A new approach to the synthesis of 4'-carbon-substituted nucleosides: development of a highly active anti-HIV agent 2', 3'-didehydro-3'-deoxy-4'-ethynylthymidine

Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):343-7. doi: 10.1081/ncn-200059774.

Abstract

Oxidation of 3'-O-TBDMS-4',5-unsaturated thymidine 3 with dimethyldioxirane (DMDO) allowed the isolation of the epoxide 4. Upon reacting with organosilicon reagents in the presence of SnCl4, 4 underwent stereoselective ring opening to give 4'-alpha-allyl (6), 4'-alpha-(2-bromoallyl) (7), 4'-alpha-(cyclopenten-3-yl) (8), and 4'-alpha-cyano (9) derivatives of thymidine. Reactions of the 3'-epimer 12 with organoaluminum reagents gave 4'-alpha-methyl (13), 4'-alpha-vinyl (14), and 4'-alpha-ethynyl (15) analogues. Compounds 13-15 were transformed into corresponding 2',3'-didehydro-3'-deoxy derivatives. Evaluation of their ability to inhibit the replication of HIV in cell culture showed that 4'-ethynyl-d4T (19) is more potent and less toxic than the parent compound d4T.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Carbon / chemistry*
  • Cell Line
  • HIV / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Nucleosides / chemical synthesis*
  • Oxygen / metabolism
  • Stavudine / analogs & derivatives*
  • Stavudine / chemical synthesis
  • Stavudine / pharmacology

Substances

  • Anti-HIV Agents
  • Nucleosides
  • 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine
  • Carbon
  • Stavudine
  • Oxygen