4 -substituted Nucleoside

A new class of 2,4 -0-cyclonucleoside (29) has been obtained as outlined in Scheme 7 4 -substituted nucleosides prepared from this compound included the methoxy derivative (30), obtained using methanolic silver nitrate, and hence the uridine analogues (31) by reduction. ... 

STRUCTURE-ACTIVITY RELATIONSHIPS AMONG HIV INHIBITORY 4 -SUBSTITUTED NUCLEOSIDES... 

We have recently reported the potent in vitro HIV inhibitory activity of 4 -azido-thymidine. This compound is unique among all other nucleoside inhibitors because it retains the 3 -hydroxyl group. However, in spite of the presence of a 3 -hydroxyl group, it too can act as a chain terminator besides being a potent reverse transcriptase inhibitor. In order to delineate the breadth of activity as it extends over other 4 -substituted nucleosides, we have synthesized a series of analogues. In this series, we have varied the base while an azido group remained at the 4 -position, we have made substitutions at the 3 -position of 4 -azidothymidine, and we have examined the effect of other substituents at the 4 -position of thymidine. From these studies some general trends in structure—activity relationships are evident. 

From the 4 -subsdtuted nucleosides examined thus far, it can be concluded that anti-HTV activity extends over a sizable range of modification if certain positions are left intact. Figure 1 summarizes where changes are tolerated. It appears that in order to retain good activity the 4 -substituted nucleoside must be a 2 -deo y-fi-D-erythro derivative. However, it is remarkable that once these criteria were satisfied, none of the changes of the heterocyclic base resulted in a dramatic loss of activity. Furthermore, as mentioned before, the 4 -substituent could be of different types, although azido and cyano were the most effective. 

That the antiviral activity of the 4 -substituted nucleosides extends over a variety... 

K. A.M. Walker, 4 -Substituted nucleosides as inhibitors of HIV An unusual oxetane derivative,... 

This synthesis appears to be quite general for the preparation of 1-substituted nucleosides and was used with small modifications for the synthesis of l-ribofuranosyl-6-azathymine and 2 -deoxyribo-furanosyl-6-azauracil and -6-azathymine. In the case of 2 -deoxy-ribofuranosyl a mixture of a- and )8-anomers is produced, their ratio depending on the reaction conditions. In the preparation of 2 -deoxy-ribofuranosyl-6-azathymine only one anomer was obtained having probably the )8-configuration, ... 

This present chapter is devoted to the recent advances, for the last decade, in fluorinated analogues of natural products developed as pharmaceuticals and now/ marketed or in development (registered or in clinical development). These mainly concern fluorine-substituted nucleosides, alkaloids, macrolides, steroids, amino acids and prostaglandins. 

Synthesis of 2 -/i-Fluoro-Substituted Nucleosides by a Direct Approach ... 

Application of this reaction to 2, 2-anhydrouridine (LXXXVII) led to a 3-substituted nucleoside (CIV) which, upon acylation followed by reduction with Raney nickel, yielded 3-deoxyuridine (CV, R = uracilyl). Reductive cleavage of CV, by the sodium-liquid ammonia procedure,72 afforded 3-deoxy-D-en/fAro-pentose ( 3-deoxy-D-ribose ), a result which establishes position 3 as the site originally containing the ethylthio function. The authors suggest,248 as a plausible route to CIV, the initial formation of the anion CII, followed by formation of the 2,3-anhydride structure. The anhydride (CIII) is then attacked, at C3, by the ethanethiol ion, to yield... 

As with other nitrogen-containing heterocycles, TV-alkylation is a reaction of some interest. This is particularly true when the products are nucleosides. One interesting example of nucleoside formation arises from reaction of a suitable furo[3,4-J]pyrimidine (41) and l-O-acetyl-2,3,5-tribe nzoyl-/ -D-ribose the product formed seems to be solvent dependent. The N-l substituted nucleoside (42 R = tribenzoylribose) is formed in 81 % yield when the heterocycle and the protected sugar are treated with tin(IV) chloride in acetonitrile. However, use of 1,2-dichloroethane as solvent affords only 17% of this product together with 81% of the N-l,N-3 disubstituted product (Equation (10)) <83CPB3074>. 

A palladium-catalyzed ring expansion of aziridines provided a novel route to highly substituted pyrroles <07TL2267>. Treatment of methylene aziridines 33 with Pd(0) in the presence of symmetrical 1,3-diketones 34 led to the formation of 3-ketopyrroles 35. Pyrrole-substituted nucleoside analogues were prepared using a vanadium-mediated transformation of 2-azirines in the presence of symmetrical 1,3-diketones <07SL2723>. 

Potential, chemotherapeutic activity of this class of compounds stimulated the synthesis313,337,352 of a series of benzimidazole-, pyrimidine-, and purine-substituted nucleosides of D-glucuronic acid derivatives, using, as the starting sugar-component, bromide 1 and methyl (2,3,4-tri-0-acetyl-D-glucopyranosylamine)uronate, respectively. 

A useful approach that has emerged from study of protecting groups for the cis-diol groupings of ribonucleoside involved the subtle use of 0-2 (3 )-substituted nucleoside 5 -diphosphates in single-addition... 

Single addition reactions to primer oligonucleotides, catalyzed by polynucleotide phosphorylase (EC 2.7.7.8), have been reported using 2 (3 )-0-substituted nucleoside 5 -diphosphate, where, apparently, the 2 -substituent prevents further reaction at the free 3 -hydroxyl group.302 Almost quantitative yields have been obtained by use of... 

Numerous azido-substituted nucleosides have been evaluated as potential antitumour agents. De Clercq et al. found that of a series of 2 - and 3 -azidonucleoside analogues prepared and evaluated for antitumour activity against murine LI210 cells in vitro, the most potent derivative was 3 -azido-2, 3 -dideoxyadenosine (146), with 3 -azido-2, 3 -dideoxyguanosine (102), 3 -azido-3 -deoxyadenosine (147) and 2 -azido-2 -deoxycytidine (148) proving moderately active [170], the activity of the last compound having been reported previously [171, 172], AZT was also evaluated in this study... 

Zinc-mediated Barbier-t) e addition of 238, followed by Luche s procedure obtained a mixture of the homoallylic alcohol diastereomers 239 and 240. Alcohol 239 was carried through benzoylation, deketalization, silylation, and ozonolysis, to produce C-branched y-lactone 241. Benzoylation of 240 followed by hydroboration, PCC oxidation, debenzoylation, and alkaline-promoted cyclization directly formed C3-branching 2-deoxyfuranose 242 [87] (O Scheme 63). A novel method for stereoselective synthesis of 4 -a-carbon-substituted nucleosides, through epoxidation of 4, 5 -unsaturated nucleosides and SnCU-promoted epoxy ring opening, was... 

An improved protocol for the efficient conversion of inosine into its 3 -phosphoramidite synthons for solid-phase oligonucleotide synthesis has been described. This procedure, which almost doubled the literature reported overall yields starting from inosine, was optimized for scale-up to multigram quantities. The portion-wise addition of DMT-Cl to a solution of inosine in DMSO and pyridine prevented multiple-site protections, which was also reported to occur in the presence of DMAP or triethylamine. Treatment with TBDMSCl in the presence of silver nitrate and pyridine in THF offered a mixture of the 2 - and 3 -substituted nucleosides from which the 5 -0-dimethoxytrityl-2 -0-tert-butyl-dimethylsilyl-protected inosine was crystallized in ethyl acetate. The mother liquor was enriched with the 2 -isomer by treatment with triethylamine in methanol. Standard conditions for phosphitylation were then applied to yield... 

Trifluoromethyl substituted nucleoside 118 was synthesized from a-trifluoromethyl-a,p-unsaturated ester 117 <02JOC1016> in eight steps involving the usual Pummerer rearrangement. Compound 119 was synthesized from L-xylose via 2-deoxy-2-C-difluoromethylene-4-thiosugar... 

Intramolecular cyclization of appropriately substituted nucleosides is a general approach to the preparation of cyclic nucleosides, such as (170) and (171), which are derivatives of the parent system (58) <71JOC4105, 75JOC2372, 78JPR157, 81CJC468, 85CPB3689). 

Nucleotide A phosphate-substituted nucleoside—a building block of DNA or RNA. 

The Pd°-catalyzed coupling reaction of j5-5-iodo-2 -deoxy-3, 5 -di-0-acetyluridine with 2-trimethylstannylthiophene and 2-phenyl-5-trimethylstannylthiophene has given the corresponding thiophene substituted nucleosides <91JHC529>. The unprotected 5-iodo-2 -deoxyuridine has also been coupled with 2-(trimethylstannyl)- or 2-(tributylstannyl)thiophene <91JMC2383> a Pd catalyst was used in a coordinating solvent (THE or dioxane), whereas in a noncoordinating solvent (toluene), a Pd° catalyst was found to be essential. 

More recently, this group has incorporated these and related porphyrin-substituted nucleosides into tetranucleotides using standard solid support techniques to assemble chiral homo- and heteroporphyrinic arrays 38a-c. In this way, the composition and the physical properties of the array can easily be made to order simply by programming the DNA synthesis on an automated DNA synthesizer. The tetranucleotides were then able to form duplexes with the complementary strands (e.g. tetra-adenosine dA4 39). It was shown that the porphyrin electronic ground state environment is not particularly influenced by the presence or absence of the complementary strand, but the fluorescence intensity is decreased. CD measiuements confirm the helical nature of the duplexes. 

Recent methods for the synthesis of nucleoside derivatives which have been tested for anti-HIV activity, or which, because of their structure, may be good candidates for testing are described. The nucleoside derivatives considered in this review are 3 -azido-2, 3 -dideoxynucleosides, 2, 3 -dideoxy-3 -fluoronucleosides, 2, 3 -dideoxy-3 -C-substituted nucleosides, 2, 3 -dideoxy-P-D-glycero-pent-2-enofuranosyl nucleosides, 2, 3 -dideoxynucleosides and carbocyclic, acyclic and C-nucleosides. Structure-activity relationships are also considered. 

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