Bioinorganic Chemistry And Its Pharmaceutical Applications

DAVID M.TAYLOR and DAVID R.WILLIAMS

CONTENTS

13.1 INTRODUCTION 510

13.2 THE IMPORTANCE OF TRACE

ELEMENTS IN HUMANS 512

13.3 METAL COORDINATION CHEMISTRY 516

13.3.1 General aspects 516

13.3.2 Metal-ligand specificity 517

13.3.2.1 Complex stability 517

13.3.2.2 The hard and soft acid and base approach (HSAB) 518

13.3.2.3 The HSAB principle in biochemistry and pharmacy 518

13.3.2.4 In vivo complexing and metabolic specificity 520

13.4 PHARMACOLOGICAL AND PHARMACEUTICAL CONSIDERATIONS 521

13.5 METALS AS THE MODUS OPERANDI OF DRUGS 522

13.5.1 Metals as drugs 522

13.5.1.1 Bismuth in the treatment of peptic ulcer 522

13.5.1.2 Metals as anti-cancer agents 523

13.5.1.3 Copper and rheumatoid arthritis 525

13.6 DRUGS WHICH EXERT THEIR EFFECTS VIA METAL COMPLEXATION OR CHELATION 528

13.6.1 Metal chelation in antimicrobial activity 528

13.6.2 Metal ion removal 529

13.6.2.1 Removal of copper in Wilson's disease 529

13.6.2.2 Removal of iron in haematochromatosis 530

13.6.2.3 Treatment of exogenous metal poisoning 531

13.7 METAL-DEPENDENT SIDE EFFECTS OF DRUGS 532

13.7.1 Metal ion sequestration by a metabolite 533

13.7.2 Sequestering drug-non-specific metal ion interactions 534

13.8 TRACE ELEMENT SUPPLEMENTATION 534 13.8.1 Iron, zinc and copper supplementation 535

13.9 CONCLUDING REMARKS 536 FURTHER READING 537

13.1 INTRODUCTION

The human body contains about 50 of the elements in the Periodic Table, about half of these are either essential or beneficial to life, while the remainder are adventitious having been introduced from local dietary or environmental influences. Ten of these essential elements, oxygen, carbon, hydrogen, nitrogen, calcium, phosphorus, sulphur, potassium, sodium and chlorine, are present in amounts ranging from tens of kilogrammes to a few tens of grammes, and these so called bulk elements are contained in the proteins, fats and carbohydrates that are the building blocks for the organs and tissues. The major emphasis of this review will rest on the remaining twenty or so of the essential and beneficial elements which, because they are generally present in very small quantities, are often called trace elements. The total mass of these elements in the human body is less than 50 grammes, yet they must be present in the correct concentrations and forms if the individual is to enjoy a healthy life.

Of the adventitious elements, some can be described as pollutants arising from human activities, especially from the industrial developments of the past two centuries, while the remainder enter the human body simply because they are present naturally in drinking water or in the plant and animal tissues which make up our food. The concentrations of the adventitious elements vary from person to person, depending on their geographical environment and their eating habits.

There are strict criteria which must be fulfilled before a trace element is classified as essential—it must be present in all healthy tissues and it must cause reproducible symptoms of ill-health if it is excluded from the diet. The essential and beneficial trace elements and their locations in the Periodic Table are shown in Figure 13.1, while Table 13.1 lists the amounts of the thirty essential and beneficial elements found in the human body. The selection of these elements from the 80 stable elements in the Periodic Table has been critically dependent upon the composition of the earth's surface.

Life on this planet probably began about five billion (~5x109) years ago from primitive cells which evolved in the ancient oceans utilizing biochemicals synthesised on the surfaces of sand particles on tidal beaches. Such evolution was based on the elements readily available in the ancient sea bed and the primitive oceans and any life forms dependent on less readily available elements would have been bred out many millions of years ago. Thus the composition of the human body broadly resembles the elemental composition of the ancient sea bed and the primitive oceans. These are the lighter elements of the Periodic Table, since, when the planet was formed from a cloud of dust particles, the middleweight and heavier elements were compacted by gravity into the mantle and core of the earth, respectively.

The evolution of life has not been a smooth process. The earliest cells evolved under the highly reducing atmosphere of water vapour, hydrogen sulphide, ammonia and methane that was present at the beginning of terrestrial time. Around two billion years ago the early cell probably contained only about 100 different protein molecules, as

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Figure 13.1 The Periodic Table indicating those elements that are known, or firmly believed, to be essential (bold type) or beneficial (italics) elements.

Table 13.1 The masses of the essential and beneficial elements occurring in a 70 kg reference person (adapted from Taylor and Williams 1995).

Element

Mass

grammes

moles

Hydrogen

7000

3500

Carbon

12600

1050

Nitrogen

2100

75

Oxygen

45500

1425

Phosphorus

700

22.5

Sulphur

175

5.5

Chlorine

105

3.0

Sodium

105

4.6

Potassium

140

3.6

Calcium

1050

26

Lithium

0.0007

0.0001

Boron

0.01

0.0009

Fluorine

0.8

0.02

Magnesium

35

1.4

Silicon

1.4

0.05

Vanadium

0.02

0.0004

Chromium

0.005

0.0001

Manganese

0.02

0.00036

Iron

4.2

0.075

Cobalt

0.0007

0.00001

Nickel

0.01

0.0002

Copper

0.11

0.0016

Zinc

2.3

0.035

Arsenic

0.014

0.0002

Selenium

0.02

0.003

Bromine

0.2

0.0025

Molybdenum

0.005

0.00005

Tin

0.03

0.0002

Iodine

0.013

0.001

Barium

0.016

0.00012

compared to many thousands of proteins found in modern cells; it also contained a range of metal ions, some of which fulfilled structural or osmotic roles while others acted as catalysts. Magnesium would have been particularly good in this latter role, since it is known to catalyse condensation reactions and to have been present in high concentrations in the primeval oceans.

The heaviest metals used in evolution are those from the first transition series of the Periodic Table, and such metals as manganese, iron, cobalt and copper all existed in their lower oxidation states in primitive cells. Then, relatively suddenly, perhaps about 1.8 billion years ago, blue-green algae in the oceans began to produce oxygen in sufficient quantities to slowly convert the Earth's reducing atmosphere into the present oxygen-containing one. This had the effect of raising the oxidation states of the aforementioned transition metals and of releasing the previously insoluble cuprous ores into the biosphere as the more soluble cupric salts. At the same time iron and manganese were immobilised as their higher oxidation states, Fe3O4, FeOOH, Mn3O4 and MnO2.

The atmospheric ozone content also began to rise, reaching ~1%, which was sufficient to screen out the harmful effects of the sun's ultraviolet radiation which was apparently more destructive to aerobic rather than to anaerobic systems. As a result of these dramatic environmental changes, organisms that had evolved using ferrous ions as oxygen carriers became vulnerable to oxidation and probably died out. However, biochemical systems involving cupric complexes and oxygen were now possible. Thus, because of the chequered history of the four metals, iron, manganese, cobalt and copper, in their different oxidation states—some being originally rejected by nature and only relatively recently incorporated into essential biochemical mechanisms—it is to be expected that in complex multicellular species, such as Homo Sapiens, serious disturbances in biochemical reactions may arise from changes in metal balances and from challenges to optimal concentrations of such metals caused by environmental factors or by pharmacological intervention.

13.2 THE IMPORTANCE OF TRACE ELEMENTS IN HUMANS

Homo Sapiens is a complex multicellular species that depends for its health upon the correct functioning of ~1015 cells of many different, yet interdependent, types. Thus, the maintenance of good health will also depend on the supply of all 30 essential or beneficial elements in adequate, but not excessive, quantity and in a chemical form that is utilisable within the body.

The principle of biphasic response, Figure 13.2, reminds us that while an insufficiency of an element may lead to ill health by preventing the optimal function of some biochemical process, an excess may cause serious, even life-threatening toxic reactions. Trace element insufficiency or imbalances of elemental intake arise either because there has been some imbalance lower down in the food chain from soil to plant to animal to man, or because the element has been ingested in a chemical form that cannot readily be transferred from the lumen of the gastrointestinal tract into the plasma. Such lack of bioavailability may arise because the element is present in a highly insoluble form, or because it has formed complexes with constituents of the gastrointestinal tract contents, or perhaps with a pharmaceutical, which carry a pattern of electrical charge that limits or prevents transfer across the mucosa.

METAL CONCENTRATION [arbitrary units]

Figure 13.2 A generalised dose-response curve for an essential or beneficial element, illustrating the principle of the biphasic response. At very low concentrations there may be insuffient metal for optimal biological effect, while at higher levels the same metal may be toxic.

METAL CONCENTRATION [arbitrary units]

Figure 13.2 A generalised dose-response curve for an essential or beneficial element, illustrating the principle of the biphasic response. At very low concentrations there may be insuffient metal for optimal biological effect, while at higher levels the same metal may be toxic.

The transition metals, which collectively weigh less than 10 g are particularly vulnerable to interactions that may produce the effects of a deficiency. For example:

1. Each of these trace elements may be present in an organ or body fluid in only microgramme quantities, yet drugs which can interact with them may be administered in milligramme or greater quantities—the same pharmaceuticals may have little influence upon the 1.7 kilogrammes of calcium or the 42 grammes of magnesium but they may easily render a few microgrammes of copper or zinc biochemically inert.

2. Poorly controlled industrial activities have resulted in the release of elements not normally present into our environment or diet, for example lead, cadmium and mercury. Such metals can compete with essential ones for important biochemical binding sites in vivo.

3. Modern food processing, preservation and packaging techniques, as well as the advent of convenience foods, and even junk-food diets, have all influenced the spectrum of trace element and metal complexing chemical ligand intakes into humans.

4. Advances in medicine and pharmacy have extended human lifespan towards ninety or more years and long-continued dietary or therapeutic practices that cause even very minor disturbance of trace elements may over years lead to serious deficiency or imbalance. The importance of this can be seen in the treatment of conditions such as arthritis, hypertension, gout or minor cardiac disorders which may require medication to be continued for perhaps twenty or more years.

5. As has already been mentioned, our basic biochemistry evolved under anaerobic conditions and even in to-day's aerobic atmosphere we often still require metals such as manganese, iron, cobalt and copper in their lower oxidation states. Thus, drugs which interfere with oxidation-reduction (redox) mechanisms may lead to biochemical inactivation of such metals.

Fortunately, trace element balances can usually be easily restored if deficiencies or excesses are recognised early enough. The correction of trace element deficiency is no simple task and a series of criteria need to be satisfied; the elements must be supplied in solution at the correct pH to avoid precipitation, in an appropriate oxidation state and in a form that is bioavailable. It may be the dispensing pharmacist—patient relationship that first discusses such trace element dependent side effects. Thus it is important for pharmacists to have some understanding of trace element biochemistry.

In fact, there is no known aspect of biochemistry in which trace metals are not involved. Table 13.2 contains a partial listing of conditions associated with trace element imbalance—a full list would require many pages (see Frausto da Silva and Williams 1991; Taylor and Williams 1995). For a more detailed discussion of the normal and pathological biochemistry of trace elements the reader is referred to some of the general texts listed in the references (Frausto da Silva and Williams 1991; Hay 1984; Taylor and Williams 1995; Williams 1976) but a few of the more important roles of such elements are mentioned here.

• Some elements are essential as cations or anions for the maintenance of osmotic pressures and to neutralise species of opposite charge. Sodium and potassium ions and even the humble proton fall into this category. Nature has evolved a very specific biochemistry to maintain the concentrations of these elements at just the correct levels. For example, in blood the pH is buffered at ~7.4 despite severe challenges from the metabolic production of bicarbonate ions etc.; changes of even 0.1 of a pH unit are seriously life-threatening. Similarly, the sodium and potassium concentrations in blood are strictly maintained at 140 and 4 mmol.dm-3, respectively; whereas inside cells the concentrations are 20 and 95 mmol.dm-3. Thus specific mechanisms have evolved to keep sodium out of cells while encouraging the influx of potassium. Similarly, chloride is kept outside cells, whereas intracellular fluid is rich HPO42-.

• More than 1000 metalloenzymes are known to date; about half contain zinc either as part of the active site or in a structural role, while others require manganese, molybdenum, copper, nickel or selenium for their activity.

• Cobalt, once a very important element in primitive cells, now appears to plays an important role only in vitamin B12 and in allowing free radical chemistry at low redox potentials.

• Copper, although less than 1 g is found in the average person, has been linked to very many low molecular mass metal complexes and to caeruloplasmin, metallothionein and other proteins in blood plasma and in tissues. Copper is now recognised as playing many roles in vivo, for example, copper oxidases play important roles in scavenging free radicals and in removing excess neurotransmitter amines and in the development of hormonal messengers such as adrenaline.

Table 13.2 Examples of some metal associated disorders.

Element Disorder associated Disorder associated with with a deficiency an excess

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