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RSC Paperbacks LIFE SAVING DRUGS The Elusive Magic Bullet JOHN MANN Queen’s University Belfast, UK RSeC advancing the chemical sciences ISBN 0-85404-634-8 A catalogue record for this book is available from the British Library 0 The Royal Society of Chemistry 2004 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for pri- vate study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accor- dance 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. Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 OWF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Typeset by Macmillan India Ltd., London, UK Printed by TJ International, Padstow, Cornwall, UK Preface At the start of the 20th century, there were only a handful of effective drugs: mor- phine, quinine, cocaine, aspirin, and a few inorganic salts for gastrointestinal prob- lems. A serious bacterial infection and most cancers would usually be a death sentence for the patient. One hundred years later, there are literally thousands of effi- cacious drugs - bacterial and viral infections (including HIV) can be successfully treated, and even certain cancers can now be cured. This book describes the evolu- tion of these life-saving drugs that have so revolutionised the treatment of disease, and emphasises the roles played by those who discovered these molecules. The three main chapters deal with drugs for the treatment of bacterial and viral infections, and cancer; then, the final chapter reveals the new advances that have been facilitated by our growing understanding of the genetic basis of disease. It was never my intention to write a research text, although the bibliography will allow readers to gain access to key research papers; the book is also not intended to com- pete with the standard textbooks of medicinal chemistry. It should, however, provide an excellent source of background material for students of medicinal chemistry, pharmacy, and even medicine and pharmacology. The first edition of the book was written primarily for the popular science market; hence, it could not contain chemical structures. It was well-received, with excellent reviews in both Nature and the Times Literary Supplement; but without the chemical structures, it was impossible to give due prominence to all the fabulous molecular species that have so improved our quality of life and chances of survival. This new edition has been completely updated and expanded, and includes the chemical struc- tures and modes of action for most of the drugs discussed. I hope that it will be of interest to anyone who wants to know more about the molecular entities that com- prise the life-saving drugs. It is a pleasure to thank Liz Hunter and Ian Gibson for the illustrations, and the staff at the RSC for their help during the production of the book. V for Cressida and Octavia Contents Chapter I The Elusive Magic Bullet: Introduction 1 Chapter 2 Fighting Bacteria 11 The Black Death 11 Miasmata, Animalcules and Ma1 aria 14 Antiseptics 18 From Dyes to Sulfonamides: The First Antibacterials 27 Penicillins: Early Ideas of Antibiosis 33 Penicillins: Fleming’s Serendipitous Discovery 35 Chain and Florey and the Penicillin Production Line 42 Semi-synthetic Penicillins and the Growing Problem of Resistance 48 The Mould that Grew on Sewage: Evolution of the Cephalosporins 53 The Mode of Action of the Penicillins and Cephalosporins 56 The White Plague and its Treatment 61 More ‘Treasures’ from the Streptumyces 70 The Rise of the ‘Superbugs’ 77 Chapter 3 Antiviral Treatments 85 Introduction 85 What is a Virus? 86 Antibodies: Nature’s Magic Bullets 89 Smallpox 89 Rabies 99 Polio 101 Gene Technology 102 Coughs and Colds and Influenza 105 Influenza: The Disease 105 vii ... Vlll Contents Influenza: The Treatments 111 The Common Cold 114 Herpes: Colds Sores and Chicken Pox 116 Aids: History of the Disease 120 Aids: Prevention and Treatment 126 Haemorrhagic Fever Viruses 135 Chapter 4 Cancer: The Disease and its Treatment 141 Aetiology 143 Cancer Chemotherapy 156 From Poison Gas to Platinum Drugs 157 Beating Leukaemia 167 Other Anti-metabolites 172 Periwinkles, Mayapples and Yew Trees: Anti-Cancer Drugs from Plants 175 Microorganisms also Produce Anti-Tumour Agents 189 Anti-Tumour Drugs from the Sea 195 Turning off Hormonal Influences 20 1 Breast Cancer 205 Prostate Cancer 209 Biological Warfare Against Cancer Cells 21 1 Prevention is Better Than Cure 22 1 Chapter 5 Magic Bullets: Still Elusive After all These Years 223 Further Reading 233 Subject Index 241 Chapter 1 The Elusive Magic Bullet: Introduction Theophrastus Philippus Aureolus Bombastus von Hohenheim would not have been surprised that arsenic was a major component of the first effective treatment for syphilis. This 16th-century alchemist and physician, better known as Paracelsus, is reputed to have acquired his skills from barber sur- geons, alchemists and gypsies, although he acquired notoriety after his appointment as Professor of Medicine in Basel. He was renowned for his use of mercury, arsenic, antimony and tin salts for the treatment of syphilis, intestinal worms and sundry other conditions endemic in mediaeval Europe - although it is probable that he killed more patients than he cured with these very toxic metal salts. Four hundred years later, Paul Ehrlich discovered the arsenic-containing drug ‘606’ (later called Salvarsan), the first true anti- syphilitic and immediately hailed as a ‘magic bullet.’ It was to remain the mainstay of treatment until the arrival of another ‘wonder drug’ of the 20th century - penicillin. Paracelsus rejected the druglore (mainly plant-based) laid down by the famous Greek physicians Dioscorides and Galen, and believed instead in the so-called ‘Doctrine of Signatures.’ The main belief was that the shape of a plant revealed the disease or organ that would benefit from therapy involving extracts of that particular plant. Thus, the tooth-shaped seeds of henbane were given for toothache, brain-shaped walnuts for headache and liverwort for liver complaints. His prescribing also owed much to the Arab preference for sulfur, mercury and common salt - the essence of combustibility, fluidity and earth- iness - coupled with a firm belief in magic, necromancy and astrology. These strange ideas (at least in contemporary terms) should not, however, overshadow his major contribution to medicine, which was his forthright belief that each disease had a specific cause and its own remedy. There is an interesting congruence between this belief and the later triumphs of Paul 1 2 Chapter 1 Ehrlich, who invented just such a treatment for syphilis caused by the organ- ism Treponema pallidum. Paul Ehrlich was born in March 1854 and was brought up in Upper Silesia, in the town of Strehlen. The son of an innkeeper, he received a major part of his education at the University of Breslau. Here, he developed a fascination for the properties of aniline dyes, then a very important product of the German fine chemicals industry. Even in early experiments, he was able to show how certain dyes could help in the identification of cells and for the definition of their fine structure. His secretary of many years, Martha Marquardt, records in her excellent biography of Ehrlich that he was visited in his laboratory one day by Robert Koch, who had become famous through his studies on the causative organisms of anthrax, tuberculosis, diphtheria and several other common diseases. Ehrlich’s teacher apparently introduced him to this honoured guest with the words: “That is ‘little Ehrlich’. He is very good at staining, but he will never pass his examinations.” Ehrlich did pass his exams and then completed his studies at the University of Leipzig, graduating in 1878 (aged 24) with a doctorate in Medicine.