects, compared to two type 2 diabetic individuals receiving a placebo. Adapted from Thompson, K.H., et al. (2009 Vanadium treatment of type 2 diabetes: a view to the future. J. Inorg. Biochem., 103, 554–558 (Figure 4). Copyright 2009, Elsevier. Reproduced with permission of Elsevier.

Figure 6.21 Energy states for an electron in an applied magnetic field, H.

Figure 6.22 EPR absorption curve (a) and the first derivative of the absorption curve (b) at 3350 G (0.3350 T), ν = 9388.2 MHz.

Figure 6.23 EPR spectrum of a complex containing vanadyl, VO²+.

Figure 6.24In-vivo blood-circulation monitoring using electron spin resonance (ESR). (a) Schematic representation of the experimental set-up involving the live Wistar rat and the ESR spectrometer. (b) ESR spectra of a vanadyl VO²+ species in blood as a function of time after injecting the rat with a solution containing the insulin-mimetic VO(pic)2, VPA. (c) Plot of the concentration of the vanadyl species, Cb, as a function of time in the blood of the rat. Adapted from Yasui, H., et al. (2000) Metallokinetic analysis of disposition of vanadyl complexes as insulin-mimetics in rats using the BCM-ESR method. J. Inorg. Biochem., 78, 185–196 (Figures 2, 5, and 6). Copyright 2000, Elsevier. Reproduced with permission of Elsevier.

Chapter 7

Figure 7.1 Drugs used to treat malaria.

Figure 7.2 Cartoon showing the uptake of hemoglobin by Plasmodium falciparum and its degradation inside the digestive vacuole of the parasite. The uptake and sites of action of the antimalarial drug chloroquine (CQ) are also shown. Adapted from Salas, P.F., Herrmann, C., and Orvig, C. (2013) Metalloantimalarials. Chem. Rev., 113, 3450–3492. Copyright 2013, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 7.3 Structures of iron-protoporphyrin IX complexes involved in hemozoin formation.

Figure 7.4 The hemozoin crystal is composed of a series of sheets represented by blue, gold, and pink. A view down one of the axes of the hemozoin crystal is shown. Adapted from Klonis, N., Dilanian, R., Hanssen, E., et al. (2010) Hematin-hematin self-association states involved in the formation and reactivity of the malaria parasite pigment, hemozoin. Biochemistry, 49, 6804–6811. Copyright 2010, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 7.5 (a) Kinetic profiles for the percentage conversion of hemin to hemozoin for different cosolvents. (b) Effect of added lipid (DOPE) on the kinetics of hemozoin formation. Adapted from Pasternack, R.F., Munda, B., Bickford, A., et al. (2010) On the kinetics of formation of hemozoin, the malaria pigment. J. Inorg. Biochem., 104, 1119–1124. Copyright 2010, Elsevier. Reproduced with permission of Elsevier.

Figure 7.6 Structures of metal complexes with antimalarial activity.

Figure 7.7 Antimony drugs used to treat leishmaniasis.

Figure 7.8 The antimony (Sb³+) binding site in the catalytic cleft of reduced trypanothione reductase (TR). The reduced form of trypanothione, T(SH)2, is modeled into the catalytic cleft. Adapted from Baiocco, P., Colotti, G., Franceschini, S., et al. (2009) Molecular basis of antimony treatment in leishmaniasis. J. Med. Chem., 52, 2603–2612. Copyright 2009, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 7.9 Structures of some agents with antileishmaniasis activity.

Figure 7.10 Actively used drugs and drug candidates for treating American trypanosomiasis (Chagas disease).

Figure 7.11 Atomic force micrographs of closed-circular pBR322 DNA reacted with two Ru-arene complexes with trypanocidal activity. Adapted from Demoro, B., Rossi, M., Caruso, F., et al. (2013) Potential mechanism of the anti-trypanosomal activity of organoruthenium complexes with bioactive thiosemicarbazones. Biol. Trace Elem. Res., 153, 371–381. Copyright 2013, Springer. Reproduced with permission of Springer.

Figure 7.12 Diagram showing the organization of organelles in eukaryotic and bacterial cells. Source: Science Primer (National Center for Biotechnology Information). Vectorized by Mortadelo 2005.

Figure 7.13 Structures of isoniazid and some metal complexes with antituberculosis activity.

Figure 7.14 Activation path of the prodrug isoniazid and its pentacyanoferrous complex, Na3[Fe(CN)5(INH)], in M. tuberculosis.

Figure 7.15Helicobacter pylori crossing the mucus layer in the stomach. Source: Zina Deretsky, National Science Foundation.

Figure 7.16 Cluster building in bismuth subsalicylate (BSS; Pepto-Bismol®). Adapted from Andrews, P.C., Deacon, G.B., Forsyth, C.M., et al. (2006) Towards a structural understanding of the anti-ulcer and anti-gastritis drug bismuth subsalicylate. Angew. Chem. Int. Ed., 45, 5638–5642. Reproduced with permission of John Wiley & Sons.

Figure 7.17 Nonprescription bismuth containing anti-ulcer drugs and new agents in development.

Figure 7.18 Old and new antibacterial agents.

Figure 7.19 Proposed structure of the G-Ag+-G DNA crosslink. Source: Swasey, S.M., Espinosa-Leal, L., Lopez-Acevedo, O., et al. (2015) Silver (I) DNA glue: Ag+-mediated guanine pairing revealed by removing Watson–Crick constraints. Sci. Rep., 5:10163. doi: 10.1038/srep10163. http://europepmc.org/articles/pmc4431418. Used under CC-BY 4.0 https://creativecommons.org/licenses/by/4.0/.

Figure 7.20 Structures of ligands which, when complexed with Zn²+, produce compounds with anti-HIV activity.

Figure 7.21 Serpentine (in the plane of the membrane) and helical wheel diagram (viewed perpendicular to the plane of the membrane from the extracellular side) of the CXCR4 receptor. Shown are the locations of Asp171 (yellow circle) and Asp262 (blue circle), which are important binding sites for AMD3100 and its metal complexes (indicated by connected red rectangles). Adapted from Gerlach, L.O., et al. (2003) Metal ion-enhanced binding of AMD3100 to Asp262 in the CXCR4 receptor. Biochemistry, 42, 710–717. Copyright 2003, American Chemical Society. Reproduced with permission of American Chemical Society.

Figure 7.22 (a) Barrel-shaped Wells–Dawson polyoxometalate (POM), [P2W18O62]⁶−, where green = W⁶+, violet = P⁵+, and red = O−2. Adapted from Pu, F. Wang, E., Jiang, H., et al. (2013) Identification of polyoxometalates as inhibitors of basic fibroblast growth factor. Mol. BioSys., 9, 113–120, with permission of The Royal Society of Chemistry. (b) Ribbon diagram of the homodimeric HIV-1 Protease (HIV-1P) with the two monomers of the dimer indicated by purple and gold. The locations of the active site, the catalytic amino acids (ball and stick) and the cationic lysine-rich hinge regions of the monomers of HIV-1P (indicated with +) are also shown. HIV-1P, Creative Commons Attribution-Share Alike 4.0 International license.

Chapter 8

Figure 8.1 Schematic representations of the amyloid cascade hypothesis, the metal ion hypothesis, and the metal-Aβ-mediated oxidative stress hypothesis. The amino acid sequences of Aβ40/Aβ42 are shown: metal-binding residues (purple); hydrophilic and hydrophobic residues (blue and gray, respectively); and self-recognition sequence (underlined). Adapted from Savelieff, M.G., DeToma, A.S., Derrick, J.S., et al. (2014) The ongoing search for small molecules to study metal-associated amyloid-Aβ species in Alzheimer's disease. Acc. Chem. Res., 47, 2475–2482. Reproduced with permission of American Chemical Society.

Figure 8.2 Structural model for a pentamer in fibrils formed with Aβ42 indicating two β-sheets (ribbons), residues L17–S26 (β1) and I31–A42 (β2), the disordered region, D1-K16, the location of the salt bridge between D23 (–) and K28 (+) on adjacent monomers and the location of the fibril axis. Image created from the PDB file 2BEG using PyMol v.1.8.0.5

Figure 8.3 Proposed structures of the components of Cu²+–Aβ16 present in solution at physiological pH.

Figure 8.4 Structures of some chelating agents being investigated for the treatment of Alzheimer's disease.

Figure 8.5 Structures of the Cu²+ and Zn²+ complexes of clioquinol (CQ).

Figure 8.6 Chelating agents for treating Wilson disease.

Figure 8.7 Structure of [TTM][(Cu)(Cu-Atx1)3]. Color coding in the structure is: turquoise (Mo), bronze (Cu), gold (S), green (C). Shown are the Cys (C) residues of three Atx1 proteins bound to Cu+ ions. Image created from the PDB file 3K7R using PyMol v.1.8.0.5.

Figure 8.8 Proposed structures of Cu²+–His complexes at near-neutral pH. The main complex present (at pH 7.4) is [Cu(His)2], with a smaller amount of [Cu(His)2(H2O)].

Figure 8.9 Structures of ligands for treating iron overload.

Figure 8.10 Structure of fac-Δ-ferrioxamine B. The color coding in the structure is: silver (C), blue (N), red (O) and green (Fe). Adapted from Zheng, T. and Nolan, E.M. (2012) Siderophore-based detection of Fe(III) and microbial pathogens. Metallomics, 2, 866–880. Reproduced with permission of Royal Society of Chemistry.

Figure 8.11 Structure of ranelic acid, the di-strontium salt of which is the anti-osteoporotic drug, strontium ranelate (Protelos®).

Figure 8.12 Structures of some chelating agents used in chelation therapy.

Chapter 9

Figure 9.1 Decay scheme for ⁹⁹Mo, showing the nature and energy of the radiation released and the first-order decay half-life, t1/2.

Figure 9.2 General procedure for preparing an imaging drug containing ⁹⁹mTc. While the apparatus used in a hospital setting for isolating ⁹⁹mTcO4−, pertechnetate, called a Tc 99m generator, is compact and different than the conventional ‘gravity’ column shown, the figure provides basic information for how ⁹⁹mTcO4− is isolated and used to make a ⁹⁹mTc imaging drug. (a) An alumina column (Al2O3) with adsorbed ⁹⁹MoO4²−, ⁹⁹mTcO4− and ⁹⁹TcO4− at the top of the column; (b) the pertechnetate ions, ⁹⁹mTcO4− and ⁹⁹TcO4−, are separated from the permolybdate ion, ⁹⁹MoO4²−, by eluting with normal saline solution (150 mM NaCl); (c) both ⁹⁹mTcO4− and ⁹⁹TcO4− are reduced using SnCl2 (stannous chloride), and the reduced technetium species are reacted with the ligands to form an imaging drug; (d) a solution containing the ⁹⁹mTc imaging agent is administered to the patient.

Figure 9.3 A gamma camera is used to carry out single-photon emission computed tomography (SPECT) on a patient who has received a ⁹⁹mTc imaging drug.

Figure 9.4 Structures of commonly-used ⁹⁹mTc imaging drugs. The brain and kidney imaging agents exist as mirror-image isomers; that is, enantiomers.

Figure 9.5 SPECT images using ⁹⁹mTc-MDP of the mandible (lower jaw) and cranium of a patient having secondary hyperparathyroidism (SHPT). (a–c) Anterior (front) and (d–f) posterior (back) views. (a, d) Control group; (b, e) patient with SHPT with a concentration of parathyroid hormone (PTHi) in the blood of ≤1000 pg ml−1; (c, f) patient with SHPT with PTH >1000 pg ml−1. Adapted from Boasquevisque, E., et al. (2008) ⁹⁹mTc-MDP bone uptake in secondary hyperparathyroidism: comparison of the mandible, cranium, radius, and femur. Oral Radiol., 24, 55–58 (Figure 1). Reproduced with permission of Springer.

Figure 9.6 Three SPECT images using the ⁹⁹mTc imaging agent Ceretec of normal elderly patients and those with early Alzheimer's disease (AD). The images shown are the differences between the regional cerebral blood flow (rCBF) detected by Ceretec during a memory provocation minus rCBF at rest. Patients with early AD have reduced blood to the brain. Three views of the brain are shown. Adapted from Sundström, T., Elgh, E., Larsson, A., Näsman, B., Nyberg, L., and Riklund, K.Å. (2006) Memory-provoked rCBF-SPECT as a diagnostic tool in Alzheimer's disease? Eur. J. Nucl. Mol. Imag., 33, 73–80 (Figure 1). Copyright 2006, Springer. Reproduced with permission of Springer.

Figure 9.7 Three SPECT images of the kidneys of a patient, using the imaging agent Tc-MAG3. (a) Image of kidneys before administration of the drug candidate, seliciclib. (b) Image three days after administration. (c) Image 14 days after administration. The imaging agent shows that the renal function of the right kidney (R) is poorer than that of the left kidney, and that drug-induced impairment of renal function [lighter shades of gray on panel (b)] is recovered in 14 days. Adapted from Benson, C., et al. (2007) A Phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br. J. Cancer, 96, 29–37. Copyright 2007, Nature Publishing Group. Reproduced with permission of Nature Publishing Group.

Figure 9.8 Schematic of a ⁹⁹mTc compound with an appended molecule for targeting specific sites in the body.

Figure 9.9 Structure of Tc-99m-depreotide, showing the receptor-binding group, the linker and the syn and anti diastereomers associated with the metal-binding region. The syn and anti isomers refer to the relative dispositions of the oxo ligand on Tc (yellow highlight) and the ϵ-amino side chain of Lys (green) on the peptide.

Figure 9.10 Whole-body SPECT image of a 70-year-old male patient with squamous cell carcinoma in the right lung, imaged using Tc-99m-depreotide. That the primary tumor in the lung has spread to bone is evident from the intense image of the left sacro-iliac, double-headed arrow. Adapted from Mena, E., Camacho, V., Estorch, M., Fuertes, J., Flotats, A., and Carrió, I. (2004) ⁹⁹mTc-Depreotide scintigraphy of bone lesions in patients with lung cancer. Eur. J. Nucl. Med. Mol. Imaging, 31, 1399–1404 (Figure 4). Copyright 2004, Springer. Reproduced with permission of Springer.

Figure 9.11 (a) Synthesis of fac-[Tc(H2O)3(CO)3]+. (b) Synthesis of an imaging agent with the [Tc(CO)3]+ core attached via a linker to the fMLF peptide capable of recognizing the formyl peptide receptor (FPR) on white blood cells (neutrophils).

Figure 9.12 Diagram of the PET acquisition process. Creative Commons Attribution-ShareAlike License, Jens Maus (author).

Figure 9.13 A proton with a nuclear spin quantum number, I = ¹/2, indicating the presence of one unpaired nuclear spin. The spinning proton generates a magnetic moment which has two possible orientations in an applied magnetic field, which are described by the nuclear spin angular momentum quantum number mI. The splitting between the mI = +1/2 and mI = −1/2 states in the presence of the magnetic field, ΔE, is proportional to the strength of the applied magnetic field, Ho

Figure 9.14 Schematic diagram of a patient in a magnetic resonance imaging (MRI) instrument. The main magnetic field is created by an electromagnet, and the field within volume elements in the tissue of the patient is modified by gradient electromagnets. After analysis using a computer program, a 3D ‘image’ of the relaxation lifetimes of water molecules in the tissue of the patient is obtained.

Figure 9.15 Some clinically used MRI contrast agents.

Figure 9.16 Coordination geometries of Gd³+ MRI contrast agents. Depending on the structure of the octadentate ligand, which contributes eight donor groups to Gd³+, denoted by X, and the location of the water molecule, each geometry can exist in a