Cyclic nucleoside analogs

Azauridine was also synthesized using the knowledge of the course of alkylation of 6-azauracil 2-methylmercapto derivatives (e.g., Section II,B,4,b). The 1-ribofuranosyl derivative obtained by reaction of the mercury salt of the 2-methylmercapto derivative with tri-O-benzoyl-jS-D-ribofuranosyl chloride on removal of the methyl-mercapto and then benzoyl groups yielded crystalline 6-azauridine, The main difference between uracil and 6-azauracil nucleosides consists in the preparation of cyclic nucleosides. It is known that uridine can be readily converted to cyclic nucleosides by the reaction of 2 (50-O-mesyl derivatives with nucleophilic agents, Analogous... 

As it is evident from the chemical strnctnre, acyclovir looks like a nucleoside analog of gnanosine in side chain of which, instead of the traditional cyclic sugar residue a 2-hydrox-yethoxymethyl acyclic side chain is present. Acyclovir possesses antiviral activity with respect to types 1 and 2 of herpes simplex, shingles vims, Epstein-Barr virus, and cytomegalovirns. 

Cyclic hemiacetals and acetals are readily formed from y-hydroxyaldchydes," ketones, or acetals.Either the carbonyl compound or the alcohol is deblocked before spontaneous cyclization occurs. Aldehydes are regularly synthesized from alkeiies via ozonolysis or periodate cleavage. Acetal 7. a starting material for nucleoside analogs, is prepared directly by transacctalization of alcohol 6 with 1 % ethanol/hydrogen chloride. 

The concept is not limited to analogs of simple linear organophosphates (e.g. phosphoenol pyruvate analog as inhibitor of 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase [71]) but can be extended to cyclic phosphates (e.g. cyclic phosphoinositol analog as a phospholipase C inhibitor [72]) and transition state analogs (e. g. purine nucleoside phosphorylase (PNP) inhibitor [73]) (Scheme 4.30). 

These are C-nucleoside analogs (18) in which the cyclic sugar moiety and the heterocyclic base are flanked by one carbon. 

Little is known of the mechanism by which ribose is reduced. It has been suggested on the basis of chemical analogy (97) that the process could occur by displacement of the hydroxyl on C-2 of ribose to form the cyclonucleotide (IX). This could be followed bya reductive cleavage of theCj—O bond to form the deoxyribonucleotide. Cyclic nucleoside formation might be assisted by a preliminary phosphorylation of the 2 -hydroxyl group. H H... 

Treatment of the allylic sulfoxide 1227 a with diisopropylethylamine (DIPEA) or of 1227 b with N-trimethylsilyldiethylamine 146 and TMSOTf 20 leads in ca. 90% yield to the quaternary amino derivatives 1228 and 1229 and HMDSO 7 [36] (Scheme 8.15). Tetramethylene sulfoxide 1230 reacts with silylated thymine 1231 in the presence of three equivalents of TMSOTf 20 to give the 4 -thio-nucleoside analogue 1232 and HMDSO 7 [37]. Other silylated pyrimidine, pyridine, and purine bases react analogously with cyclic sulfoxides to give 4 -thio-nucleoside analogues [37, 37a, 38]. 

The most convincing evidence in favor of a uniform 3,5-diester linkage between nucleotides has been obtained by the action of various enzymes on synthetic diesters of known constitution.218 217 Ribonuclease and spleen extracts were found to act only on nucleoside 3-(benzyl hydrogen phosphates), but not on other isomers, to give nucleoside cyclic phosphates which are broken down further to give nucleoside 3-phosphates. It is concluded, by analogy, that polynucleotides, which are substrates for these enzymes, also possess ester groupings at the 3-positions, rather than at the... 

The reaction of 1,3-dipolar cycloaddition of enantiopure cyclic nitrones to protected allyl alcohol, is the basis of stereoselective syntheses of bicyclic N, O-iso-homonucleoside analogs (747), of isoxazolidine, to analogs of C-nucleosides related to pseudouridine (748) and to homocarbocyclic-2 -oxo-3 -azanucleosides (749) (Fig. 2.36). 

As in the preparation of the cyclic analog 236, the l,2,4-triazolo[4,3-a]pyridin-3-yl acyclo C-nucleoside 239 was obtained, together with the 1,2,4-... 

Acyclo C-nucleoside 575 was prepared in a similar way to the cyclic analog 573 by reacting 2-[2-(benzoyloxy)-ethoxy]thioacetimidate 228 with... 

The acyclo C-nucleoside 811 was prepared in a closely similar plan to that used for the synthesis of its cyclic analog 808. [2-(Benzoyloxy)ethoxy]-acetic acid was condensed with 6-aminomethyl-l,2,4-triazin-5-one to give amide 810, which was then cyclized and de-C>-benzoylated to 811. This truncated sugar acyclo C-nucleoside did not inhibit herpes simplex viruses (HSV-1 and HSV-2) in cell culture (84JHC697) (Scheme 213). 

Under basic conditions (0.2 M barium hydroxide, 100°, 30 minutes), the nucleoside 3 5 -cycIic phosphates are converted into the 3 - and 5 -phosphates in the ratio of about 5 1. For cytidine 3 5 -cyclic phosphate, some concomitant deamination to the uridine nucleotide analogs is also observed (as noted with cytidine 3 -phosphate), so that the nucleotides obtained are similar to those found in the alkaline hydrolyzate of uridine 3 5 -cyclic phosphate. In addition, one of the nucleotides obtained in these hydrolyzates differs from the 3 - or 5 -phosphates in its ion-exchange chromatographic behavior. The presence of an unidentified nucleoside monophosphate in small proportion was also observed when 2 -deoxy-cytidine 3 5 -cyclic phosphate was hydrolyzed with barium hydroxide under similar conditions. 

Cyclic vinyl epoxides are versatile building blocks (Table 11) which have been used in palladium-assisted routes to carbocyclic nucleosides. A formal synthesis of ( )-aris-teromycin101, the carbocyclic analog of adenosine, has been accomplished employing ni-tromethane as the nucleophile which serves as an acyl anion equivalent (Table 11. entry 2). The aldehyde is released by subsequent basic potassium permanganate oxidation. If nitromethane is used diluted in tetrahydrofuran, then a mixture of mono- and bis-alkylated product is formed. Whereas the alkylation of cyclohexenoxide with dimethyl malonate proceeds in a 1,4-crs fashion under palladium(O) catalysis, the 1.2-/ra/i.v-product is formed under basic conditions in the absence of the palladium(O) catalyst. 

Acyclo C-nucleoside 575 was prepared in a similar way to the cyclic analog 573 by reacting 2-[2-(benzoyloxy)-ethoxy]thioacetimidate 228 with 5-benzyloxy-4-hydrazino-pyrimidine. Evidently, the first-formed 1,2,4-triazolo[4,3-c]pyrimidin-3-yl product 574 isomerized to 575 (89JHC991) (Scheme 153). 

Nucleoside Cyclic Phosphates - Monophosphoryiation of 2 -protected ribonucleosides with the biftmctional reagent hi5-U6-trifluoromethyl)benzotriazol-l-yllmethylphosphonate (63) or the analogous phosphonothioate (64) and subsequent addition of A(-methylimidazole, has been... 

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