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JOHN CURTIN SCHOOL OF MEDICAL RESEARCH 622/1963
DEPARTMENT OF MEDICAL CHEMISTRY
ANNUAL REPCRT TO THE CCUNCIL 1962
Staff
Professor A. Albert, Ph .D., D. Sc ., F.R.I.c., F.A.A.
Reader D. J. Brown, Ph . D., D,Sc .
Senior Fellows D. D. Perrin , M.Sc., Ph.D., F.R.r.c. E. Spinner, M. Sc .Tech., Ph .D.
Microanalyst (Fellow) Joyce E. Fildes, M.Sc., Ph .D.
Research Fell•ws w. L. F. Armarego, Ph .D. G. B. Barlin, M.Sc., Ph.D. J, Clark, Ph.D., F.R.r.c. (from Jan.). R. F. Evans, D.Phil.
I
Honorary Research Fellow R. E. Willette , Ph.D. (u.s.A. National Institutes of Health Postdoctoral Fellow) .
Head Technician J. S. Harper
Student and Teaching Activities
Mr. N. W. Jacobsen, M. Sc ., was awarded the Degree of Doctor of Philosophy for his thesis 11 Methylation of aminopteridines and aminopyrimidines"; likewise Mr. J. c. B. White , M.Sc., for his thesis "Physico-chemical investigations of substituted hydroxypyridines". The following are proceeding to the Degree of Doctor of Philosophy• Mr. C. J. Hawkins , B. Sc ., (commenced 19 March 1960); Mr. Y. Inoue, M.Sc., (commenced 14 April , 1960); Mr. T. Teitei, M.Sc., (commenced 9 April, 1962); Mrs . J. M. Lyall, B.Sc., (nee Scott) (commenced 26 March, 1962) and Mr. I. Pitman, B.Sc., (commenced 26 November, 1962). These scholars are respectively, working on the oxidation-reduction potentials of copper complexes, the kinetics of the covalent hydration of the carbon-nitrogen bond, the tautomerism of pyrimidines, the amination of pyrimidines, and the kinetics of the Dimroth rearrangement.
Dr. E. Spinner arranged fortnightly seminars in the Department.
Research Programme
The detailed study of nitrogen heteroaromatic substances, because of their great importance in the economy of the living cell, continues to play a prominent part in the activities of this Department . For similar reasons, attention is focussed on studies of equilibrium phenomena in organo-metallic complexes, and on the elucida t ion by spectrometric techniques of changes in the structure of the amide (-CO.NH-) bond in changing electronic environments .
The occurrence of covalent hydration in 1,4,5- and 1,4,6- triazanaphthalenes has been demonstrated, and is being correlated with structure (Albert, Barlin) .
Cova lent hydration was also found in 2-(butnot in 4-) aminopteridine, and could be partly suppressed by the steric hindrance exerted by a methylgroup in the 4- position (Albert, Howell, Spinner) .
Covalent hydration is being sought in the aza-purine family with a view to further elucidating the mode of action of the enzyme, xanthine oxidase (Albert).
/The surprising resolution
2. 622/1963
The surprising resolution of a racemic pteridine into its D- and Lisomers has been obtained by simple chromatography on a sheet of paper (Albert, Serjeant).
Further study of the Dimroth rearrangement (the apparent migration of an alkyl-group from a heterocyclic nitrogen atom to an a-amino- or imino- group) has shown that the mechanism is a slow rate-determining ring-fission followed by a relatively rapid recyclization. Such rearrangements as that of l-methyl-1, 2-dihydro-2-iminopyrimidine to 2-methylaminopyrimidine (and corresponding pteridine reactions) were followed spectrophotometrically and found to be apparently first order reactions. The fission is mildly hastened by increase in size of the alkyl-group, and profoundly hastened by electron-attracting substituents (e.g. bromine). The fission is retarded by electron-releasing groups (C-alkyl-, or dimethylamino- substituents) and is, quite surprisingly, not base-catalysed (Brown, Harperi kinetic studies by Perrin).
Cytosine has recently been formulated in the u.s.A., from nuclear magnetic resonance data, as a zwitterion (i.e. with a positive charge on the primary amino- group). This conclusion has been investigated by examination of the ionization constants and ultraviolet spectra of cytosine and appropriately methylated derivatives. The predominant tautomeric form present in aqueous solution was found to be 4-amino-1,2-dihydro-2-oxopyrimidine, and hence the zwitterion formulation is shown to be incorrect (Brown, Lyall).
The predominant tautomeric form of 4-hydroxy-6-mercapto-pyrimidine is being examined by comparison of the ultraviolet spectra with those of all possible derivatives in which the two tautomeric hydrogen atoms have been substituted by immobile methyl- groups . During these studies a process has been discovered for methylating 4-aminopyrimidines on N{ 3 ), which was not previously possible. This was accomplished by the temporary insertion of a chloro-, methoxy- or methylthio- substituent in the 6-position (Brown, Teitei).
Hydrolysis of the zinc cation has been investigated as part of a quantitative study of hydrolytic equilibria involving transition metal ions. Programmes are being written, for the IBM 1620 Computer, to enable stability constants to be calculated directly from titration data. Similar techniques have already been used successfully in the analysis of the systems magnesium ion - adenosinetriphosphate, of the copper (II)-cystine (and related) systems, and for compiling tables of enbar(fi) functions (Perrin).
Kinetics and equilibria for the reversible addition of water to nitrogen heterocycles have been further investigated with particular reference to the effects of substituents. So far, most examples have been found to be first-order reactions, acid-base catalysed (Perrin, Inoue).
The oxidation-reduction potentials of cupric/cuprous complexes coupled with the sterically hindered substances: 2,9-dimethyl-1,10-phenanthroline and 2-chloro-l, 10-~henanthroline have been determined, and also the stability constants of some 1:1-and 1:2- metal complexes of these ligands. Polynuclear complex formation of copper (II) with cystine (and related aminoacids) has been examined quantitatively (Perrin, Hawkins) .
A new and complete series of buffers has been devised for spectrometric determination of ionization constants. These are optically transparent, and of low, constant ionic strength (Perrin).
A determination of the electronic spectra of some mono-substituted pyridines and pyridinium ions has revealed several differences between spectral substituent effects in the benzene and the pyridine series, in particular a large spectral effect by the higher halogens in the latter. The spectra obtained throw light on several doubtful cation structures. A comparison of the electronic spectra of the pyridinium, quinolinium and isoquinolinium ions with those of their quaternary ~-methyl derivatives has shown that on quaternization all absorption bands undergo small bathochromic shifts (Spinner).
;Vibration-spectral band
3. 622/1963
Vibration-spectral band assignments for the pyridinium ion have been examined by a study of pyridine deuteriochloride and li-methylpyridinium chloride. The latter strongly resembles toluene with regard to the Raman bands arising from substituent-sensitive aromatic vibrations (Spinner).
The infrared and Raman spectra of several series of substituted pyridines have been compared with those of their cations. The spectral characteristics of 2-, ~-, and 4-substituted pyridinium ions are mostly affected to a small extent only by the nature of the substituent. The few aromatic vibrations which are strongly influenced by the substituent are very similar in the substituted benzene, substituted pyridine, and substituted pyridinium ion (generally irrespective of the position of substitution) (Spinner).
The proton magnetic resonance spectra of the hydrochlorides of urea and of 2-, 3- and 4-hydroxypyridine in dimethyl sulphoxide exhibit only one combined signal for all labile protons, which shows that proton exchange is rapid. The proton magnetic resonance spectrum of 4-hydroxypyridine hydrochloride in dimethyl sulphoxide is different from that in sulphur dioxide; this is unlikely to be due to a difference in cation structure in the two solvents but probably reflects different consequences of high proton mobility (Spinner).
In the vibration spectra of the mono- and poly- halogeno- acetate ions the frequency of the band normally attributed to antisymmetric OCO stretching displays (strongly) the substituent dependence expected for carbonyl stretching bands, but the frequency of the band normally attributed to symmetric OCO stretching changes little and irregularly with substitution. The latter band seems to be more satisfactorily assigned to antisymmetric CCO stretching (Spinner).
Research is being carried out to find a more satisfactory method for the microdetermination of chlorine in organic antimonial compounds, and of mercury in organic mercurichlorides (Fildes).
Preliminary studies have been made for an ultramicro-method for the determination of nitrogen in the minute accounts of material submitted by biochemical workers. The example studied is the determination of nitrogen in solutions of hyaluronic acid containing protein equivalent to 0.03 mg. of nitrogen per mil. Reasonably satisfactory results can already be obtained with 1 mil. samples of these solutions, as well as with 0.5 mg. samples of standard organic chemicals. The rrethod, based on a sealed-tube Kjeldahl digestion of the sample, utilises a spectrometric measurement of the complex given by ammonia and indanetrione in buffered solution. The sample is weighed, in the first instance, on a Mettler UM7 seven-place balance (Fildes).
An investigation of the N-oxides of quinazolines showed, unexpectedly, that these have as strong a tendency to hydrate covalently as have the parent compounds (Armarego).
A study of covalent hydration has been made in those triazanaphthalenes that are based on pyrimidine. This study is being extended to the pyrazinopyrazines and some naphthyridines (Armarego).
A convenient preparation of the useful intermediate, pyridine -3, 4-dicarboxylic acid has been discovered (Armarego, Evans).
The reduction of pyrimidi~s, their alkyl-, amino-, and hydroxyderivatives has been pursued with a variety of techniques in order to find new ways of producing hydropyrimidines (a poorly-investigated class of substances) and of finding their chemical and physical properties (Evans),
New and very conven i ent syntheses of ~-aminobenzaldehyde, and its N-methyl- and -dimethyl- derivatives, have been found in the conversion of ethyl anthranilate (and its N-methyl- derivatives) to the corresponding tosyl hydrazides which were subjected to alkaline decomposition (Barlin).
/Difficulties in the conversion
4. 622/1963
Difficulties inthe conversion of 6-hydroxypteridine to 6-chloropteridine have been overcome, and a study of the reaction and its by-products made (Clark).
After many frustrations, a new route to the azaindoles (substances of current research interest in neuropharmacology) has been found in the condensation of chloroacetic acid with various aminopyridine -carboxylic acids (Willette).
Other Activities
Professor Albert spent 7 months abroad on study-leave. For 5 months he was based on the London School of Hygiene and Tropical Medicine, and made a study of the connexions between the chemistry of structures in micro-organisms and the chemistry of drugs which act specifically on these special structures. He also visited the United States, Russia, Sweden, Denmark, Germany, Switzerland, France and Italy, where he lectured and took part in symposia and conferences.
During September, Dr. D. J. Brown attended the International Symposium on Pteridines by special invitation, in Stuttgart, and also lectured in the u.s.A. Dr. D. D. Perrin lectured to the Sydney University Chemical Society on 'Rapid reactions and some biological consequences'.
Dri. Armarego, Barlin, Evans, Perrin and Mr. Hawkins and Mrs. Lyall read papers at the A.N.Z.A.A.s. Meeting in Sydney.
Dr. R. Norman Jones, of the National Research Council, Ottawa, and Secretary of the I.U,P.A.c. Spectrographic Commission spent several days in the DepaFtment in October and gave lectures.
Specimens of substances, discovered in this Department have been sent upon request to the Hospital for Sick Children (Great Ormond St.~ London, to the Cancer Chemotherapy Center, Bethesda, Maryland, to the U.K8 Atomic Energy Authority, Harwell, and to the University of Cambridge.
Four projects in the large-scale laboratory and eight high pressure reactions have been carried out for colleagues in other departments.
During the year, 99 ionization constants were determined on 75 substances for research workers in this School . Spectroscopic service work included 200 ultraviolet and 100 infrared spectra, several of the latter being far other departments of the School.
A total of 1670 requests for elemental microanalyses, micro-weighings and related micro-manipulations on 746 samples were submitted by 47 research workers in this School. Of this work, 46% was done for other Departments in the School (Physiology 13.7; Inorganic Chemistry 22.5~ Biochemistry 7ol; other Departments 2.8%). Special apparatus was designed for the combustion of deuterated and tritiated substances used in biochemistry, and for collecting the products in a form convenient for isotope analysis.
Publications
Albert, A., Barlin, G.B.
'Ionization Constants of Heterocyclic Substances. Part V. Mercaptoderivatives of Diazines and Benzodiazines '. J,Chem.Soc., 3129.
Albert, A., Howell, C.F.
'Pteridine Studies. Part XVII. Addition to 2-Hydroxypteridines'. J.Chem,Soc, 1591.
Albert, A., Howell, C.F., Spinner, E.
'Pteridine Studies, Part XIX. J,Chem.Soc., 2595.
Covalent Hydration of 2-Aminopteridines 1•
/Albert, A., Matsuura , s.
5. 622/1963
Albert, A., Matsuura, s.
'Pteridine Studies. Part XVIII. The Reduction of Hydroxypteridines'. J,Chem,Soc., 2162.
Albert, A., Serjeant, E.P,
'Ionization Constants, a laboratory manual'. London, Methuens , pp.xii+ 180.
Armarego, W. L. F.
1Quinazolines 1 , Chapter 10 in 'Advances in Heterocyclic Chemistry', ed. A. R. Katritzky. London, Academic Press .
'Quinazolines. Quinazolines'.
Part IV. Covalent Hydration in the,Cations.of .Substit~ted J,Chem.Soc., 561.
'Triazanaphthalenes , Part I. Covalent Hydration in 1,3,5 -, 1,3,6-, 1,3,7-, and 1,3,8-Triazanaphthalene', J,Chem.Soc,, 4094.
'Quinazolines, Part V. Covalent Hydration in Quinazoline -3- oxides'. J,Chem.Soc,
Armarego, W,L.F., Evans , R,F.
'A Convenient Preparation of Pyridine-3,4-Dicarboxylic Acid'. J,Appl.Chem., ~. 45,
Barlin, G.B.
'A Convenient Synthesis of ~-Aminobenzaldehyde and its N-Methyl-Derivatives, from ~-Aminobenzoic Esters'. J.Appl.Chem., J,1, 148.
Belcher, R., ~ Fildes, Joyce, E.
'Titrimetric Methods for t he Micro Determination of Sulphur and Halogens in Organic Compounds by the Rapic Combustion Procedure . Part III, The simultaneous determination of sulphur and t he halogens'. Analyt,chim.Acta, 2fl, 155,
Brown, D. J.
'The Pyrimidines ', New York, Interscience, pp.xxvi + 776.
Brown, D. J., Evans, R, F,
1Hydropyrimidines. Part I , 1,4,5,6-Tetrahydropyrimidine and its Derivatives', J,Chem,Soc,, 527,
' Hydropyrimidines . Part II. A New Genera l Synthesis of Substituted 1,4,5,6-Tetrahydropyrimidines ', J,Chem,Soc,, 4039.
Brown, D, J., Jacobsen, N. w.
' Pyrimidine Reactions . Part IV , imidine and Related Compounds ',
Brown , D. J., Lyall, Janice M,
The Methyiation of 2,4- and 4,5-DiaminopyrJ ,Chem,Soc ,, 3172.
'The Fine Structure of Cytosine'. Aust ,J,Chem.
Evans, R, F.
'The Use of Chloromercurates to Facilitate the Infrared Examination of Bases (Exemplified by Tetrahydropyrimidines)', J,Chem.Soc., 4259.
/'Recent Advances
6. 622/1963
Evans, R. F.
'Recent Advances in the Organic Chemistry of Hydrazine'. Reyiews of Pure and Appl.Chem., 12, 146.
Hawkins, c. J., Perrin, D. D.
'Oxidation-Reduction Potentials of Metal Complexes in Waters Some Copper Complexes. J.Chem,Soc., 1351.
Inoue, Y., Perrin, D. D.
'Pteridine Studies. Part XX. Reversible Water Addition to Hydroxypteridines'. J.Chem,Soc., 2600,
'Kinetics of the Reversible Hydration of 2-Hydroxypteridine'. J,Phys.Chem., ~' 1689.
Perrin, D. D.
'Pteridine Studies, Part XVI. Equilibria in Aqueous Solutions of Pteridine', J,Chern.So~., 645.
'The Hydrolysis of Manganese (II) Ion 1 • J,Chem,Soc., 2197.
'The Hydrolysis of Metal Ions. Part III. Zinc'. J,Chem.Soc., 4500.
Perrin, D, D., Perrin, D.R. ~
'The N.m.r. Spectrum of Pisatin', J,Amer.Chem.Soc., ~' 1922,
Spinner, E.
'The Vibration Spectra ano Structures of the Hydrochlorides of Aminopyridines'. J,Chem,Soc., 3119.
'The Infrared Spectra and Structures of the Hydrochlorides of 4-MercaptopyridinE and 4-Mercaptoquinoline'. J,Chem,Soc., 3127.
Spinner, E., White, J, C. B.
'The Vibration Spectra of the Cations of Methoxypyridines'. J,Chem,Soc., 3115.
~ Not a member of this University.
