Overview

NICHOLAS P. FARRELL

Department of Chemistry, Virginia Commonwealth University, 1001 W. Main Street, Richmond, VA 23284, USA

1 Introduction

The field of inorganic chemistry in medicine may usefully be divided into two main categories – drugs which target metal ions in some form, whether free or protein-bound, and secondly, metal-based drugs where the central metal ion is usually the key feature of the mechanism of action. Metal-based drugs are a commercially important sector of the pharmaceutical business. Applications continue to grow and approaches to further clinically useful agents are ever more sophisticated. How to approach this field from a didactic and systematic manner, rather than a simple listing of clinical and potential uses, is a challenge. Nevertheless, it is important to attempt to do so to harness the diversity of inorganic chemistry to systematic developments in medicine.

Any consideration therefore of the uses of inorganic chemistry in medicine must bridge at least two areas – bioinorganic chemistry and medicinal chemistry. Bioinorganic chemistry is best considered as understanding all aspects of the role of metal ions in biology and has been traditionally heavily involved in understanding their processing, incorporation into protein and the nature and function of metalloproteins. In a 'steady-state' environment all essential metals are incorporated in the right place at the right time and the organism functions normally. Alternatively, genetic factors may lead to failure to incorporate and subsequent metabolic disorders may be caused by free metal ions. Advances in our understanding of how cells process metals and the genetic basis of disease is naturally expanding the traditional directions of bioinorganic chemistry toward an appreciation of its medical importance – especially with respect to the role of metalloproteins in human health and disease. Medicinal chemistry requires intimate knowledge of the metabolism and stability, as well as target interactions of the drug. Most mechanistic work is performed in tissue culture or with isolated proteins, DNA and/or RNA. In tissue culture assays to measure the efficacy of a potential drug in inhibiting cell growth, the drug is usually in direct contact with medium throughout the experiment. There is not always a direct extrapolation to the clinically relevant in vivo situation when biodistribution and pharmacokinetics play an increasingly important role in determining drug efficacy. Many compounds with exciting in vitro results have failed to display the same promise in vivo. Nevertheless the mechanistic information of tissue culture experiments is very useful and, aside from target interactions, may also inform on approaches to in vivo efficacy. Finally, medicinal chemistry distinguishes between drugs acting by a pharmacodynamic mechanism and chemotherapeutic drugs. In the former case, the drug action must be rapid and essentially reversible. A patient who submits to an anaesthetic does not expect to be deprived of feeling forever. Further, a graded response is required to balance effects – a drug to reverse a stroke must be aware of the severity of that stroke and concentrations adjusted accordingly. Chemotherapeutic agents on the other hand involve cell killing, an irreversible process.

In this volume we review aspects of the use of inorganic compounds as drugs and chemotherapeutic agents. The status with respect to some known drugs is reviewed as well as introductions to newer drugs of potential clinical significance. We do not intend to be comprehensive but rather present specific case studies for reading. In this introduction we give a broad overview of the area from a didactic point of view. In attempting to do so, four main subdivisions logically present themselves: (i) uses of chelating agents to sequester specific metal ions or metal-loproteins; (ii) inorganic-based drugs acting by a pharmacodynamic mechanism; (iii) inorganic-based chemotherapeutic agents and (iv) inorganic-based imaging agents. The reader is referred to the many comprehensive reviews in both bioinorganic and medicinal chemistry for further reading.

2 Metal Ions in Disease. The Use of Chelating Agents

It is well understood that many metals are essential for the human organism and endogenous concentrations are tabulated in most bioinorganic chemistry textbooks. However, a corollary of this situation is that uncontrolled mobilization may lead to the presence of excess free metal ion, with subsequent health problems. The classic examples are those of iron and copper overload. Wilson's disease is an autosomal disorder of copper accumulation, which untreated is inevitably fatal. Alloyed to this is the prospect of disease occurring through adventitious exposure to toxic doses of either essential elements and non-essential elements such as cadmium, mercury and lead. The treatments for copper and iron overload are well documented and a list of clinically used chelating agents is found in most textbooks – typical examples are shown in Figure 1. Their chemistry and toxicology is also very well documented. A major consideration for the improvement of chelating agents is of course that of metal ion selectivity – few chelating agents can be stated to be specific for simply one metal ion.

Metalloproteins as Drug Targets

A more recent and related question to the specificity of chelating agents is that of metalloprotein targets. It is not surprising that many metalloproteins and metalloenzymes play vital metabolic roles as well as being critical in genetic information transfer. Drug design and discovery relies more and more on the elucidation of the three-dimensional structure of a target by X-ray crystallography or nuclear magnetic resonance methods, followed by modelling and synthesis of potential inhibitors of the protein or enzyme active site. Metalloproteins are being increasingly recognized and examined as drug targets. Ribonucleotide reductase, the diiron enzyme essential for de novo synthesis of deoxyribonucleotides for DNA synthesis has long been recognised as a drug target. The pharmaceutical and chemical properties of chelating thiosemicarbazones and their potential interference with the active site iron moieties has been an extensively studied...