AMINO ACIDS AND PEPTIDES WITH ANTIMETABOLIC ACTIVITY Ciba Foundation Symposia General Volumes : - - - - Mammalian Germ Cells - Preservation and Transdantation of Normal Tissues - - - - - - LeuksemiaResearch - - - - Chemistry and Biology of Pteridines - Porphyrin Biosynthesis and Metabolism Histamine - - - - - - Extrasensory Perception - - - - Bone Structure and Metabolism - - Paper Electrophoresis - - - - Ionizing Radiations and Cell Metabolism TheNatureof Viruses - - - - Chemistry and Biology of .Purines - - Drug Resistance in Micro-organisms - Chemistry and Biology of Mucopolysac- charides - - - - - - - The CerebrospinalFluid - - - - - Neurological Basis of Behaviour - - - A leaflet giving fuller details of these volumes, also of Ihc Ciba Foundation Colloquia on Endocrinology and Colloquda on Ageing, is available from the Publishers. CIBA FOUNDATION SYMPOSIUM ON AMINO ACIDS AND PEPTIDES WITH ANTIMETABOLIC ACTIVITY Editors for the Ciba Foundation G. E. W. WOLSTENHOLME, O.B.E., M.A., M.B., B.Ch. end CECILIA M. O’CONNOR, B.Sc. With 28 Illustrations LITTLE, BROWN AND COMPANY BOSTON THE CIBA FOUNDATION for the Promotion of International Co-operatwni n Medical and Chemical Research 41 PORTLANPDLA CEL, ONDONW, .l. Trustees : TEE RIGHTH ON.L ORDA DRIAN,O .M., F.R.S. THE RIGHTH ON.L ORDB EVERIDGEK, .C.B., F.B.A. SIR RUSSELLB RAIN, BT. THE HON. SIR GEORQEL LOYD-JACOB SIR RAYMONDN EEDHAMQ, .C., F.S.A. Executive Council : SIR RAYMONDN EEDAAMC, hairman PROFESSDORR. DR. h.c. R. MEIER LORDB EVERIDGE MR. PHILIPM AIR PROFESSAO. RH ADDOWF,. R.S. PROFESSFO. RG . YOUNGF, .R.S. Director, and Secretary to the Ezecutive Council: DR. G. E. W. WOLSTENHOLMOE.B, .E. Deputy Director: DR. H. N. H. GENESE Assistant Secretary : Editorial Assistants : Miss N. BLAND MISS CECILIA M. O'CONNOR, B.Sc. MISS MAEVE O'CONNORB, .A. Librarian : MISS JOANET EERINQTON ALL RIQHTSR EEERVED This book mny not be reproduced by any means, in whole or in part, with- out the permission of the Publishers Published in London by J. & A. Churchill Ltd. 104 Gloucester Place, W.l First published 1958 Printed in Greai Britain PREFACE IN 1956 Professor Sir Alexander Todd and Professor F. Bergel suggested to the Director of the Ciba Foundation that it would be useful and timely to hold one of the Foundation’s small international symposia on the biochemistry of amino acids and peptides with antimetabolic and cytotoxic pro- perties. They proposed the early part of 1958 as an appro- priate date for the meeting. During the ensuing months the Deputy Director of the Foundation had a number of dis- cussions with Professor Bergel, Sir Alexander Todd and Professor A. J. Birch and received a great deal of helpful advice. Professor Bergel also agreed to act as Chairman at the conference and although at one stage it seemed possible that a severe illness would prevent him from doing so, he happily recovered in time to take the Chair as originally planned. The meeting eventually took place in March 1958 and this book is a record of its proceedings. Following the normal pattern of Ciba Foundation Symposia, the number of participants was small, only twenty-nine altogether. The size of the group thus allowed for very full discussion of each paper presented. It is hoped that these discussions which, with the papers presented, are fully set out in this volume, may be of interest to the many chemists, biochemists and pathologists who could not be invited to attend because the need for informality made strict limitation of numbers desirable. For those readers who may not have previously come across the work of the Ciba Foundation, it should be explained that it is an educational and scientific charity administered by the distinguished Trustees and Members of Council whose names are set out on the opposite page. It is an entirely independent organization, although it was originally set up through the generosity of the Swiss firm CIBA Limited of Basle who V vi PREFACE established it in London so that it would conveniently serve scientists from the old world and the new. Here, it occupies a house nearly 200 years old and provides accommodation which is used each year by nearly 1,000 scientists from thirty to forty different countries. It arranges conferences such as the one reported here, as well as shorter meetings on scientific subjects relating to medicine and chemistry. Its further activities include annual lectureships, a medical postgraduate exchange scheme between Great Britain and France, and the support of basic research on ageing. Finally, by publishing the results of its work in volumes such as this, the Foundation attempts to provide some assistance for the individual research worker when dis- tance and circumstances make it difficult for him to keep in touch with what his colleagues in the field may be doing in other countries. CONTENTS PAGE Chairman’s opening remarks . F.BERGEL 1 The stereochemistry of naturally occurring p-amino acids . by K. BALENOVI~ 5 Discussion : ABRAHAMB, ALENOVI~B,E RGEL, BRENNER, BUCETANAHNA, RLEY-MASONK,E NNER, SCHWYZER, . SHEEHANS,T OCKW, IELANDY, OUNG 16 The mode of action of chloramphenicol . by E. F. GALE 19 Discussion : ABRAHAMB,R ENNERB, UC. HANANGA, LE,R YDON, SKIPPERS, TOCKT, ODDW, ORK 34 A preliminary study of the influence of amino acid deA- ciencies on experimental cancer chemotherapy . by H. E. SKIPPERA ND J. R. THOMSON 38 Discussion :A BRAHAMBE, RGELB, UCH.A NAFNA, RBESRH, EEHAN, SKIPPERS, TOCKW, RETLIND 59 Some aspects of azaserine, 6-diazo-5-oxo-~-norleucine and P-2-thienylalanine . by H. CHRISTINE REILLY 62 The interference of azaserine in purine biosynthesis . by J. M. BUCHANAN 75 Discussion: BALENOVI~B, ERGEL, BIRCH, BRENNER, BUCHANANC,R AIG, FARBER,H ARLEY-MASORNE, ILLY, . SHEEHANS,K IPPERS, TOCKW, IELANDW, ORKY, OUNG 81 Amino acid and peptide derivatives with potential anti- tumour properties . by J. A. STOCK 89 Clinical effects of amino acids carrying nitrogen mustard groups . by EVEW ILTSHAWan d D. A. G. GALTON 104 Vii viii CONTENTS PAGE Further clinical observations on p-di(2-ch1oroethyl)aino- DL-phenylalanine (sarcolysine) in comparison with some other chloroethylamine derivatives . by NATALIAI. PEREVODCHIKanOdV NA. N. BLOKHIN 110 Discussion : BERGEL,B UCHANAND,A LBY,F ARBER,G ALE, PEREVODCHIKROYVDAO,N S, CHWYZESRK, IPPERS, TOCK, . . WILTSHAWW, ORKY, OUNG 115 Recent developments in actinomycin chemistry . . by A. W. JOHNSON 123 Discussion : ABRAHAMB, ERGEL,B IRCH, CRAIG, FARBER, HARLEY-MASONJ, OHNSONK, ENNERR, EILLY,R YDON, . . SCHYWZESRH, EEHANS,K IPPERW, IELAND 134 Clinical and biological studies with actinomycins . . by S. FARBER 138 Discussion : ABRAHAMBE, RGELB, UCHANAFNA, RBE.RG ,A L.E , JOHNSONR,E ILLYS, HEEHANS,K IPPERW, IEIAND 145 The chemistry of etamycin . by J. C. SHEEHANH, . G. ZACHAUan, d W. B. LAWSON 149 Discussion : ABRAHAMB, ERGELB, RENNERC, RA.IG J, OHNSO. N, KENNERR, YDONS, HEEHANS,T OCKW, ORK 153 The aminoacyl insertion reaction and peptide chemistry . . by M. BRENNER 157 Discussion :B ALENOVBIR~,E NNERC,R AIGJ,O . HNSKOENN,N ER. , RYDONS, HEEHANW, IELANDY, OUNG 166 Synthesis of cyclic polypeptides . . by R. SCHWYZER 171 Discussion : ABRAHAMB,E RGEL,B UCHANANCR,. A IG, GAL.E , KENNERS, CHWYZESRT, OCKW, ORKY, OUNG 181 General Discussion : ABRAHAMB, ERGELB, IRCH,B UCHANAN, FARBERG, ALE, MULLJNSS,C HWYZESRH, EEHANS,K IPPER 185 Disulphide crosslinking in. c ysteine peptides . byH.N.RmoN 192 Discussion : BERGEL,H ARLEY-MASONK.,E NNER, RYDO.N , SCHWYZESRH, EEHANW, ADE,Y OUNG 201 CONTENTS ix PAGE Structure and function of some sulphur- containing pept i de s . by E. P. ABRAHAaMnd G. G. F. NEWTON 205 Discwssion : ABRAHAMB,. IRCH, CRAIG, GALE, KENNER, SHEEHANS,K IPPER 223 Bacitracin . by L. C. CRAIGW, . KONIGSBERanGd R. J. HILL 226 . Discussion: ABRAHAMC,R AIGN, EWTONW, ADE,W IELAND 243 Oxidative formation of biologically active compounds from peptides . by A. J. BIRCHa nd H. SMITH 247 Discussion :A BRAHAMBE, RGELB, IRCHB, RENNERB,U CHANAN, CRAIGG, ALE,S HEEHANS,K IPPERT,O DD . 257 General Discussion: ABRAHAMB, ERGELB, RENNER,C RAIG, FARBERG,A LE,R EILLYR, YDON,S CHWYZESRH, EEHAN, . SKIPPERS,T OCKW, IELANDW, ORK 261 Chairman’s closing r.e marks . F.BERGEL 273 List of those participating in or attending the Symposium on “Amino Acids and Peptides with Antimetabolic and Cytotoxic Properties” 18th-20th March, 1958. E. P. ABRAIIAM . Sir William Dunn School of Pathology, University of Oxford . . K. BALENOVIC University Chemical Laboratory, Zagreb . . A. DE BARBIERI. . Istituto Sieroterapico Milanese, Milan F. BERCEL Chester Beatty Research Inst., London . . A. J. BIRCH Dept. of Chemistry, University of Manchester . . M. BRENNER Dept. of Organic Chemistry, University of Basle . Division of Biochemistry, Dept. of Biology, Massachusetts Inst. of Technology, Cam- bridge, Mass. . . L. C. CRAIG Rockefeller Inst. for Medical Research, New York . . J. E. DALBY Radiobiology Dept., Christie Hospital & Holt Radium Inst., Withington, Manchester . S. FARBER Children’s Cancer Research Foundation, Bos- ton, Mass. . E. F. GALE Medical Research Council Unit for Chemical Microbiology, School of Biochemistry, University of Cambridge . J. HAHLEY-MASON University Chemical Laboratory, Cambridge . . A. W. JOHNSON . Dept. of Organic Chemistry, University of Nottingham . . G. W. KENNER Dept. of Organic Chemistry, University of Liverpool . . . L. J. MULLINS Dept. of Biophysics, Purdue University, Lafayette . G. G. F. NEWTON , Sir William Dunn School of Pathology, Uni- versity of Oxford NATALIAI. PEREVODCEIKOInVstA. o f Experimental Pathology and Therapy of Cancer, Academy of Medical Sciences of . the U.S.S.R., Moscow . H. CHRISTINE REIUY Division of Experimental Chemotherapy, Sloan-Kettering Inst. for Cancer Research, . . . hTewY ork H. N. RYDON . . . Dept. of Chemistry, University of Exeter R. SCRWYZER CIBA Limited, Bade xi