Diacetoxylation of 1-(2,5-dideoxy-beta-L-glycero-pent-4-eno-4-thiofuranosyl)thymine (13) with Pb(OAc) 4 allowed introduction of an acetoxy leaving group to the 4'-position. Nucleophilic substitution of the resulting 4'-acetoxy derivative (14) with silicon reagents enabled us to prepare the 4'-phenylthio (17a), 4'-azido (18a), 4'-methoxy (20a), and 4'-allyl (21a) analogues of 4'-thiothymidine. 4'-Cyano ( 25a) and 4'-ethynyl (31) nucleosides were also synthesized from 3',5'-bis-O-TBDMS derivative (24). Among novel 4'-substituted 4'-thiothymidines, the 4'-azido (33), 4'-cyano (36), and 4'-ethynyl (37) derivatives were found to show potent inhibitory activity against HIV-1 and HIV-2. It is noteworthy that 36 and 37 were also inhibitory against replication of HIV variant resistant to 3TC (HIV-1 M184V), being as potent as against HIV-1 IIIB.
2'-Beta-methyl- and 2'-beta-hydroxymethyl-2'-deoxy-4'-thionucleosides have been synthesized through PhSeCl-mediated electrophilic glycosidation using 4-thiofuranoid glycals having carbon substituents at the C2-position as a glycosyl donor. Preparation of these glycals were carried out by means of the C2 lithiation of 1-chloro-4-thiofuranoid glycal with LTMP followed by the Birch reduction of the chlorine atom. [reaction: see text]
The synthesis of 4’-ethynyl-2’-deoxy-4’-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal 16 served as a glycosyl donor. Electrophilic glycosidation between 16 and the silylated nucleobases (N4-acetylcytosine, N6-benzoyladenine and N2-acetyl-O6-diphenylcarbamoylguanine) was carried out in the presence of N-iodosuccinimide (NIS) leading to the exclusive formation of the desired β-anomers 29, 33 and 36. Anti-HIV studies demonstrated that these 4’-thio nucleosides were less cytotoxic to T-lymphocyte (i.e. MT-4 cells) than the corresponding 4’-ethynyl derivatives of 2’-deoxycytidine (44), 2’-deoxyadenosine (45) and 2’-deoxyguanosine (46). Comparison of the selectivity indices (SI) was made between 4’-thionucleosides (32, 41 and 43) and the corresponding 4’-oxygen analogues 44–46 by using the reported CC50 and EC50 values. In the case of cytosine and adenine nucleosides, comparable SI values were obtained: 32 (545) and 45 (458); 41 (>230) and 45 (1,630). In contrast, 4’-ethynyl-2’-deoxy-4’-thioguanosine 43 was found to possess a SI value of >18,200, which is twenty times better than that of 46 (933).
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