The chemistry of some streptomycin derivatives

McGilveray, Iain J (1964) The chemistry of some streptomycin derivatives. PhD thesis, University of Glasgow.

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The history of the chemotherapy of tuberculosis is reviewed, with emphasis on the newer experimental drugs such as ethambutol, kanamycin and 4,4'-di-isoamyl oxythiocarbanilide. The recognised regimens in tuberculo-therapy are discussed briefly in order that the current status of streptomycin may be appreciated. The chemistry of the aminoglycoside antibiotics is reviewed in detail, evidence of the recently assigned structures of the neomycin-paromomycin group and the kanamycins being cited as well as the more classical degradation and structural determination of streptomycin. Suggested biogenetic pathways and recent mode of action studies are noted, the introduction being completed by an inventory of synthetic derivatives of this group of antibiotics. The remaining points of the chemistry of dihydrostreptomycin to be elucidated are discussed. This includes confirmation of the configuration of the glycosidic linkages, and direct proof of the nature and ring form of dihydrostreptose, the central moiety of dihydrostreptomycin. Early workers degraded the trisaccharine dihydrostreptomycin with methanolic hydrogen chloride into the diguanidinoinositol, streptidine, and the methyl glycoside of the glucosaminidem dihydrostreptobiosaminide, the latter is composed of the methyl lyxofuranoside, dihydrostreptose, linked glycosidically to the hexosamine, N-methyl-L-glucosamine. Further acid degradation, however, led to destruction of the dihydrostreptose and this was not isolated. D-glucosaminides are known to be very stable to acid hydrolytic conditions, a stability attributed to the positive charge on the amino nitrogen group causing repulsion of the proton and suppressing formation of the intermediate carbonium ion. N-Substitution of the methyl D-glucosaminides with an electron withdrawing group has been shown to facilitate glycosidic cleavage; the formation of an electronically neutral substituted amino group, such as the acetamido group, apparently allowing protonation of the glycosidic bond. Hydrolysis of the N-substituted glucosaminides, however, is accompanied by removal of the substituting group, and the rate at which this occurs at the expense of glycosidic hydrolysis is apparently dependent on the electrophilic properties of the substituting group. In this present work dihydrostreptose was obtained from the L-glucos-aminide methyl dihydrostreptobiosaminide by application of the above theories. The N-(2,4-dinitrophenyl)-(DNP), N-acetyl- and, N-tosyl-derivatives of methyl dihydrostreptobiosaminide have been prepared, the N-acetyl derivative has been obtained by a variety of routes. Samples of N-methyl-D and L-glucosamine and some novel N-acyl derivatives have been also prepared for comparison by paper chromatography with various hydrolysis products. The acid hydrolysis of methyl N-(2,4-dinitrophenyl)-dihydrostreptobiosaminide has been investigated in detail; paper chromatographic results showed that hydrolysis had occurred with 2N hydrochloric acid. The hydrolysis of methyl N-acetyldihydrostreptobiosaminide yielded a small sample of dihydrostreptose, which was characterised as the free sugar and the monoacetate. Methyl N-acetylstreptobiosaminide dimethylacetal the analogous derivative of streptomycin under the same acid conditions gave only N-methyl-L-glucosamine, the streptose moiety being degraded. Deamination of methyl dihydrostreptobiosaminide with 1,2,3-indane trione hydrate was attempted unsuccessfully, as was cation-exchange hydrolysis of this compound. Enzymatic cleavage of methyl N-acetyldihydrostreptobiosaminide was also unsuccessful under the conditions tried. The second section of the thesis is devoted to glycosides of dihydrostreptobiosaminide. Methods of glycosidation, the Koenigs-Knorr, the Helferich and the Fischer syntheses are reviewed. Transglycosidation the acid-catalysed replacement of the methyl by another aglycone was attempted with methyl dihydrostreptobiosaminide and yielded the benzyl, phenyl, ?-bromoethyl, cyclohexyl, m-cresyl and anisyl glycosides. No mechanism has heretofore been proposed for this substitution. An examination of its relation to the Fischer glycoside synthesis suggests that the furanose ring of dihydrostreptose would facilitate the reaction and that the ease of glycosidation provides indirect evidence of the nature of this ring in dihydrostreptobiosaminide. The phenyl and ?-bromoethyl dihydrostreptobiosaminide have been tested in vitro against Mycobacterium tuberculosis. Nuclear Magnetic Resonance studies of various dihydrostreptomycin derivatives are also interpreted.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: A M Courie
Keywords: Pharmacology
Date of Award: 1964
Depositing User: Enlighten Team
Unique ID: glathesis:1964-73860
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jun 2019 08:56
Last Modified: 14 Jun 2019 08:56

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