Dynemicin A, Uncialamycin and Analogues

By Daniel Best, Mickael Jean and Pierre Van De Weghe

Enediynes are natural products with highly active cytotoxicity and antibacterial activity, and thus have significant potential in the development of anti-cancer treatments. However, they are not readily available and can degrade rapidly during isolation; one solution is to produce them using total synthesis.Dynemicin A and uncialamycin are two such enediynes, with similar structures, for which total synthesis has been achieved. This book presents the isolation and preparation of these two compounds and their analogues through various synthesis strategies. Details of the structural elements essential to their anti-cancer activity are presented, with the objective of explaining and optimizing their biological activities and potential development as drugs.

• Presents two natural ènediynes with similar structures whose total syntheses have been accomplished
• Explores structural analogs of preparation for purposes of optimizing the anti-cancer activity
• Describes the total syntheses of dynemicin A, the uncialamycine, as well as analogs by emphasizing the synthesis strategies adopted
• Features studies of the biological activities and data to bring out the structural elements of these essential compounds

• Language: English
• Publisher: Elsevier Science
• Release date: Jun 14, 2016
• ISBN: 9780081010860

Daniel Best

Daniel Best is a postdoctoral researcher at the University of Rennes 1 in France. He is currently developing the synthesis of uncialamycin analogues.

Book preview

Dynemicin A, Uncialamycin and Analogues

Isolation, Biological Activities and Syntheses

Daniel Best

Mickael Jean

Pierre van de Weghe

Table of Contents

Cover image

Title page

Copyright

Introduction

1: Dynemicin A

Abstract:

1.1 Isolation and characterization

1.2 Biosynthesis

1.3 Total synthesis, analogues and biological activities

2: Uncialamycin

Abstract:

2.1 Isolation and characterization

2.2 Biosynthesis

2.3 Total synthesis and analogues

Conclusion

Appendix

Bibliography

Index

Copyright

First published 2016 in Great Britain and the United States by ISTE Press Ltd and Elsevier Ltd

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Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

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© ISTE Press Ltd 2016

The rights of Daniel Best, Mickael Jean and Pierre van de Weghe to be identified as the authors of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.

British Library Cataloguing-in-Publication Data

A CIP record for this book is available from the British Library

Library of Congress Cataloging in Publication Data

A catalog record for this book is available from the Library of Congress

ISBN 978-1-78548-150-5

Printed and bound in the UK and US

Introduction

Abstract: Enediynes are a class of highly cytotoxic natural products mainly produced by actinobacteria and are among the most potent naturally occurring antitumor and antibiotic agents known. The enediyne function, which generally forms the part of a 9- or 10-membered ring, is one of several organic functions that make up these structurally complex, chiral compounds. The limited availability of enediynes through natural product isolation along with their structural complexity, outstanding biological activities and unusual mechanism of action has made this family of molecules a highly attractive synthetic target for both therapeutic applications and more fundamental research.

Keywords: Chromophore, Dynemicin A, Enediynes, 9-membered natural enediynes, 10-membered natural enediynes, Mylotarg, Neocarzinostatin, Uncialamycin

Enediynes are a class of highly cytotoxic natural products mainly produced by actinobacteria and are among the most potent naturally occurring antitumor and antibiotic agents known. The enediyne function, which generally forms the part of a 9- or 10-membered ring, is one of several organic functions that make up these structurally complex, chiral compounds. The limited availability of enediynes through natural product isolation along with their structural complexity, outstanding biological activities and unusual mechanism of action has made this family of molecules a highly attractive synthetic target for both therapeutic applications and more fundamental research [HAM 11].

Neocarzinostatin 1-1 (Figure I.1) was isolated from Streptomyces carzinostaticus as a chromoprotein in 1965, but its structure was not determined until 20 years later. It occurs naturally as a combination of a protein (apoprotein) and the neocarzinostatin chromophore 1-2; the apoprotein ensures the stability of the highly strained 9-membered enediyne motif. The first biological evaluations of 1-1 presented a wide range of antibiotic activity, and excellent inhibitory activity against the proliferation of tumor cells from a large number of cell lines was subsequently shown. 1-1 became the first antitumor protein derivative approved as a drug for clinical use in combination with lipiodol for the treatment of hepatocellular carcinoma in Japan. Its proposed mechanism of action is the induction of apoptosis via radical DNA damage (Scheme I.1) [ISH 65, EDO 85, BAK 07, CHI 11]: chromophore 1-2 is released from chromoprotein 1-1 in the cell and binds to the minor groove of DNA. After a series of reactions initiated by glutathione, a 1,4-benzenoid biradical 1-4 is generated via Myers-Saito cycloaromatization of 1-3 [MYE 89, NAG 89]. This highly reactive biradical 1-4 abstracts hydrogen from the deoxyribose backbone of DNA, leading to oxidative DNA cleavage and apoptosis.

Figure I.1 Structure of neocarzinostatin 1-1 and its chromophore 1-2

Scheme I.1 Mode of action of neocarzinostatin and its chromophore 1-2

After isolation of neocarzinostatin 1-1 and subsequent structural determination of its chromophore 1-2, other enediynes were isolated as secondary metabolites from soil and marine microorganisms. These compounds can be split into two structural classes: the 9-membered enediynes, usually associated with a stabilizing apoprotein (Figure I.2), and more stable 10-membered enediynes, which can be isolated without stabilizing cofactors (Figure I.3). Among the 9-membered enediynes, so far only N1999A2 1-9, isolated from Streptomyces sp. AJ9493, is stable enough for isolation and characterization without an associated apoprotein [AND 98].

Figure I.2 Examples of 9-membered natural enediynes

Figure I.3 Examples of 10-membered natural enediynes

In addition to neocarzinostatin 1-1, other natural enediynes have also been developed and advanced to clinical phases only to be dropped in the final stages, even shortly after being released onto the market. Esperamicin A1 1-11 1-10 1-10 bound to the humanized monoclonal antibody anti-CD33 successfully obtained accelerated FDA approval and was marketed as Mylotarg (gemtuzumab ozogamicin) in the early 2000s for the treatment of acute myeloid leukemia in elderly patients. In 2010, the product was withdrawn from the market following the observation of excessive fatal toxicity in a post-approval clinical trial started in 2004 [ROW 13]. At the end of 2014, a new temporary authorization of use was granted for a closely monitored patient group.

Among the 10-membered enediynes are the related anthraquinone-bearing dynemicin A 1-16 and uncialamycin 1-17 (Figure I.4), which are structurally distinct from the calicheamicin-type enediynes (Figure I.3). Dynemicin A 1-16 was isolated and identified in 1989 from Micromonospora chersina [KON 89], and uncialamycin 1-17 was first described in 2005 following isolation from cyanobacteria of the lichen Cladonia uncialis [DAV 05]. Due to the excellent antitumor activities of these two compounds, various research groups became interested in their total syntheses and the preparation of synthetic analogues.

Figure I.4 Structures of dynemicin A 1-16 and uncialamycin