I n Part V1 we described the preparation of a series of streptidine-, strepturea-and streptamine-P-glucosides and -P-glucosaminides. Concurrently with this work we also considered the preparation of other streptomycin analogues such as streptidine-oxyethyl-2-Nmethylamino-2-deoxy-a-~-glucopyranoside (I), which bears a formal resemblance to streptomycin (11). We now report the synthesis of streptidine-oxyethyl P-D-glucopyranoside (I11 ; R = H) which has been prepared as a model compound for these studies.
I n preliminary experiments 2-chloroethyl-tetra-O-acetyl-~-~-glucopyranoside2 and 2 -bromoethyl-tetra -0 -acetyl -P -D -glucopyranoside,4 prepared from acetobromoglucose and the corresponding ethylenehalohydrin, failed to yield any condensed product in reactions with a model compound, cyclohexanol. This can be attributed to the lower reactivity of the alkyl halides compared with the halogen at the reducing carbon of O-acetylglycosyl halides. Attention was then turned to the use of the tosyloxy group, which is known to be replaceable in ether formation by methoxy3 and benzylphenoxy4 radicals using sodium hydride and other condensing agents. The required condensation can be approached in two ways, using the tosyl ester of either hepta-acetylstreptidine or -2-hydroxyethyl-tetra-0-acetyl-P-~-glucopyranoside as intermediate. The greater reactivity of primary alcohol tosylates compared with secondary alcohol tosylates53 in such condensatioils favoured the choice of the latter intermediate.2-Hydroxyethyl-tetra-O-acetyl-P-~-glucopyranoside (IV ; R = H), prepared from acetobromoglucose and ethylene glycol by the method of Fischer and Fischer, was condensed with p-toluenesulphonyl chloride in dry pyridine at 0" to yield 2-toluene-psulphonyloxyethyl-tetra-o-acetyl-p-D-glucopyranoside (IV ; R = Ts). Reaction of the product with hepta-acetylstreptidine
The antibacterial action of streptomycin (I ; R = CHO, R' = H) has been studied widely, and was'reviewed in 1951l and more recently by Williamson,2 but the mechanism of its action against Mycobacterium tuberculosis is still only incompletely understood. Thus, inhibition of fatty acid oxidation by streptomycin can be traced in E . coli to a block in the terminal respiration system at a point which involves a pyruvate-oxalacetate condensation. 39 One product of such a metabolic condensation, 2-phospho-4-hydroxycarbonyladipic acid, has been isolated. Its formation is markedly inhibited by streptomycin, and the condensation mechanism is entirely lost in streptomycin-resistant strains.Oxidation of fatty acids in M . tuberculosis, on the other hand, occurs by some alternative and unidentified mechanism, which does not involve pyruvate, oxalacetate or other members of the citric acid cycle, and which is only partially inhibited by streptomycin.6 This accords with the observations of Bernheim' on the oxidation of fatty acids by the tubercle bacillus. I n general, young actively-growing cultures are more susceptible to streptomycin than older or resting organisms,S and this suggests that streptomycin blocks the synthesis of metabolites essential for growth or cell division. Certain cell constituents such as protein^,^ nucleoproteins, lo deoxynucleic acidlot and possibly ribonucleic acidlS form precipitable streptomycin complexes, and even relatively simple precursors of these substances such as purines and pyrimidines14 have been reported to antagonize the action of streptomycin against M . tuberculosis. The activity of streptomycin is also reduced by inclusion in the culture medium of peptone,16* l6 and the amino acids methionine, cysteine, tyrosine and aspartic acid.16~17 Of these, antagonism by cysteine is of * See References.
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