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

J Med Chem. 1992 Nov 27;35(24):4567-75. doi: 10.1021/jm00102a009.


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 1H NMR UV, 13C NMR, and CD spectroscopy, as well as elemental (C, H, N) analysis. The C2'-endo-C1'-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 microM while its 5'-phosphite derivative exhibited modest anti-HIV-1 activity.

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Avian Myeloblastosis Virus / enzymology
  • Base Sequence
  • Chemical Phenomena
  • Chemistry, Physical
  • Circular Dichroism
  • Crystallization
  • Deoxyribose / chemistry
  • Deoxyuridine / analogs & derivatives*
  • Dideoxynucleosides*
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Molecular Sequence Data
  • Molecular Structure
  • Nucleic Acid Synthesis Inhibitors*
  • Reverse Transcriptase Inhibitors
  • Spectrophotometry, Ultraviolet
  • Uridine / analogs & derivatives*
  • Uridine / chemical synthesis
  • Uridine / pharmacology
  • X-Ray Diffraction


  • Antiviral Agents
  • Dideoxynucleosides
  • Nucleic Acid Synthesis Inhibitors
  • Reverse Transcriptase Inhibitors
  • 3'-C-methylidene-2',3'-dideoxy-5-methyluridine
  • Deoxyribose
  • HIV Reverse Transcriptase
  • Deoxyuridine
  • Uridine