3'-C-Branched 2'-deoxy-5-methyluridines: synthesis, enzyme inhibition, and antiviral properties

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Abstract
A synthesis scheme for 3'-C-methyl-2'-deoxynucleosides and 3'-C-methylidene-2',3'-dideoxy-5-methyluridine has been proposed with 2-deoxyribose as the starting material. Methyl 5-O-benzoyl-2-deoxyribofuranose was oxidized and the mixture of the 3'-keto derivatives was separated into the alpha- and beta-anomers. The beta-keto derivative was converted by reaction with MeMgBr, and after reaction with thymine and subsequent deprotection 1-(3'-C-methyl-2'-alpha-deoxy-alpha-D-threo-pentofuranosyl)thymine and its beta-anomer were obtained. The same reactions with the alpha-keto sugar gave 1-(3'-C-methyl-2'-deoxy-alpha-D-erythro-pentofuranosyl)thymine and its beta-anomer. 1-(5-O-Benzoyl-3'-C-methyl-2'-deoxy-alpha-D-threo-pentofuranosyl)thymine was converted to a mixture of 3'-C-methylidene-2',3'-dideoxy-5-methyluridine and 3'-C-methyl-2',3'-dideoxy-2',3'-didehydro-5-methyluridine, which were separated. The stereoselectivity of the Grignard reagent's attachment to 2-deoxyfuranose 3-ulosides has been ruled by the substitute configuration at Cl. Also, the effect of the hydroxyl or OBz group configuration at C3 on the condensation stereoselectivity of 3-C-methyl-2-deoxyfuranosides with silylated thymine has been studied. The structure of the obtained compounds was proved by H-1 NMR UV, C-13 NMR, and CD spectroscopy, as well as elemental (C, H, N) analysis. The C2'-endo-Cl'-exo conformation, the anti conformation of thymine in relation to the glycosidic bond, and the gauche+ conformation in relation to the C4'-C5' bond are characteristic for the 3'-C-methyl-2'-deoxythymidine structure in the crystals. 3'-C-Methyl-2'-deoxythymidine 5'-triphosphate was synthesized and proved to be a competitive inhibitor, with respect to dTTP, of a number of DNA polymerases, including the reverse transcriptases of human immunodeficiency virus type 1 (HIV-1) and avian myeloblastosis virus (AMV). None of the DNA polymerases examined were able to incorporate this compound into the growing DNA chain. In contrast, 3'-C-methylidene-2',3'-dideoxy-5-methyluridine 5'-triphosphate was found to be incorporated at the 3'-end of the DNA chain by HIV-1 reverse transcriptase, albeit with very low efficiency. 3'-C-Methyl-2'-deoxy-5-methyluridine did not suppress HIV-1 replication in MT-4 cells at 500 muM while its 5'-phosphite derivative exhibited modest anti-HIV-1 activity.

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