Metal chelation in medicine

335 Pages·2017·10.704 MB·English

by  Crichton, Robert R., Hider, Robert C., Ward, Roberta J

Metal Chelation in Medicine
1
0
0
P
F
2-
9
8
3
2
6
2
8
7
1
8
7
9
9/
3
0
1
0.
1
oi:
d
g |
or
c.
s
s.r
b
u
p
p://
htt
n
o
6
1
0
2
er
b
o
ct
O
8
1
n
o
d
e
h
s
bli
u
P
View Online
RSC Metallobiology Series
Editor-in-Chief:
Professor C. David Garner, University of Nottingham, UK
1
0
0
FP Series Editors:
2-
9 Professor Hongzhe Sun, University of Hong Kong, China
8
3
2 Professor Anthony Wedd, University of Melbourne, Australia
6
2
8 Professor Stefano L. Ciurli, University of Bologna, Italy
7
1
8
7
9
9/ Editorial Advisor:
3
0
1 Professor Alison Butler, University of California Santa Barbara, USA
0.
1
oi:
g | d Titles in the Series:
or 1: Mechanisms and Metal Involvement in Neurodegenerative Diseases
c.
s.rs 2: Binding, Transport and Storage of Metal Ions in Biological Cells
ub 3: 2-Oxoglutarate-Dependent Oxygenases
p
p:// 4: Heme Peroxidases
htt 5: Molybdenum and Tungsten Enzymes: Biochemistry
n
o 6: Molybdenum and Tungsten Enzymes: Bioinorganic Chemistry
6
01 7: Molybdenum and Tungsten Enzymes: Spectroscopic and Theoretical
2
er Investigations
b
cto 8: Metal Chelation in Medicine
O
8
1
n
o
d
e
h
s
bli
u
P
How to obtain future titles on publication:
A standing order plan is available for this series. A standing order will bring
delivery of each new volume immediately on publication.
For further information please contact:
Book Sales Department, Royal Society of Chemistry, Thomas Graham House,
Science Park, Milton Road, Cambridge, CB4 0WF, UK
Telephone: [phone], Fax: [phone],
Email: [email protected]
Visit our website at www.rsc.org/books
View Online
Metal Chelation in Medicine
1
0
0
P
F
2- Edited by
9
8
3
2
26 Robert Crichton
8
7
1 Universite Catholique de Louvain, Louvain-la-Neuve, Belgium
8
7
9 Email: [email protected]
9/
3
0
1
0. Roberta J. Ward
1
oi: Universite Catholique de Louvain, Louvain-la-Neuve, Belgium
d
g | Email: [email protected]
or
c.
s
s.r and
b
u
p
http:// Robert C. Hider
n King's College London, London, UK
o
16 Email: [email protected]
0
2
er
b
o
ct
O
8
1
n
o
d
e
h
s
bli
u
P
View Online
1
0
0
P
F
2-
9
8
3
2
6
2
8
7
1
8
7
9
9/
3
0
1
0.
1
oi: RSC Metallobiology Series No. 8
d
g |
or Print ISBN: 978-1-78262-064-8
sc. PDF eISBN: 978-1-78262-389-2
bs.r EPUB eISBN: 978-1-78262-921-4
u
p://p ISSN: 2045-547X
n htt A catalogue record for this book is available from the British Library
o
6
01 © The Royal Society of Chemistry 2017
2
er
ob All rights reserved
ct
O
18 Apart from fair dealing for the purposes of research for non-commercial purposes or for
on private study, criticism or review, as permitted under the Copyright, Designs and Patents
d
e Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may
h
blis not be reproduced, stored or transmitted, in any form or by any means, without the prior
Pu permission in writing of The Royal Society of Chemistry or the copyright owner, or in
the case of reproduction in accordance with the terms of licences issued by the Copyright
Licensing Agency in the UK, or in accordance with the terms of the licences issued by the
appropriate Reproduction Rights Organization outside the UK. Enquiries concerning
reproduction outside the terms stated here should be sent to The Royal Society of
Chemistry at the address printed on this page.
The RSC is not responsible for individual opinions expressed in this work.
The authors have sought to locate owners of all reproduced material not in their
own possession and trust that no copyrights have been inadvertently infringed.
Published by The Royal Society of Chemistry,
Thomas Graham House, Science Park, Milton Road,
Cambridge CB4 0WF, UK
Registered Charity Number 207890
For further information see our web site at www.rsc.org
Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK
5
0
0
P
F
2-
9 Preface
8
3
2
6
2
8
7
1
8
7
9
9/
3
0
1
10. The importance of metals in biology and medicine has grown exponentially
oi: since the emergence, in the early 1980s, of the scientific discipline once
d
g | known as Inorganic Biochemistry or Bioinorganic Chemistry, which is now
or
c. designated as Biological Inorganic Chemistry (BIC). Since the first Interna-
s
s.r tional BIC Conference (ICBIC) in Florence in 1983, the role of metals in med-
b
u
p icine has never been far from the programme. However, metals, even when
http:// they are essential, can be toxic, as can a number of non-essential metals,
n often referred to as ‘heavy metals’. As Paracelsus pointed out in the 1500 s,
o
6 anything can be toxic, only dependent on the dose and, while in the case
1
0
2 of essential metals toxicity is associated with excessive accumulation of the
er
b metal ion, often in specific organs, tissues or cell types, non-essential metal
o
Oct ions become toxic when a particular threshold concentration of the metal
8
1 ion is exceeded.
n
d o As we point out in this latest contribution to the RSC Metallobiology series,
e
h in very many clinical situations, the only realistic and appropriate therapeu-
s
bli tic option is to administer a specific metal chelator which can remove the
u
P
metal excess. For essential metals, the aim is to restore the perturbed metal
ion homeostasis, whereas for non-essential metal ions the objective is to
remove the ‘xenometal’ (my apologies for this literary extravaganza).
We begin with an introductory chapter on metal toxicity, by both essential
and non-essential metal ions, which is followed by a chapter reviewing the
principles involved in the design of metal chelates. The removal of heavy
metals by chelation therapy is then reviewed, followed by chapters on the
use of iron chelators in the treatment of transfusional iron overload and their
potential in the treatment of neurodegenerative diseases where iron load-
ing in specific brain regions involved in the particular disease highlights the
need to target iron chelation to specific locations. Then, the development of
RSC Metallobiology Series No. 8
Metal Chelation in Medicine
Edited by Robert Crichton, Roberta J. Ward and Robert C. Hider
© The Royal Society of Chemistry 2017
Published by the Royal Society of Chemistry, www.rsc.org
v
View Online
vi Preface
octadentate chelators for selective complexation of actinides, which would be
absolutely essential in the unthinkable scenario of the terrorist use of a ‘dirty
bomb’, is cogently reviewed (representing a totally different level of chelation
therapy). The concluding chapters detail the non-invasive techniques which
5 are being increasingly developed for the evaluation of iron overload and their
0
P0 use in diagnostic imaging.
F
2- We hope that this volume will help in the search for appropriate therapeu-
9
38 tic measures to deal with the complex problems of metal toxicity.
2
6
2
8 Robert R. Crichton, Roberta J. Ward and Robert C. Hider
7
1
8
7
9
9/
3
0
1
0.
1
oi:
d
g |
or
c.
s
s.r
b
u
p
p://
htt
n
o
6
1
0
2
er
b
o
ct
O
8
1
n
o
d
e
h
s
bli
u
P
7
0
0
P
F
2-
9 Contents
8
3
2
6
2
8
7
1
8
7
9
9/
03 Chapter 1 Metal Toxicity – An Introduction 1
1
0. Robert R. Crichton
1
oi:
d
g | 1.1 Introduction 1
or
c. 1.2 Essential Metals 2
s
s.r 1.2.1 Sodium and Potassium 2
b
u
p 1.2.2 Magnesium and Calcium 2
http:// 1.2.3 Zinc 3
n 1.2.4 Other Essential Metals 3
o
6 1.3 Toxicity Due to Essential Metals 4
1
0
2 1.3.1 Sodium and Potassium 4
er
b 1.3.2 Calcium and Magnesium 7
o
Oct 1.3.3 Zinc 8
18 1.3.4 Other Essential Metals 9
n
o 1.4 Non-Essential Metals 12
d
he 1.5 Toxicity Due to Non-Essential Metals 13
s
bli 1.5.1 Lead 13
u
P
1.5.2 Cadmium 14
1.5.3 Mercury 15
1.5.4 Aluminium 15
1.6 Sources and Routes of Exposure with Particular
Reference to Non-Essential Metals 18
1.7 Conclusions 19
Abbreviations 20
References 20
RSC Metallobiology Series No. 8
Metal Chelation in Medicine
Edited by Robert Crichton, Roberta J. Ward and Robert C. Hider
© The Royal Society of Chemistry 2017
Published by the Royal Society of Chemistry, www.rsc.org
vii
View Online
viii Contents
Chapter 2 Basic Principles of Metal Chelation and Chelator Design 24
Robert C. Hider and Yongmin Ma
2.1 Introduction 24
7 2.2 Ligand Chemistry 26
0
P0 2.3 Ligand Selectivity 29
F
2- 2.4 Comparison of Bidentate Ligands 31
9
38 2.4.1 Catechols 31
2
26 2.4.2 Hydroxamates 33
8
17 2.4.3 Hydroxypyridinones 33
8
97 2.4.4 Hydroxypyranones 35
9/
3 2.4.5 Aliphatic Diamines 35
0
1
0. 2.4.6 Heterocyclic Amines 35
1
oi: 2.4.7 Hydroxyquinolines 36
d
g | 2.4.8 Aminocarboxylates (Including Oligodentate
c.or Ligands) 36
s
s.r 2.4.9 Hydroxycarboxylates (Including Tri- and
b
pu Hexadentate Ligands) 37
p:// 2.5 Ligand Denticity – The Chelate Effect 37
n htt 2.6 Complex Lability 39
o
6 2.7 Redox Activity 41
1
20 2.8 Biological Properties 43
ber 2.9 Lipophilicity and Molecular Weight 43
o
ct 2.10 Ligand Metabolism 44
O
8 2.11 Ligand Binding to Serum Albumin 45
1
on 2.12 Chelator Pharmacokinetics 47
d
e 2.13 Toxicity of Chelators 49
h
s
bli 2.13.1 Inhibition of Metal-Dependent
u
P Enzymes 49
2.13.2 Nephrotoxicity 51
2.13.3 Neurotoxicity 51
2.13.4 Immunotoxicity 51
2.13.5 Genotoxicity 52
2.14 Chelators and Nutrition 52
2.15 Conclusions 53
Abbreviations 53
References 53
Chapter 3 Chelation Therapy For Heavy Metals 56
Peter Nielsen
3.1 Introduction 56
3.2 G eneral Strategies Against Heavy Metal
Intoxication 58
3.2.1 Toxicology of Heavy Metals 58
3.2.2 Treatment for Heavy Metal Intoxication 59
3.2.3 Drawbacks and Misuse of Chelators 62
View Online
Contents ix
3.3 Arsenic 63
3.3.1 Absorption and Metabolism of Arsenicals 63
3.3.2 Toxicity of Arsenicals 64
3.3.3 Diagnostic Measures and Interventional
7 Levels 66
0
P0 3.3.4 Chelation Therapy for Arsenic Intoxication 66
F
2- 3.4 Mercury 68
9
38 3.4.1 Absorption and Metabolism of Mercurials 70
2
26 3.4.2 Toxicology of Mercury 73
8
17 3.4.3 Diagnostics and Intervention Levels 75
8
97 3.4.4 Chelation Treatment for Mercury Poisoning 76
9/
3 3.5 Lead 78
0
1
0. 3.5.1 Lead Absorption and Metabolism 78
1
oi: 3.5.2 Toxicity of Lead 80
d
g | 3.5.3 Diagnostic Measures and Intervention Levels 82
c.or 3.5.4 Treatment of Lead Poisoning 82
s
s.r 3.6 Cadmium 85
b
pu 3.6.1 Absorption and Metabolism of Cadmium 86
p:// 3.6.2 Toxicity of Cadmium 87
n htt 3.6.3 Diagnostic Markers and Intervention Level
o
6 for Cd Intoxication 90
1
20 3.6.4 Chelation Treatment for Cadmium Poisoning 90
ber 3.7 Noble Metals 92
o
ct 3.7.1 Silver Poisoning 92
O
8 3.7.2 Gold Poisoning 93
1
on 3.8 Other Metals 94
d
e 3.8.1 Acute Iron Poisoning 94
h
s
bli 3.8.2 Acute Copper Poisoning 95
u
P 3.8.3 Thallium Poisoning 95
3.9 Conclusion 96
Abbreviations 97
References 98
Chapter 4 Treatment of Systemic Iron Overload 106
John Porter
4.1 Consequences of Transfusional Iron Overload 106
4.1.1 Iron Homeostasis in the Absence of Blood
Transfusion 106
4.1.2 Effects of Inherited Anaemias and Blood
Transfusion on Iron Homeostasis 107
4.2 Impact of Transfusion on Iron Distribution and its
Consequences 109
4.3 Desirable Features of Clinically Useful Iron
Chelators 113
4.3.1 High Iron Binding Constant and Selectivity
for Iron 113
View Online
x Contents
4.3.2 Chelation of Iron Pools for Balance Without
Inhibition of Key Metabolic Pools 114
4.4 Monitoring Iron Overload and Its Treatment 117
4.4.1 Monitoring Trajectory of Iron Overload and
7 Distribution 117
0
P0 4.5 Properties and Clinical Beneficial Effects of
F
2- Available Iron Chelators 124
9
38 4.5.1 Desferrioxamine (Desferal) DFO 124
2
26 4.5.2 Deferiprone (DFP) 127
8
17 4.5.3 Deferasirox (Exjade®) DFX 130
8
97 4.6 Unwanted Effects of Iron Chelators 132
9/
3 4.6.1 Role of Iron Deprivation in Chelator Toxicity 132
0
1
0. 4.6.2 Desferrioxamine Tolerability and
1
oi: Unwanted Effects 133
d
g | 4.6.3 Deferiprone Tolerability and Unwanted
c.or Effects 134
s
s.r 4.6.4 Deferasirox Tolerability and Unwanted
b
pu Effects 134
p:// 4.7 Practical Use of Chelators: A Personal Approach 135
n htt 4.7.1 Patients with Acceptable Levels of Body Iron
o
6 but Continuing Transfusion 135
1
20 4.7.2 Patients with Unacceptably High Levels of
ber Body Iron 136
o
ct 4.7.3 Patients with Unacceptably High Levels of
O
8 Myocardial Iron 136
1
on 4.7.4 Patients in Heart Failure 137
d
e 4.7.5 Patients with Rapidly Falling Serum Ferritin
h
s
bli or Low Values <1000 µL−1 138
u
P 4.7.6 Patients not Responding to Monotherapy
Regimes: Combined Chelators 139
4.7.7 Combinations of DFP with DFO 139
4.7.8 Combinations of DFO Plus DFX 140
4.7.9 Combination of DFP Plus DFX 140
4.8 Conclusions 140
Abbreviations 141
References 141
Chapter 5 Treatment of Neurodegenerative Diseases by
Chelators 153
Roberta J. Ward, David T. Dexter and Robert R. Crichton
5.1 Introduction 153
5.2 The Aging Brain 154
5.2.1 Brain Iron Homeostasis and Aging 154
5.2.2 Brain Copper Homeostasis and Aging 156
5.2.3 Brain Zinc Homeostasis and Aging 156
5.3 Inflammation and Aging 157