3,-Azido-2 ,3 -dideoxynucleosides

As shown in Scheme 18, the reaction of 3-azido-2,3-dideoxynucleoside 36 with polystyryl diphenylphosphane resin (37) affords iminophosphorane 38, which gives amine 39 after hydrolysis. Dioxane or pyridine is used as a solvent, and the purity of the products obtained is identical with those obtained by the normal method (94S789). 

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. 

Another route for the synthesis of azidonucleosides involved the transformation of preformed 3 -azido-2, 3 -dideoxynucleosides. These transformations usually follow standard procedures in nucleoside chemistry. 3 -Azido-2, 3 -dideoxy-inosine 7d has been prepared by deamination of the adenosine analogue 7a with adenosine deaminase [54]. A variety of 3 -azido-2, 3 -dideoxycytidine derivatives, such as 7b [36-38, 50], 7g [38], 7h [38], and 7i [38] have been prepared from the corresponding 3 -azido-2, 3 -dideoxyuridine and thymidine derivatives following known procedures for the amination at position 4. 3 -Azido-2, 3 -dideoxyuridine 7f has also been used as starting material for the synthesis of a variety of 3 -azido-2, 3 -dideoxy-5-substituted uridines, such as 7j-7m and 7p-7t [38, 51, 53]. 

Azido-2, 3 -dideoxynucleosides have also been prepared by glycosylation [40-42] of nucleic acid bases with 3-azido-2,3-dideoxy-D-erytbro-pento-... 

An alternative route for the synthesis of 3 -azido-2, 3 -dideoxynucleosides involves the preparation of a 3 -azido-3 -deoxypentofuranosylnucleoside followed by 2 -deoxygenation. A variety of 3 -azido-3 -deoxy-P-D-rifeo [47, 48], arabino [58-61, 63] and xylo [62, 63] pentofuranosyl nucleosides have been prepared, but their 2 -deoxygenation to afford the corresponding 3 -azido-2, 3 -dideoxynucleosides have not been described. 

A variety of derivatives of 3 -azido-2, 3 -dideoxynucleosides have been prepared in order to study the mechanism of action, to improve the transport of the drug or to obtain more selective compounds. These include tritium labelled derivatives of AZT [64, 65], various derivatives of 3 -azido-3 -deoxythymidine triphosphate [66, 67] and quaternary salts and dihydropyridine derivatives of AZT [68]. 

A number of H-phosphonate derivatives of 3 -azido-2, 3 -dideoxynucleosides with adenine, guanine, and cytosine [59,63-65] exhibit antiviral acivities with selectivity similar to or higher than that of the corresponding nucleoside. 

Vol.21, p.258), derived from D-mannitol, has been converted, via (26), into AZT and 3 -azido -2, 3 -dideoxyuridine, and a full report has appeared on the synthesis of the highly crystalline (27) from D-jylose, and its use for preparing 3 -azido -2, 3 -dideoxynucleosides (see Vol 21. p 104). An alternative approach to a synthon closely related to (26) is mentioned in Chapter 10. A number of other base-modified 3 -azido -2, 3 -dideojynucleosides have also been reported and evaluated for anti-HIV activity, and AZT has been prepared labelled with tritium at C-5 ly a redox procedure. ... 

A new route to AZT involves bromomesylate 37 reductive removal of the bromine, followed by treatment with sodium azide and lithium carbonate gave 5 -0-benzoyl-AZT, presumably via a 2,3 -anhydronucleoside. 2-Alkylthio- and the 4-methylthio-analogues of AZT have been made by base-sugar condensation, as have 3 -azido-2, 3 -dideoxynucleosides of hydantoins. Some computational work on conformations of AZT is mentioned in Chapter 21. 

G.B. Komilayeva, M.A. Rodina, and G.A. Galegov, Inhibition of human immunodeficiency virus (HIV) production by 5 -hydrogenphosphonates of 3 -azido-2 ,3 -dideoxynucleosides, Nucleosides ... 

Figure 5 Dideoxynucleoside (ddN) analogues 2, 3 -dideoxycytidine (DDC), 3 -azido-2, 3 -dideoxythymidine (AZT), 3 -fluoro-2, 3 -dideoxythymidine (FLT), 2, 3 -didehydro-2, 3 -dideoxythymidine (D4T), 3 -thia-2, 3 -dideoxycytidine (3TC), 3 -thia-2, 3 -dideoxy-5-fluorocytidine (FTC), and 2, 3 -dideoxy-L-cytidine (l-DDC).

Table 3.6. COMPARATIVE CYTOTOXICITY OF 3 -AZIDO AND 3 -AMINO-2, 3 DIDEOXYNUCLEOSIDES IN CLONOGENIC CFU-GM AND BFU-E HUMAN PROGENITOR CELLS [108]...

Table 3.15. GROWTH-INHIBITORY ACTIVITY OF 3 -AZIDO- AND 3 -AMINO-2, 3 -DIDEOXYNUCLEOSIDES AGAINST LI210 AND S180 CELLS IN K/TRO [118, 174, 175]...

AZT-5 -triphosphate is a potent competitive inhibitor of the enzyme Ki = 0.04 //M), and by contrast, the triphosphate exhibits K, values of 230 and 70 UM for mammalian DNA polymerases a and j , respectively [201]. The triphosphates of other clinically useful dideoxynucleosides, including those derived from 2, 3 -dideoxycytosine (96) and 3 -azido-2, 3 -dideoxyuridine, (92) are also selective and potent inhibitors of isolated RT [204, 214]. 

Interestingly, AZT-resistant strains were found to be cross-resistant to related S -azido-substituted dideoxynucleosides including AzddU (92) and AzddG (102) but, in general, retained their sensitivity to those dideoxynucleosides without an azido group, most notably 2, 3 -dideoxycytidine (96) and 2, 3 -dideoxyinosine (101) [238-240]. This observation suggests that the 3 -unsubstituted nucleosides should be effective in the treatment of infection due to AZT-resistant strains, although the clinical implications of resistance to AZT are as yet unknown, and strains resistant to 2, 3 -dideoxycytidine... 

Terasaki T, Pardridge WM. 1988. Restricted transport of 3 -azido-3 -deoxy-thymidine and dideoxynucleosides through the blood-brain barrier. J. Infect. Dis. 158 630-32... 

Several 2, 3 -dideoxynucleosides are given to patients with HIV. These analogs include 3 -azido-2, 3 -dideoxythymidine (zidovudine, AZT), 2, 3 -dideoxycytidine (zalcitabine, ddC), 2, 3 -dideoxyinosine (didanosine, ddl), 2, 3 -didehydro-3 -deoxythymidine (stavudine, d4T), and (-)-2 -deoxy-3 -thiacytidine (lamivudine, 3TC). A related molecule is abacavir (ABC), which contains a cyclopentene-methanol moiety instead of the dideoxyribose moiety of the above-mentioned... 

The most potent and selective anti-HIV agents, which seem to act through inhibition of reverse transcriptase, are the 2, 3 -dideoxynucleosides [7, 9, 10]. 3 -Azido-3 -deoxythymidine (Zidovudine, AZT, 7e) has been licensed for AIDS treatment in humans. 2, 3 -Dideoxyadenosine (109a), 2, 3 -dideoxyinosine (109c) and 2, 3 -dideoxycytidine (109d) are undergoing clinical trials in patients with... 

The 3 -substituents such as azido and fluoro, may stabilize the Cy-exo conformation and help the molecule to keep a suitable geometry for interaction with the enzyme. An additional role has been suggested for the 3 -azido group which, when present, enhances the activity of the 3 -azido 2, 3 -dideoxynuc-leosides as compared to that of the corresponding 2, 3 -dideoxynucleosides. 

The interesting analogue 77 of 5-adenosylmethionine has been made by a process in which 5 -deoxy-2, 3 -0-isopropylidene-5-methylaminoadenosine was first prepared, and then linked to a side-chain unit derived from L-glutamic acid. Thymidine analogues with a hydroxyalkylammonium moiety, such as 78, and 5 -amino- and 5 -azido-2, 5 -dideoxynucleosides of thieno[2,3-[Pg.278]

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