Synthesis, antiviral and contraceptive activities of nucleoside-sodium cellulose sulfate acetate and succinate conjugates

Bioorg Med Chem Lett. 2010 Dec 1;20(23):6993-7. doi: 10.1016/j.bmcl.2010.09.133. Epub 2010 Oct 19.

Abstract

Chemical conjugates between sodium cellulose sulfate (CS), displaying contraceptive and HIV-entry inhibiting properties, and nucleoside reverse transcriptase inhibitors (NRTIs) (3'-azido-2',3'-dideoxythymidine (AZT), 3'-fluoro-2',3'-dideoxythymidine (FLT), or 2',3'-dideoxy-3'-thiacytidine (3TC)) were designed to simultaneously provide contraceptive and anti-HIV activity. Two linkers, acetate and succinate, were used to conjugate the nucleoside analogs with CS. The conjugates containing cellulose sulfate-acetate (CSA) (e.g., AZT-CSA and FLT-CSA) were found to be more potent than CS and other conjugates (e.g., AZT-succinate-CS, and FLT-succinate-CS). The presence of both sulfate and the acetate groups on cellulose were critical for generating maximum anti-HIV activity. In addition to showing equal potency against wild-type and multidrug resistant HIV-1, the AZT-CSA conjugate displayed significant contraceptive activity in an animal model, providing the initial proof-of-concept for the design and synthesis of dual-activity compounds based on these combinations.

Publication types

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

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Cellulose / analogs & derivatives*
  • Cellulose / chemistry
  • Contraceptive Agents / chemical synthesis*
  • Contraceptive Agents / pharmacology
  • Drug Therapy, Combination / methods*
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • Humans
  • Models, Animal
  • Nucleosides / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Succinates / chemistry*

Substances

  • Anti-HIV Agents
  • Antiviral Agents
  • Contraceptive Agents
  • Nucleosides
  • Reverse Transcriptase Inhibitors
  • Succinates
  • Cellulose
  • cellulose sulfate
  • HIV Reverse Transcriptase