Synthesis and antiviral activities of 1'-carbon-substituted 4'-thiothymidines

Bioorg Med Chem. 2004 Oct 15;12(20):5309-16. doi: 10.1016/j.bmc.2004.07.057.

Abstract

4-Thiofuranoid glycals substituted at the 1-position with methyl (5), (t-butyldimethylsilyloxy)methyl (7), and acetoxymethyl (8) groups were prepared from the 3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) (TIPDS)-4-thiofuranoid glycal (3) by way of LDA-lithiation. N-Iodosuccimide-initiated electrophilic glycosidation between silylated thymine and these 1-carbon-substituted 4-thioglycals gave the respective beta-anomers (9, 10, and 13) stereoselectively. Tin radical-mediated removal of the 2'-iodine atom from these products provided the corresponding 1'-branched 4'-thiothymidine derivatives (11, 12, and 14) in good yields. The 1'-hydroxymethyl derivative (15) served as a precursor for the preparation of the formyl (16), cyanoethenyl (17), and cyano (19) derivatives. Among the deprotected 1'-branched 4'-thiothymidines (20-25), the 1'-methyl analogue 20 showed the most potent anti-HSV-1 activity, but it was much less active than the parent compound 4'-thiothymidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • HIV-1 / drug effects
  • Herpesvirus 1, Human / drug effects
  • Humans
  • Thionucleosides / chemistry*
  • Thionucleosides / metabolism
  • Thionucleosides / pharmacology*
  • Thymidine / analogs & derivatives*
  • Thymidine / chemistry*
  • Thymidine / metabolism
  • Thymidine / pharmacology*

Substances

  • Antiviral Agents
  • Thionucleosides
  • 4'-thiothymidine
  • Thymidine