Unsaturated ketonucleosides

This Subsection deals with the preparation of 2 - and 4 -ketohexosyl-purines and -pyrimidines, which have proved to be versatile synthetic intermediates. A 5 -keto derivative of a hexofuranose nucleoside is also described. The synthesis of epoxy-, halogeno-, unsaturated, epimino-, and thio-ketonucleosides will be developed in subsequent Subsections and Sections. 

The synthesis of the first reported51,52 unsaturated ketonucleoside, 61a, was accomplished by acetylation of the known 7-(6-deoxy-/ -L-h/xo-... 

Among the unsaturated ketonucleosides may be classified the disaccharide derivative 74, which is an analog of the biologically active compound 68c. The key intermediate for the synthesis of this unsaturated ketodisaccharide nucleoside was the partially protected, disaccharide nucleoside 73, which was prepared by two separate routes,56 Treatment of 73 with the Me2SO-acetic anhydride reagent for two days at room temperature afforded 7-[2,3-di-0-benzoyl-4-0-(3-0-benzoyl-2,6-di-deoxy - / - d - glycero - hex - 2 - enopyranosyl - 4 - ulose) - 6 - deoxy - / - d -glycopyranosyl]theophylline (74), isolated crystalline.56... 

Unsaturated ketonucleosides have been shown to be remarkably stable under acidic conditions. 7-(3-0-Acetyl-4,6-dideoxy-/ -L-g/t/cm>-hex-3-enopyranosyl-2-ulose)theophylline (61a) proved to be stable in 0.1 M hydrochloric acid, as no glycosylic cleavage had occurred51 after 20 h. Similarly, no decomposition was observed when 7-(3,6-di-0-ace-tyl-2-deoxy-/ -D-gh/cero-hex-2-enopyranosyl-4-ulose)theophylline (66) was treated with 0.1 M sulfuric acid during 48 h at room temperature, and attempted, ionic hydrogenation with triethylsilane - trifluoroacetic acid failed.31... 

Some examples of the behavior of unsaturated ketonucleosides under alkaline conditions have also been reported. The enol acetate 61a is more stable than the parent ketonucleoside 36a. In 0.1 M methanolic sodium hydroxide, free theophylline was detected only after 4 h, by which time, loss of the acetyl group was complete a reaction time of more than 18 h was needed for complete cleavage of the glycosylic bond.51 In alcoholic solution, the unsaturated 4 -ketonucleoside 66 was very sensitive to nucleophilic attack, and decomposed rapidly, with elimination of the nitrogenous base.31 Thus, treatment with sodium borohydride at — 70° led to complete decomposition within 10 min but, when sodium borohydride was added to a solution of 66 in 1,2-dichloroethane containing acetic acid, fast reduction occurred, and no degradation was observed.31... 

The reduction of ketopentose-, as well as ketohexose-, nucleosides with metal hydrides has been used to obtain biologically important nucleosides and rare sugar nucleosides, by epimerization of a chiral center. Moreover, reduction of unsaturated ketonucleosides with borohydride provides new and direct routes to unsaturated and deoxy-nucleosides. 

Fast reduction was observed when the unsaturated 4 -ketonucleoside 66 was treated with sodium borohydride in solution in 1,2-dichloroeth-ane containing acetic acid.31 An unexpected attack from the most-hindered side gave 7-(4,6-di-0-acetyl-2-deoxy-/ -D-arahino-hexopyrano-syl)theophylline (92) almost exclusively. The mechanism proposed... 

A variety of nucleophiles could also be added to unsaturated ketonucleosides, to afford (by way of a 1,4-addition mechanism) amino-, azido-, aziridino-, and thio-ketonucleosides. The action of metal hydrides on ketonucleosides has been extensively discussed in Section V. 

A thorough investigation12 of the effects of the unsaturated ketonu-cleoside 61a on KB cells in culture confirmed the high cytotoxic potency of this compound. Moreover, it appeared that, at low doses, where no cytotoxic effect occurs, the ketonucleoside impaired DNA, RNA, and protein synthesis, and strongly inhibited cell multiplication. 

The first, in vivo study on the antitumor activity of ketonucleosides appeared14 in 1977. The action of l-(6-deoxy-2,3-0-isopropylidene-a-L-h/xo-hexopyranosyl-4-ulose)thymine (45) and of 7-(3-0-acetyl-4,6-dideoxy-/ -L-gfi/cero-hex-3-enopyranosyl-2-ulose)theophylline (61a) against LI 210 leukemia in mice was examined comparatively. From the results obtained, it was clear that the unsaturated ketohexosylpurine 61a was much more active than the ketohexosylpyrimidine 45, whereas the parent nucleosides (44 and 34a, respectively) were inactive under the same experimental conditions. 

A thorough study15 of the structure-activity relationship of the four unsaturated ketonucleosides 61a, 68b, 68c, and 72b showed that all of the compounds examined exhibited significant activity against LI 210 leukemia, and the presence of a methyl group on C-5 of the hexose did not appear to be a necessary prerequisite for significant activity. In the meanwhile, nucleosides 68b and 72b proved to be less toxic, and repeated administration of a dose appeared to decrease the toxic effects without affecting the antitumor activity of the compounds. 

In order to establish the possible mode of action of the tumor-inhibitory, unsaturated ketonucleosides, the reaction of 61a, 68b, 68c, and 72b with a variety of physiologically occurring nucleophiles was examined.75 Glutathione and cysteine reacted much more rapidly, as did other biological nucleophiles. 

Interestingly, as in the addition42 of benzenethiol to the unsaturated ketonucleoside 71, the addition of N-acetyl-L-cysteine occurred by a 1,4-mechanism. 

The ability of unsaturated ketonucleosides to react with protein sulf-hydryl groups was demonstrated by measuring their inhibitory action towards beef-heart lactate dehydrogenase.75 These results led to the conclusion that the primary targets for unsaturated ketonucleosides are glutathione and reactive thiol groups of proteins. 

The inhibition of tumor growth by unsaturated ketonucleosides could, therefore, be due to selective alkylation of the SH groups of key proteins that control cell division. Because the plasma membrane is the first barrier encountered by the drugs, it seems important to consider the interaction of unsaturated ketonucleosides with this cellular structure.76... 

Three additional approaches to the synthesis of CNT are shown in Fig. 9. The first [77, 78] involves transformation of 3 -ketonucleoside 44 into cyanohydrin 45, followed by deoxygenation at 3 and then at 2 to afford 47, which is easily epimerized to 31 by treatment with base (pH = 9). Treatment of 2 -0-acyl derivatives of 46 with bases produced elimination to give the 2, 3 -unsaturated nucleoside 48. An important factor in the chemistry of these cyanonucleosides is the acidity of the H-3 hydrogen atom in a-position to the nitrile group. This acidity is responsible for the facile epimerization 47 31 and for the elimination... 

R). Unsaturated C-nucleosides and unsaturated ketonucleosides are mentioned below. 

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