MEDICINAL CHEMISTRY a Series of Monographs a Complete List of Titles in This Series Appears at the End of This Volume
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MEDICINAL CHEMISTRY A Series of Monographs A complete list of titles in this series appears at the end of this volume. DOXORUBICIN Anticancer Antibiotics FEDERICO ARCAMONE Farmitalia Carlo Erba Ricerca e Sviluppo Chimico Milano, Italy 1981 ACADEMIC PRESS A Subsidiary of Har court Brace Jovanovich, Publishers New York London Toronto Sydney San Francisco COPYRIGHT © 1981, BY ACADEMIC PRESS, INC. ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER. ACADEMIC PRESS, INC. Ill Fifth Avenue, New York, New York 10003 United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London NW1 7DX Library of Congress Cataloging in Publication Data Arcamone, Federico. Doxorubicin. (Medicinal chemistry, a series of monographs) Includes bibliographies and index. 1. Adriamycin. 2. Cancer—Chemotheraphy. 3. Anti neoplastic agents. I. Title. II. Series. [DNLM: 1. Doxorubicin. 2. Doxorubicin—Analogs and derivatives. 3. Antibiotics, Antineoplastic. Wl ME64 / 0V 269 A668d] RC271.A37A72 616.99Ά061 80-1106 ISBN 0-12-059280-0 PRINTED IN THE UNITED STATES OF AMERICA 81 82 83 84 9 8 7 6 5 4 3 2 1 To my Wife and Children Preface The successful development of doxorubicin as a wide-spectrum antitumor an tibiotic was the result of a systematic search of the most effective chemical species within a group of biologically active microbial metabolites, namely the anthracycline glycosides. Starting from the classical rhodomycins, an inter mediate step was represented by the study of the first S. peucetius-den\ed metabolite, daunorubicin. Important determinants of this development (sum marized in Chapter 1) were (a) the involvement of organic chemistry at an early stage (in the elucidation of the detailed structure and stereochemistry of daunorubicin), which allowed the rapid identification of doxorubicin and ensured its prompt availability for the clinical trials; (b) the well-established, pioneering expertise in experimental chemotherapy of Professor Aurelio di Marco and his group at Istituto Nazionale Tumori, Milan, who demonstrated the high therapeu tic potential of the new drug; and (c) the highly motivated interest of experienced clinicians whose contributions are clearly visible in the early relevant medical literature in a frame of extensive international cooperation, most importantly, that provided by the United States National Cancer Institute, Division of Cancer Treatment, Bethesda, Maryland. Chemotherapy as a clinically useful approach to the treatment of human cancer, as an alternative or an addition to surgery and radiotherapy, is now nearly 40 years old; but only in the last decade have its objectives become those of cure or even of prolonged survival of a disease that strikes people at a rate of almost one in four and that represents the second leading cause of death in the United States (as estimated by the American Cancer Society in "Cancer Facts and Fig ures," 1978). The future of antitumor drug development rests in part on a more rational use of presently known, clinically effective agents and in part on the discovery and selection of new chemical compounds affording a reduction both of host toxicity and of variations in tumor responsiveness. The advantages as- XI xii Preface sociated with optimal drug dosage, scheduling, and combination are certainly important, but they lie outside the field of the medicinal chemist. However, the latter have already produced highly active compounds by synthesizing analogues of proven active leads (e.g., methotrexate, doxorubicin itself, CCNU, vincris- tine, cyclophosphamide). The analogues development approach in the field of anthracyclines is fully justified by the outstanding antitumor activity exhibited by doxorubicin and by the identification of its major side effects, whose dissociation from the therapeutic effects seems, at least in part, possible. Although adequate knowledge of the chemistry involved is a necessary prerequisite for performing appropriate structural variations of the parent drug, the consideration of biochem ical and pharmacological properties presumably associated with the clinical ef fects is of undoubted importance in assisting the medicinal chemist. Chapters 2 through 8 provide an overview of basic studies in the area of medi cinal chemistry and related fields that have been generated as a consequence of doxorubicin development. Such studies have been concerned, on the one hand, with both biochemical and biophysical investigations at the molecular level (the interaction of anthracyclines with DNA having attracted much attention since this cellular constituent appears to be the main receptor of these drugs) and at different levels of biological organization as well. On the other hand, a large body of work whose objective is the development of synthetic procedures for the drug and for new related analogs of potential clinical usefulness has been carried out. New biosynthetic anthracyclines have also been isolated as interest in this family of antibiotics has grown in recent years. This approach remains promising for the identification of new biologically active compounds. Acknowledgments The author wishes to acknowledge the very great assistance of Mrs. Domenica Ambroggio who typed most of the manuscript and whose cooperation in the collection of photocopies of many original articles and in checking and listing the literature references was indeed essential to the completion of this work. The author is also grateful to Mrs. Mara Chierichetti for collaboration in the prepara tion of the typescript. The author was assisted in the revision of the text by his colleagues and friends—Giovanni Franceschi, Giuseppe Cassinelli, Sergio Penco, Aristide Vigevani and Milena Menozzi—who read large parts of the manuscript. This assistance was particularly valuable since they had each been directly involved in many of the studies reported in this book. Xlll 1 Discovery and Development of Doxorubicin ANTITUMOR ACTIVITY OF AN ANTHRACYCLINE PIGMENT The history of the antitumor anthracyclines begins in the late 1950s when a pigmented compound originated from a strain of Streptomyces sp. was characterized and found to exhibit antitumor properties (7). The strain (number 1683 in Farmitalia collection) was isolated from a sample of soil collected in India and displayed a tendency to produce varieties differing phenotypically in the color and the amount of pigmentation. Solvent ex traction of both the mycelium and the filtered broth allowed the recovery of the active materials as orange-red or red solids containing one or more hydroxyquinone compounds as shown by the typical absorption spectrum in the ultraviolet and visible regions. The product was purified by the counter- current technique in a Craig's apparatus (chloroform and pH 4.6 acetate buffer) and eventually crystallized as the hydrochloride. It was considered to be closely related to the rhodomycin complex, previously described by Brockmann (2). Later work performed in the author's laboratory showed the main pigment produced by strain 1683 to be rhodomycin B, a component of the rhodomycin complex whose structure has been established as 1 by the German authors (3). Biological activity was studied in mice bearing Ehrlich carcinoma or sarcoma 180 both in solid and ascites form. The products were administered intraperitoneally for 5 consecutive days starting the day of ascitic tumor inoculation or subcutaneously in single daily doses for 9 or 10 days starting from day 1 after the transplant of the solid tumors. The crude solids obtain ed upon H-butanol extraction of fermentation fluids allowed a marked 1 1 Discovery and Development of Doxorubicin O OH OH NMe- HO (1) inhibition of the Ehrlich ascitic tumor when administered at the daily dose of 200 mg to the experimental animals. Survival time of treated animals was, however, not different from that of the controls. Purified pigmented preparations gave similar results at daily doses in the range 0.05-0.25 mg/kg. The latter materials in their water soluble form, i.e., as the intact glycosides, showed also a marked effect on sarcoma 180 in both ascitic and solid form and on Ehrlich adenocarcinoma. In all cases, no favorable effects on survival time were demonstrated, and this was attributed to toxicity of the active principle and especially to the paralyzing effect caused by the substances on intestinal motility. Biological properties of the pigmented substances isolated from strain 1683 indicated, however, that further investigations on new compounds belonging to this class of microbial metabolites would have been of interest. This early conclusion was also supported by the cytostatic and antitumor activity exhibited by the related pigments, the cinerubins (4). Before dealing with the isolation and structure elucidation of daunorubicin and doxorubicin which took place during the 1960s, a summary of work already done in the preceding decade on this class of glycoside pigments is obligatory. This will be the subject of the following section. ANTHRACYCLINES AND ANTHRACYCLINONES: THE FIRST DECADE Starting in 1950 with a publication in Naturwissenschaften by Hans Brock- mann and Klaus Bauer entitled "Rhodomycin, ein rotes Antibioticum aus Actinomyceten," Brockmann and co-workers at the University of Göttingen had already disclosed in a number of papers the