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Polysaccharides Peptides and Proteins. Pharmaceutical Monographs PDF

205 Pages·1966·11.857 MB·English
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PHARMACEUTICAL MONOGRAPHS GENERAL EDITOR J. B. STENLAKE, D.SC,Ph.D.,F.P.S.,F.R.I.C,F.R.S.E. Professor of Pharmacy, University of Strathclyde Volume 4 POLYSACCHARIDES, PEPTIDES AND PROTEINS Already published Volume 1 AN INTRODUCTION TO MICROBIOLOGY W. B. Hugo, B.Pharm., Ph.D.(Lond.), F.P.S. Volume 2 AN INTRODUCTION TO PARASITOLOGY John M. Watson, D.Sc.(Lond.), A.R.C.Sc. Volume 3 STERILISATION AND DISINFECTION T. D. Whittet, B.Sc, Ph.D., F.P.S., F.R.I.C, D.B.A. W. B. Hugo, B.Pharm., Ph.D.(Lond.), F.P.S. G. R. Wilkinson, F.P.S. POLYSACCHARIDES PEPTIDES AND PROTEINS BY R. T. COUTTS B.Sc, Ph.D., A.R.C.S.T., M.P.S. University of Saskatchewan, Saskatoon G. A. SMAIL B.Sc, A.R.C.S.T., M.P.S. University of Strathclyde WILLIAM HEINEMANN MEDICAL BOOKS LTD LONDON First published 1966 © R. T. Coutts and G. A. Smail 1966 Printed in Great Britain by Butler & Tanner Ltd, Frome and London GENERAL PREFACE The aim of this series of pharmaceutical monographs is to provide an up-to-date series of short publications for teaching general and specialised topics to undergraduate students of pharmacy and allied subjects. Each monograph in the series is the work of an expert or group of experts actively engaged in teaching or practice. For convenience, however, groups of two or more monographs on related subjects have been collected together for publication. Each monograph is intended to serve as the basis for a group of lectures or tutorials in the honours and pre-honours years of undergraduate courses in pharmacy and allied subjects in British and Commonwealth Universities and, of necessity, some mono­ graphs are slanted toward the more specific requirements of these countries. We have, however, endeavoured to keep the mono­ graphs on a general plane to ensure their suitability for use in other parts of the world. An attempt has been made to present the subject matter of in­ dividual monographs in such detail that it provides a permanent record for study purposes capable of being used by students in lieu of lecture notes. Each monograph, however, sets out to provide not merely a detailed account of essential subject matter, such as would be required for examination purposes, but also seeks to indicate its relevance and importance to pharmaceutical studies in general. In this respect, monographs extend naturally to the boundaries of knowledge in all major aspects, and wherever possible present appropriate rival views and hypotheses in sufficient detail for the student to grasp their essential detail without reference to the original. The texts are, however, referenced to provide additional sources of information. I am indebted to the authors of the individual monographs for their willingness to collaborate with me in the preparation of this series. I should also like to express my thanks to my colleagues and many friends for their help and advice in framing the series and for discussions on individual monographs. I should further like to express my sincere thanks to Mrs S. Cohen for invaluable secre­ tarial assistance. J. B. S. v PREFACE TO VOLUME 4 A wide variety of naturally-occurring macromolecules which are either polysaccharide, peptide or protein in nature are important as medicinal and pharmaceutical agents. These include such widely diverse materials as peptide hormones and antibiotics, immuno- logical products, blood products, ligatures and sutures, surgical dressings' materials, and also such materials as starches, gums and mucilages, which are valuable as adjuncts to pharmaceutical formulation. Certain of these more specialised materials form the subject of separate monographs to appear later in this series. The prepara­ tion, use and development of pharmaceutical products of this type, which are of biological origin, depend on a better understanding than has hitherto been considered necessary of their chemical make­ up, and of the relationship between their physical and chemical properties and the corresponding properties of the biological and pharmaceutical systems with which they interact in use. The pres­ ent volume is, therefore, confined to the consideration of the basic chemical and physical properties of polysaccharides on the one hand, and peptides and proteins on the other, exemplified by con­ sideration of the detailed structure of selected examples of homo­ geneous and simple heterogeneous materials of each class which have important medical and pharmaceutical uses. An attempt has been made wherever possible to relate their properties, especially physical properties, to their pharmaceutical use. J. B. S. vii ACKNOWLEDGMENTS (Amino acids and proteins) Figure 3 page 114 Taken from S. Moore, D. H. Spademan and W. H. Stein (1958), Analyt. Chem., 30, 1186. Figure 4 page 117 Taken from R. B. Corey and L. Pauling (1953), Proc. Roy. Soc, 141B, 17. Figure 5 page 119 Taken from K. U. Linderstr0m-Lang and J. A. Schellman (1959), Protein Structure and Enzyme Activity in The Enzymes, Vol. I, edited by P. D. Boyer, H. Lardy, and K. Myrback, Academic Press, New York, p. 448. Figure 6 page 119 Taken from C. O. Wilson and O. Gisvold (1962), Textbook of Organic, Medicinal and Pharmaceutical Chemistry, 4th Ed., Pitman Medical Pub­ lishing Co. Ltd., London, p. 737. Figure 7 page 121 Taken slightly modified from H. N. Rydon (1962), Péptide Synthesis, Royal Institute of Chemistry, Lecture Series No. 5. Tables 8 9, 10 pages 129, 130, 9 Taken from V. du Vigneaud, C Ressler and S. Trippett (1953), /. Biol. Chem., 205, 949 et seq. Figure 8 page 128 J. A. Pierce and V. du Vigneaud (1950), /. Biol. Chem., 182, 362. Table 16 page 163 Taken from A. B. Lerner and T. H. Lee (1962), Vitamins and Hormones, 20, 342. Table 17 page 167 Taken from K. Hofman (1962), Ann. Rev. Biochem., 31, 228. Figure 14 page 178 Taken from K. Hallas-Moller, K. Petersen and J. Schlichtkrull (1952), Science, 116, 394. Figure 15 page 181 Taken from F. B. Peck (1956), cited by J. C. Krantz and C. J. Carr (1961) The Pharmacological Principles of Medical Practice, 5th Ed., Balliere, Tindall and Cox, London, p. 1312. 77 CHAPTER 1 INTRODUCTION Many substances of pharmaceutical importance belong to the class of compounds known as polysaccharides. Such compounds are derived by multiple combination of simple sugars which, to­ gether with the polysaccharides, are collectively termed carbo­ hydrates. The term carbohydrate (hydrate of carbon) is obtained from the empirical formula Cx(H 0)y, possessed by almost all 2 compounds of this class, though such a name is not descriptive of their nature and, furthermore, not all compounds of such a formula are carbohydrates. All carbohydrates are, however, polyhydroxy- lated compounds, the majority of which contain 'free' or 'masked' aldehydic or ketonic groups. The simple carbohydrates are called sugars and are crystalline, water-soluble substances with a sweet taste. Usually their names end in the suffix '-ose'. Sugars are classified as monosaccharides and oligosaccharides. Examples of the former containing from three to eight carbon atoms are found in nature, but the most common monosaccharides possess five or six carbon atoms. Mono­ saccharides cannot be hydrolysed into smaller units. Oligosac­ charides consist of disaccharides, trisaccharides and tetrasac- charides which yield two, three or four monosaccharide units, respectively, on hydrolysis. It has recently been suggested, how­ ever, that the term oligosaccharide should be reserved for sugars containing not more than nine monosaccharide units. Polysaccharides are more complex substances with high mole­ cular weights. They are not sweet, non-crystalline, and are usually insoluble in water. They yield a large number of monosaccharide units on hydrolysis. MONOSACCHARIDES Monosaccharides can be further classified. If they contain an aldehydic group, they are termed aldoses; if they possess a ketonic group, they are called ketoses. The number of carbon atoms in the molecule is indicated by a Greek prefix; trioses, tetroses, pen- toses and hexoses contain three, four, five and six carbon atoms 5 POLYSACCHARIDES, PEPTIDES AND PROTEINS respectively. Thus, a monosaccharide which has five carbon atoms and possesses an aldehydic group is referred to as an aldopentose; similarly a ketohexose is a monosaccharide with six carbon atoms, containing a ketonic group. All monosaccharides are reducing sugars because of their aldehydic or a-hydroxy ketonic groups, and will reduce Fehling's Solution and Tollen's Reagent. The most im­ portant monosaccharides are the pentoses and hexoses. Structure Initially it is convenient to consider the aldohexoses as being straight-chain pentahydroxyaldehydes. Such structures are in agreement with their chemical properties, some of which are illus­ trated below: NH OH —> oxime 2 CHO I —PhNHNH —> phenylhydrazone —> osazone CHOH 2 I Ac 0 —> penta-acetate 2 CHOH I Br /H 0-> HOOC(CHOH) CH OH 2 2 4 2 CHOH — HNO3 -> HOOC(CHOH) COOH I 4 CHOH Na/Hg-> HOH C(CHOH) CH OH I 2 4 2 CH2OH HI/P—> CH3CHI(CH2)3CH3 + CH3(CH2)4CH3 For similar reasons, the structure of the aldopentoses has been proved to be CHO-(CHOH) CH OH. The only important ketose 3 2 is D-(—)-fructose. It, too, forms an oxime and a penta-acetate, and on reduction yields a hexahydroxyalcohol (racemic mixture). Nitric acid oxidation converts fructose into a mixture of trihydroxyglu- taric, tartaric and glycollic acids, all of which contain less than six carbon atoms and hence indicate that the carbonyl group in fruc­ tose is a ketonic one. Fructose has been established as a 2-keto- hexose by the following sequence of reactions : CH OH CH OH CH 2 2 3 OH I I 1. HCN HI c=o >>c< -> CH-COOH heat I 2. Hydrolysis | \COOH (CH2)3 (CHOH)3 (CHOH)3 I CH2OH CH2OH CH3 fructose a-Methylcaproic acid (racemate) INTRODUCTION Stereoisomerism As the formula for an aldose, CHO CHOHCHOHCHOHCHOH CHOH 2 possesses four asymmetric carbon atoms (marked *) it follows that there are sixteen different configurations for the molecule of which eight (D-forms) will be mirror images of the other eight (L-forms). For similar reasons, there will be four D-forms and four L-forms for the aldopentoses and the ketohexoses. Emil Fischer's contribu­ tion to the elucidation of these configurations earned him the Nobel Prize in 1902. Relative configuration. The triose, glyceraldehyde, has one asym­ metric carbon atom and, therefore, exists in two forms (enantio- morphs I and II). Rosanoff (1906) proposed that dextrarotatory glyceraldehyde should be represented as in (III) and this structure is accepted as the arbitrary standard for D-sugars. Any sugar which can be prepared from or converted into D(+)-glyceralde- CHO CHO CHO CHO 1 1 1 1 H——OH HO—|—H c^CH OH 2 C / C \ 2 H OH HO H CH2OH CH2OH (I) (II) (HI) (IV) hyde will belong to the D-series. Structure (IV) is the planar for­ mula of L-(— )-glyceraldehyde, the arbitrary standard for the L-sugars. It is important to note that in the nomenclature of the sugars, the positive and negative signs, previously written d and / respectively, refer to the direction in which the monosaccharides [—C—OH HO—C—H H—C—OH HO—C—H 1 1 1 1 CH OH CH OH CH CH 2 2 3 3 D-series L-series D-series L-series rotate polarised light, and not to their configuration. Other sugars, such as those which do not possess a hydroxymethyl group, are still designated as D or L on the basis of the configuration about the lowest asymmetric carbon atom in the chain. The relationship of D-glyceraldehyde to other D-sugars can be demonstrated by various means. Nitric acid oxidation of D-(—)- 7 POLYSACCHARIDES, PEPTIDES AND PROTEINS erythrose, for example, gives mesotartaric acid while (—)-tartaric acid is the product obtained from D-(+)-threose. As the configura- CHO COOH CHO COOH I j H—!—OH H—i—OH HO- -H HO- -H H— —OH H— -OH H- —OH H- -OH CH OH COOH CH OH COOH 2 2 D-(—)-Erythrose Mesotartaric D-(+)-Threose L-(-)-Tartaric acid acid tions of the products are known, the configurations of the tetroses are established. A method of ascending the sugar series, the Kiliani Reaction, is a valuable way of determining the relative configura­ tion of an aldopentose or an aldohexose. Thus, when D-( +)-threose is treated with hydrocyanic acid, a mixture of cyanhydrins is CN CN I I CHO HCOH HOCH I I I HOCH -+ HOCH -1- HOCH I I I HCOH HCOH HCOH I I I CH,OH CH,OH \ LCH20H COOH co To COOH I I I HCOH -~ HCOH HOCH HOCH I I I I I HOCH 0 t HOCH HOCH -+ I I I I HC HCOH HCOH I I I CHZOH CH,OH CH,OH 1 1 CV) (VI) CHO COOH COOH CHO I I I I HCOH HCOH HOCH HOCH I I I I HOCH + HOCH HOCH t. HOCH I I I I HCOH HCOH HCOH HCOH I I I I CHzOH COOH COOH CH20H Cvm ( W (IX) 6 8

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