Synthesis and anti-HIV evaluation of hybrid-type prodrugs conjugating HIV integrase inhibitors with d4t by self-cleavable spacers containing an amino acid residue

J Enzyme Inhib Med Chem. 2007 Oct;22(5):608-19. doi: 10.1080/14756360701425402.

Abstract

In an attempt to combine the anti-HIV inhibitory capacity of reverse transcriptase (RT) inhibitors (NRTIs) and integrase (IN) inhibitors (INIs), several heterodimer analogues of the previously reported [d4T]-PABC-[INI] and [d4T]-OABC-[INI] prototypes have been prepared. In these novel series, we wished to extend our results to conjugates which incorporated an enzymatically labile aminoacid unit (L-alanine) connected to d4T through a self-immolative para- or ortho-aminobenzyl carbonate (PABC or OABC) spacer. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable to that of the [L-708,906]-PABC-[d4T] Heterodimer A prototype. However, although the compounds proved inhibitory to HIV-1, they were less potent than the parent compounds from which they were derived.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / chemistry*
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Cells, Cultured
  • Dimerization
  • HIV / drug effects*
  • HIV Integrase Inhibitors / chemistry*
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Reverse Transcriptase Inhibitors / chemistry*
  • Stavudine / chemistry*

Substances

  • Anti-HIV Agents
  • HIV Integrase Inhibitors
  • Prodrugs
  • Reverse Transcriptase Inhibitors
  • Stavudine
  • Alanine