Betulinic acid derivatives: a new class of specific inhibitors of human immunodeficiency virus type 1 entry

J Med Chem. 1996 Mar 1;39(5):1069-83. doi: 10.1021/jm950669u.

Abstract

A novel series of omega-aminoalkanoic acid derivatives of betulinic acid were synthesized and evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1 activity of several members of this new series was found to be in the nanomolar range in CEM 4 and MT-4 cell cultures. The optimization of the omega-aminoalkanoic acid side chain is described. The presence of an amide function within the side chain was found important for optimal activity. RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1 protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. "Time of addition" experiments suggested interaction with an early step of HIV-1 replication. As syncytium formation, but not virus-cell binding, seems to be affected, betulinic acid derivatives are assumed to interact with the postbinding virus-cell fusion process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • DNA Nucleotidyltransferases / antagonists & inhibitors
  • Enzyme Inhibitors
  • HIV Envelope Protein gp120 / metabolism
  • HIV Protease Inhibitors
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Integrases
  • Molecular Structure
  • Pentacyclic Triterpenes
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Triterpenes / chemical synthesis*
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • HIV Envelope Protein gp120
  • HIV Protease Inhibitors
  • Pentacyclic Triterpenes
  • Reverse Transcriptase Inhibitors
  • Triterpenes
  • RPR 103611
  • betulinic acid
  • DNA Nucleotidyltransferases
  • Integrases