Cragg Kingston ANTICANCER AGENTS Newman ANTICANCER from NATURAL PRODUCTS AGENTS from N A A N Praise for the First Edition NATURAL T T “The book brings home to us not only the amazing chemical complexity of the natural world but also the vast reservoir of potential new healing agents that yet remain to be U I tapped. This impressive work, which maintains a uniformly high standard throughout, C PRODUCTS R will be of major benefit to a wide readership.” A —Chemistry World A N “An ideal foundation for scientists engaged in developing new and improved drugs L based on natural sources.” C Second Edition —Memoriile Sectiilor Stiintifice P E R The approach to drug discovery from natural sources has yielded many important R new pharmaceuticals inaccessible by other routes. In many cases the isolated natural product may not be an effective drug for any of several reasons, but it nevertheless O A may become a drug through chemical modification or have a novel pharmacophore for future drug design. In summarizing the status of natural products as cancer D G chemotherapeutics, Anticancer Agents from Natural Products, Second U Edition covers the: E C N • History of each covered drug—a discussion of its mechanism on action, T medicinal chemistry, synthesis, and clinical applications T • Potential for novel drug discovery through the use of genome mining as S well as future developments in anticancer drug discovery S • Important biosynthetic approaches to “unnatural” natural products f Anticancer Agents from Natural Products, Second Edition discusses how r complex target-oriented synthesis—enabled by historic advances in methodology—has o Edited by enormously expanded the scope of the possible. This book covers the current clinically m Gordon M. Cragg used anticancer agents that are either natural products or are clearly derived from natural product leads. It also reviews drug candidates currently in clinical development David G.I. Kingston since many of these will be clinically used drugs in the future. Second David J. Newman K10713 Edition ISBN: 978-1-4398-1382-9 6000 Broken Sound Parkway, NW 90000 Suite 300, Boca Raton, FL 33487 900 711 Third Avenue New York, NY 10017 9 781439 813829 2 Park Square, Milton Park 9 781439 804223 Abingdon, Oxon OX14 4RN, UK WWW.CRC PRESS.COM ANTICANCER AGENTS from NATURAL PRODUCTS Second Edition ANTICANCER AGENTS from NATURAL PRODUCTS Second Edition Edited by Gordon M. Cragg David G.I. Kingston David J. Newman CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2012 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20110427 International Standard Book Number-13: 978-1-4398-1383-6 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the valid- ity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Contents Preface...............................................................................................................................................ix Editors................................................................................................................................................xi Contributors....................................................................................................................................xiii Chapter 1 Introduction...................................................................................................................1 Gordon M. Cragg, David G. I. Kingston, and David J. Newman Chapter 2 Camptothecin.and.Its.Analogs......................................................................................5 Nicolas J. Rahier, Craig J. Thomas, and Sidney M. Hecht Chapter 3 The.Discovery.and.Development.of.the.Combretastatins...........................................27 Kevin G. Pinney, George R. Pettit, Mary Lynn Trawick, Christopher Jelinek, and David J. Chaplin Chapter 4 Homoharringtonine.and.Related.Compounds............................................................65 Hideji Itokawa, Yukio Hitotsuyanagi, and Kuo-Hsiung Lee Chapter 5 Podophyllotoxins.and.Analogs....................................................................................95 Kuo-Hsiung Lee and Zhiyan Xiao Chapter 6 Taxol.and.Its.Analogs................................................................................................123 David G. I. Kingston Chapter 7 The.Vinca.Alkaloids.................................................................................................177 Fanny Roussi, Françoise Guéritte, and Jacques Fahy Chapter 8 The.Bryostatins.........................................................................................................199 David J. Newman Chapter 9 The.Isolation,.Characterization,.and.Development.of.a.Novel.Class.of. Potent Antimitotic.Macrocyclic.Depsipeptides:.The.Cryptophycins........................219 Rima S. Al-awar and Chuan Shih Chapter 10 Chemistry.and.Biology.of.the.Discodermolides,.Potent.Mitotic.Spindle.Poisons.....241 Sarath P. Gunasekera and Amy E. Wright v vi Contents Chapter 11 The.Dolastatins:.Novel.Antitumor.Agents.from.Dolabella auricularia..................263 Erik Flahive and Jayaram Srirangam Chapter 12 Ecteinascidin-743.(Yondelis®),.Aplidin®,.and.Irvalec®.............................................291 Carmen Cuevas, Andrés Francesch, Carlos M. Galmarini, Pablo Avilés, and Simon Munt Chapter 13 Discovery.of.E7389,.A.Fully.Synthetic.Macrocyclic.Ketone.Analog. of Halichondrin B......................................................................................................317 Melvin J. Yu, Yoshito Kishi, and Bruce A. Littlefield Chapter 14 HTI-286.(Taltobulin),.A Synthetic.Analog.of.the Antimitotic.Natural. Product Hemiasterlin.................................................................................................347 Raymond J. Andersen, David E. Williams, Wendy K. Strangman, and Michel Roberge Chapter 15 The.Actinomycins.....................................................................................................363 Anthony B. Mauger and Helmut Lackner Chapter 16 Anthracyclines...........................................................................................................383 Federico-Maria Arcamone Chapter 17 Ansamitocins.(Maytansinoids).................................................................................407 Tin-Wein Yu, Heinz G. Floss, Gordon M. Cragg, and David J. Newman Chapter 18 Benzoquinone.Ansamycins.......................................................................................429 Kenneth M. Snader Chapter 19 Bleomycin.Group.Antitumor.Agents........................................................................451 Sidney M. Hecht Chapter 20 Biochemical.and.Biological.Evaluation.of.(+)-CC-1065.Analogs.and. Conjugates with Polyamides.....................................................................................479 Rohtash Kumar and J. William Lown Chapter 21 Epothilone,.A.Myxobacterial.Metabolite.with.Promising.Antitumor.Activity........513 Gerhard Höfle and Hans Reichenbach Chapter 22 Enediynes..................................................................................................................575 Philip R. Hamann, Janis Upeslacis, and Donald B. Borders Contents vii Chapter 23 The.Mitomycins........................................................................................................623 William A. Remers Chapter 24 Staurosporines.and.Structurally.Related.Indolocarbazoles.as. Antitumor.Agents......................................................................................................647 Michelle Prudhomme Chapter 25 Combinatorial.Biosynthesis.of.Anticancer.Natural.Products...................................671 Steven G. Van Lanen and Ben Shen Chapter 26 Developments.and.Future.Trends.in.Anticancer.Natural. Products.Drug.Discovery..........................................................................................699 Gordon M. Cragg and David J. Newman Preface Natural.products.continue.to.make.new.contributions.to.cancer.chemotherapy.since.the.first.edition. of.this.volume.was.published.in.2005..These.developments.include.the.clinical.introductions.of. cabazitaxel.in.June.2010.(the.first.new.taxane.drug.to.enter.clinical.use.since.docetaxel.was.intro- duced.in.the.1990s),.of.ixabepilone.(the.first.epothilone.analog.to.enter.clinical.use),.of.the.marine. natural.product.analog.eribulin.(which.was.approved.by.the.FDA.in.November.2010.for.second.line. therapy.in.resistant.breast.cancer),.and.of.the.difluorinated.vinca.alkaloid.vinflunine.in.2009..In. addition,.antibody.drug.conjugates.are.showing.considerable.promise.in.cancer.therapy..While.the. enediyne.calicheamicin.γI.was.the.first.antibody-targeted.chemotherapeutic.agent.to.be.registered. 1 for.humans,.marketed.as.Mylotarg.(gemtuzumab.ozogamicin),.it.has.recently.been.withdrawn.from. the.US.market,.but..SMANCS,.a.neocarzinostatin.conjugate,.is.approved.in.Japan.for.patients.with. liver.cancer.metastases..Of.particular.note.are.antibody-maytansinoid.(DM1.and.DM4).conjugates,. and.a.biological.licence.application.(BLA,.equivalent.to.the.NDA.application.for.small.molecules). has.been.submitted.to.the.FDA.by.Genentech.for.marketing.approval.of.one.such.conjugate,.T-DM1. or.trastuzumab.emtansine,..as.a.treatment.for.Her2+.breast.cancer. The.chapters.in.this.book.have.all.been.substantially.revised.and.updated.from.those.in.the.first. edition..In.some.instances.where.the.original.authors.were.unable.to.undertake.the.revision.of.their. chapters,.updates.by.an.editor.have.been.included..The.editors.hope.that.this.revised.volume.will. continue.to.provide.examples.and.inspiration.to.natural.product.researchers.as.well.having.real. value.for.scientists.looking.for.information.on.the.next.generation.of.anticancer.drugs. Gordon M. Cragg, David G. I. Kingston, and David J. Newman ix