Cordycepin A New Antibiotic

Cunningham, Kenneth G (1951) Cordycepin A New Antibiotic. PhD thesis, University of Glasgow.

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A strain of the mould Cordyceps militaris (Linn.) Link has been promoted on nitrogenous media to yield solutions which inhibit the growth of several microorganisms. It has been shown that the total activity of the solutions can be absorbed upon activated charcoal from which the active principle, cordycepin, has been isolated. Dilute aqueous solutions of cordycepin reproduce the Inhibitory effect of the culture solutions towards the test organism, and the activity is sufficiently great to term cordycepin an antibiotic. The metabolic product contains the elements carbon, hydrogen, oxygen and nitrogen and is optically active. It forms salts with picric acid, picrolonic acid and flavianic acid, and elemental analyses of the metabolic product and its simple derivatives suggested the empirical formula C8H10O2N4 or C10H13O3N5. The solubility properties of cordycepin are such that a standard method of molecular weight determination could not readily be employed to distinguish between these alternatives; an accurate micro-method for the molecular weight determination of bases such as cordycepin was therefore devised and is discussed in the Appendix. The molecular weight of cordycepin was found to be 254, in close agreement with that required by C10H13O3N5 (251). The first indication of the structure of the metabolic product was obtained from a study of its ultraviolet light absorption which shows marked similarity to that of some pyrimidine and purine compounds. Cordycepin is resistant to reduction and hydrogenation, but benzoylation yielded a tetrabenzoate and from the acid hydrolysis of this ester, adenine hydrochloride was isolated, thus accounting for the total nitrogen content of the molecule. The metabolic product itself was found to be unstable in dilute hydrochloric acid, hydrolysis occurring to yield solutions from which adenine was isolated and characterised as its picrate. Solutions of hydrolysed cordycepin have been shown to react with 2:4-dinitrophenylhydrazine in hydroohlorio acid, yielding the 2:4-dinitrophenylosazone of a molecule C5H10O4 and this suggests that the linkage between adenine and the residual fragment Is glycosidic rather than amide. No carbon-methyl, methoxyl or nitrogen-methyl group was detected in cordycepin, and the absence of the grouping CH3.CHOH or CH3.CO in the side chain was confirmed by the negative result of the iodoform test, but the presence of a terminal hydroxymethyl group was proven by the tosylation of cordycepin. Deamination of cordycepin yielded hypoxanthine, proving the molecule to be unsubstituted on the 6-amino group of the adenine nucleus. The glycosidic bond therefore occurs at the 7- or 9-position and the formulation of cordycepin as an adenine-9-glyooside is much preferred on the basis of the ultraviolet absorption spectrum. Since an osazone of the glycosidic fragment has been isolated corresponding to a deoxypentose (cordycepose), cordycepin cannot be an adenine-9:2'-deoxypentoside; evidenoe that the molecule is an adenine-9:3'-deoxypentoside has been provided by the fact that cordycepin is resistant to periodate oxidation. Careful hydrolysis of cordycepin followed by removal of adenine and hydrochloric acid yielded analytically pure cordycepose as a pale straw-coloured syrup which reduces Fehling's solution; bromine oxidation of the sugar gave the corresponding lactone, cordyceponolactone, C5H8O4. The latter yields a crystalline phenylhydrazide and cordycepose must be a deoxyaldopentose. The four stereoisomeric phenylhydrazides corresponding to a straight-chain 3-deoxyaldopentonic acid have been described previously, and differ markedly in physical properties from cordyceponic acid phenylhydrazide. Cordycepose is therefore a branch-Chain sugar, and this theory is strongly supported by the fact that no optical activity could be detected in ethanolic solutions of cordycepose p-bromophenylosazone. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry, Pharmacology
Date of Award: 1951
Depositing User: Enlighten Team
Unique ID: glathesis:1951-78870
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Jan 2020 14:44
Last Modified: 30 Jan 2020 14:44

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