Ketonucleosides groups

Ketonucleosides constitute a class of nucleosides containing in the sugar moiety a keto group that results from the oxidation of an asymmetric carbon atom. This article considers all so-called ketonucleosides deriving from aldosyl derivatives, and excludes those in which the keto group of the sugar moiety is involved in the nucleosidic bond (for example, nucleosides of psicose1), which have occasionally been termed ketonucleosides. 

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 5 -0-trityl 3 -ketothymidine 33b exhibited an i.r. absorption at 1778 cm-1, attributed to the keto group introduced.44 Also, theophylline 4 -ketonucleoside derivative 41a had26,27 an i.r. spectrum similar to that of the parent 40a, except for a carbonyl band at 1755 cm-1. Thymine 4 -ketonucleoside derivative 45 exhibited a carbonyl band at 1725 cm-1, assigned to the C=0 and -C(=0)-C=C- groups of the base.30 The... 

Conformational inversions in the field of ketonucleosides were established by n.m.r.-spectral analysis. It has been reported30,32 that the introduction of a carbonyl group at C-4 of the sugar moiety of L-rhamnosyl-purines and -pyrimidines led to ketonucleosides possessing an axially attached nitrogenous base. Such unusual positions of the base have been observed in the case of a glycosyltheophylline,61 and for some derivatives of a rhamnosyl-5-fluorouracil.48... 

The value of Jv r and J2- 3. changed from 8 or 9 Hz to 2 or 3 Hz the latter values indicated the C4 conformation for the ketonucleosides. In addition, the H-3 signal shifted downfield, because of the presence of the 4 -keto group. The lC4 conformation was favored by the existence of weak interactions between the carbonyl group at C-4, and the equatorial substituents on C-3 and C-5, whereas these interactions were strong in the 4Ci conformation. 

Confirming the importance, for the biological activity,10-n of a keto group in the sugar moiety, the antiviral activity of some keto-C-nucleo-sides has also been reported.13 From this study, it was clear that the presence of a ketone group in these nucleosides, as in 4 -ketonucleoside 50a, gave a compound able to inhibit the replication of murine leukemia virus at nontoxic concentrations. 

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. 

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... 

A new radical allylation procedure has been applied to the synthesis of a 3 -C-allyl-2, 3 -dideoxypyrimidine nucleoside, and lactone 121, made by photochemical addition of isopropanol to the corresponding 2,3-ene, has been converted to the nucleoside 122. Branched-chain sulfonates 123 have been made from 3 -ketonucleosides, and the isobutyl group was found to be superior to other possibilities, it being cleavable by iodide ion to give the sulfonic acid, an analogue of a 3 -phosphate. An ingenious route to related phosphonates is outlined in... 

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