825
n'ovember, 1963
Communication to the Editor Synthesis of a 6-hlercaptopurine N-Oxide'
Sir: A theoretical advantage2 of an S-oxide ,of a chemotherapeutically effective purine is based, in part, upon the possibility that it, like adenine-l-S-~xide,~ may undergr, a reduction in civo to the parent purine. The greatly reduced toxicity and improved therapeutic index4 of 6-methylpurine-1-S-oxideover the parent purine mas the first supporting example. Direct oxidation of 6-mercaptopurine to an ?;-oxide of it has failed because of oxidation of the mercapto group. Oxidation of 6-chloropurine has resulted in a prior hydrolysis to the nonoxidizable hypoxanthine, and attempts to introduce mercapto or halogeno groups into appropriate purine S-oxides have resulted in the reduction of the N-oxide group. NHz
IT
m
Scheme I
The synthesis of a 6-mercaptopurine ?;-oxide has now been accomplished by introduction of the S-oxide function while the sulfur is protected from oxidation in a thiazole. (1) This inve3tigation u'as supported in p a r t by funds from the National Cancer Institute. Kational Institutes of Health, Public Health Service (Grant KO.CA-03190-07), and from the Atomic Energy Commission (Contract No. AT(30-1)-910). (2) G. B. Brown, "Fourth International Congress of Biocheni. Colloq u i a , " 1'01. X I I I , Perearnon Press, London, 19;28,p . 111. (3) 11. Dunn, RI. H. hlaguire, and G. B. Brown, J . B i d . Chem., 234, 020 (19.59). (4) 31. A . Stevens, .1. Giner-Sorolla, H. W , Smith, and G. B. Brown, J . O w . Chem., 27, 5 0 7 (1902).
Oxidat,ion of 7-aminothiazolo [5,4-d]pyrimidine in acetic acid with Hz02 yielded 60% of the S-oxide 11,m.p. 278' dec. Anal. Calcd. for C5H,S40S: C, 35.71; H , 2.37; S, 33.33; S, 19.05. Found: C, 33.94; H, 2.48; s,33.50; s, 19.04. Heating the S-oxide I1 in an equivalent of N S a O H results in rearrangement to a 6-mercaptopurine-Koxide (111)in 25% yield, m.p. 230' dec. Anal. Calcd. for C5H45d0S.HzO: C, 32.26; H, 3.22; X, 30.11; S, 17.20. Found: C, 32.39; H , 3.00; N, 30.26; S, 17.40. Evidence that the purine ring is present in I11 derives from the fact that treatment with Raney nickel yields purine and that irradiation with ultraviolet light results in a removal of the oxygen to yield 6mercaptopurine, a reaction characteristic of several purine N-oxides.6 The position of the oxygen has not yet been est'ablished but', in analcgy t'o adenine, I may undergo oxidation at S-6, resulting in a purine 3-Soxide after the rearrangement. Initial observations by Dr. H. C. Reilly, with Sarcoma 180 in Swiss mice,7 indicate no toxicity at 500 mg./kg./ day and a chemotherapeutic activity, including inhibitions and delayed regressions, which exceeds that obtained with toxic levels of 6-mercaptopurine. ( 5 ) G. B. Elion, W. H. Lange, and G. H . Hitchings, J . A n . Chem. Soc., 78, 2858 (1956). (6) G. Levin and G. B. Brown, Federation Proc., 21, 372 (1902), a n d unpublished observations. (7) C. C. Stock, A m J . M e d . , 8 , 658 (1950).
DIVISIOXOF NUCLEOPROTEIN CHEMISTRY GERSHON LEVIK SLOAN-KETTERIKG GEORGEBOSWORTH BROWK INSTITUTE FOR CABCER
RESEARCH
SLOAN-KETTERINO DIVISIONOF CORNELL UWIVERSITY MEDICAL COLLEGE NEW YORK,NEW PORK
RECEIVED SEPTEMBER 12, 1963
Book Rev iew s Experimental Chemotherapy. Vol. 1. R . J. SCHXITZERand FRANK HAWKING, Editors. Academic Press, Inc., New York, N. Y., 1963. xv 1008 pp. $38.00.
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This is the first of three projected volumes of a comprehensive treatise on all aspects of chemotherapy. If the other two volumes will follow the tradition of high quality set by the present book, this treatise may well become the standard reference work for biologists interested in all phases of the subject. Introduced fittingly by a photograph of the patron saint of chemotherapy, Paul Ehrlich, one of the editors survevs the history of the field from antiquity t o the present. Like all other chapters, this first one is amply and well documented. The fact that the majority of the references roncerned with the discovery of chemotherapeutic drugs come from the biological literature points t o the division of labor, as well as to the teamwork of medicinal chemists and biologists in this area. Stress is laid on decisive testing proredures in laboratory animals, on statistical analyses of these procedures, on the pharmacological and toxicological aspects of
the drugs, and on the development and treatment of resistant strains. On the whole, the clinically useful drugs are discussed primarily and their biological and host-parasite relationships are illustrated. In several cases, however, the influenre of the chemical structure in a serim of related drugs is considered, and the effect of drug metabolites is detailed wherever it is known. This first volume treats the chemotherapy of protozoan and metazoan infections. Each chapter is written by authorities in the particular field who have had long actual experience in the area. Most authors are well known members either of British industrial research organizations or of American and British university or governmental laboratories. Specific diseases and their chemotherapr treated are trypanosomiasis, leishmaniasis, trichomoniases, histomoniasis, giardiasis, amebiasis, coccidiosis, malaria, babesiasis, theileriasis, anaplasmosis, toxoplasmosis, balantidiasis, spirochetal and miscellaneous infections, helminthiases, filariasis, and myriasis. A general author and subject index concludes the book.
'llic editors. who themselves have contributed several chapters, have managed to keep the style and presentation uniform, lucid: :tnd easy t o r e : d One may look forward with pleasure to the nest two vcilurries of this work. The book niay he recoininended t o iitedicind i4heniists, experiiiiental biologists, :inti physicians who li:~veto stud!, and treat infectious diseasrs.
Enzyme and Metabolic Inhibitors. Vol. 1. General Principles of Inhibition. Ry J. LEYDENWEBB. Academic Press, New I-ork! IC.Y., 1963. sxi 949 pp. $26.00.
drolysis in methanol solutions, no reference is made to the specific effect of low concentrations of methanol [.I. .4m. Chem. Soc.. 82, 3336 (1962)j. These comments should be taken less as criticisms than aw indications of the book's scope and thought-provoking qualities. Even the first volume of the projected four represents an enormous labor. This first volume is not a reference work but often vontains incisive discussions of points concerning inhibition. .4s such it, should be in personal libraries where workers may beconie familiar \vith its contents and be able to refer to it frequently and c,onveniently. Vnfortunately, the high price reveals that tht. publishers are planning only upon the assured sale t'o libraries, on whose shelves the? valuable volume is apt to remain little used
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,\lost, enzyiiies possess more inhibitors than substrates. 111 atldition, enzyme-inhibitor interaction constants are always also ccjiiilibriuni (sonstants a-hiie an enzyme-substrate interaction i.iinst:rnt inny or may not be an equilibrium constant. For this reastin enzyme-inhibitor constants, though more difficult tu twiluate precisely, :ire more iriimediately comparable than PrizTmc-suhstrate constants. The large volume under revienhere is t.he first in it projected set of four primarily concerned with inhibitors and inhibition. While the three succeeding volunies nil1 deal tvith specific inhibitors, this first volume develops in wnsiderahle detail general principles of inhibition. 'rlic contents might best be indicated by listing the titles of the 17 r1i:iptcm: 1, Perspectives of Netabolic Inhibition; 2, The Kinetirs of Enz)~nieRewtions: 3, The Kinetics of Enzyme Int>e Inhibition and Product Inhibition; 5: Nec.hanisnis and Constants of Inhibition : ti, Inter:ic,tions i i f Inhihitors \vith E h y m e s : 7 , Inhibition in hIultirnzyriic Systems: S. Distribution and Fate of Inhibitors in living Organisms; 9, Inhil~itionin Cells and Tissues: 10, Effects of 1Iore Than One Inhibitor: 11, 1,ocalization of the Site of Intiiliitiun: 12, Rates of itiitiun: 13. Reversal of Inhibition: 14, M e r t s of pH on En rie Inhilition: 15, Effects of Various I2:tc.t i irs on Inhibitinn : , Specificity iif Inhibition; and 17. Suggestions for Planning and Reporting Inhibition Studies. i2s indicxted hj- the chapter titles, the hook is concerned with t i r o d areas of inhil)ition, froni interactions between parts of' rnirlecwlcs to aspects of inhibition in whole organisms. Chapter 6 on molecular interactivns contains a valuable discussion of the f o r m between molecules. It is rinfort,unate. however, that the :iuthor did not inrlude a more thorough discussion of hydrophohiv inter:rctioris. Xii reference is ~riaclet o the article by IT. Kauzniann, .41/wj/. Protrr'n Phrrti., 14, 33 1959), one source wherr hydrophol~ic hinds :iw discusscd. 'Their importance seems underestimated in this h o k . The free energy change for thc transfer of a niethj-1 group t'roiii :tn aqueous to a hydrocarbon environnient [ J . . i n / . ~ ' h e n b Sur., . 84,4240 (1962)) is about. equal t ( I the deficiency uf dispersion forces in :ii:counting for the binding (it' :I single substrate nietl-iyl group to 1-holinesterase as discussed I 111 1). 2Mi. -1second point inadequ:itely discussed appears in Cliaptrr 14 where the hell-shaped plots obtained when reaction r:ttc is plotted against pH itr(3 interpreted almost entirely in terms G if ionizing groups. ).et either ascending o r descending portions of :I iicll-shaped plot ni:i>. nut tx tluc. to :L simple ionization constant 1)ut f i r :in iiiniz:iiion ronst:int niodiiied hy rat,ios of other c.rluilit)riiiiii and r:itr c:onst:ints [sw for esaniple. J . -4vL. (.'he)//, Sot., 81, 4552 (195913 or simply t o ratios of rate cmstants alonr~ :is derrionstrated in a simple nonenzymatic system [ J . A m ('hvm. Soc.. 81, 5089 (1959)]. Thus the last sentence on p. 655 is not trrita. S o discxssiori of the general principles of metal ion inhibition is present,ed b u t perhaps this subject will appear \vhm specific. niet:il ion inhihitors are (.onsidered in a later v~ilunic. Xow tliat i t has been established that substrates alter ltics crlnfiirniatiriri of at Itwst soiii(1 cmzprnes it will be of interest to sf'(' to what extent various inhihitors :xt in the same fashion. In any Iiook of general principles it-ith such breadth, considerable selection is required in choosing esmiples to illustrate the principles. Though this section is admittedly largely subjective, some of the esaniples seem to have heen chosen without sufficient tliPc.riiiiiri:itiun. For instanc-e, l,hr citing on 11. 196 of the thiol M e r grouping as the re:ictive form of the sulfhydryl group in the imyirie papain ignores the fact that, the proposer of this grouping nt t.he :ic>tive (*enterhas never accounted for his own extensive Icinetir i1:tt:x in these t e r m and indeed i t does not seem possible t i l do so. On p. SO9 in ;I discwssion of the possible general c4fwts I )I. diclwl ric. mnstant ch:tnge.i on hymotrypsinh>,-
Spectrometric Identification of Organic Compounds. By R o m w r X. SILVERSTEIS and G. CLAYTON BASSLER. John Wiley rind Sons, Inc.. X e w York and London, 1963. viii 4- 177 pp. $8.50. Recent years have witnessed the explosive development and use ~ iinstrumental ' techniques as aids for the elucidation of structures of organic compounds. These developments have been largely paralleled by the appearance or erudite monographs which have helped the organir chemist apply such met,hods to his owa research. This dependence on instrumentation has now reached such proportions that ti course in the subject is definitely indicated :tnd :in increasing number of institutions are. in fact, incorporating suc.11 material in their formal study programs. Generally, suc.h ventures have I w n largely liniit>ed by the lack o f an adequate 1)oiik. a.ritten for the heginner. which describes how information olitiiined froni different instrumental methods (XI Iir risrtl in (,Iirriplenieiit:iry fashion to greatest advantage. The book hy Silverstein and Rassler is a step in this direction. I t is an i i ~ t g r o ~ of t h :I rourse given by the authors a t Yan Jose Stttte College in the spring of 1962, consisting of eleven lecture hours and four hours of discussion. The object of the book is to :tcqwiint the retrder with four instrumental techniques important to the organic i*heniist,these being mass, infrared, nuclear magnetic resonanw. and ultraviolet spectrometry: it emphasizes the value c i f romhining information obtained from t,hem in the solving of strurtural problems. The liook consists of eight vhapters, the first of which is a one :uid (!ne-half page introduction explaining the purpose of the book :tnd the scshenie followed in the remaining chapters. Each of t.he nest f o u r c,hapters is devoted to one of the techniques indicated :rl)ove. and contains a brief discussion of the theory, instrumentntion. svmple preparation, and interpretation of spectra. A n ezc-ellent list I I ~references in each case includes most of t h t , iiiort, estensive referenw works in that particular field. The discwsions of these techniques are usually clear and roncisr, and the c,hapters rontain numerous diagrams, charts, tahles, and estensive appendices (niany borrowed from other sources I \vhich help the reader to correlate and use the informatiun presented. In some instances, this reviewer had the opinion that the niuterial presented is almost too concise. In the infrared c,tiapter, For example. combination and overtone bands are inentitined in t h c s tliac~ussion of possible, pitfalls in interpreting infr:ired spet.tr:i, hut where line niight suspect their presence in :I spec,truni is not indicated. Another potential source of trouble here. Ferriii resonance, is not mentioned a t all. As another c a s r i n puint. in thr sect,ion on theory, it may have been helpfl~l for the lieginner if diagrammatic representations of the vibr:ttional modes of the AX3group, as well as the AX, group, had been included. Howevw, these shortcomings are relatively minor and do not detract appreciably from the value of the book. A particular point on the bright side is the presentation of d l infrared data in hi-ith p and em.-* units, which makes the discusto f o l l o a regardless of the system the reader is familiar [vith. Since the book is ivritten for the organic chemist, it is not surprising to find that the authors stress interpretation of spectra to a greater est,ent than the theoretical aspects of energy absorption. The theory is, however, usually treated in sufficient detail so as to provide an adequat,e understanding of the general principles involved. The chapter o i i nuclear niagnetic resonance is well presented : i n d dr:ils :iIniost c~svlusively xith prot>on magnetic. resonanrr.
