In vitro activity of steroidal dendrimers on Trypanosoma cruzi epimastigote form with PAMAM dendrons modified by "click" chemistry

Bioorg Chem. 2019 May;86:452-458. doi: 10.1016/j.bioorg.2019.01.056. Epub 2019 Jan 28.

Abstract

The increasing use of dendrimers shows promise for the treatment of inflammatory diseases, Chagas disease and other conditions such as cancer. In this study, the activity of 1st and 2nd generation dendrimers over T. cruzi in the epimastigote stage was tested. Dendrimers were derived from α-ethynylestradiol (EE) modified with PAMAM-type dendrons through a triazole ring. The activity of each compound was evaluated in five doses (from 1.3 to 20 µmol/mL) by flow cytometry, including benznidazole (Bz) as positive control. The findings show that an equivalent concentration of 14.8 µmol/mL of 2nd generation (G) dendrimer is 8 times more effective than Bz at 24 h, and it maintains its superiority at 48 h with an IC50 = 1.25 ± 0.19 µmol/mL. A TUNEL assay showed that dendrimers induce cell death in T. cruzi epimastigotes mostly via apoptosis, unlike Bz, which induces death via necrosis in more than 50% of cells.

Keywords: Dendrimers; Epimastigote; T. cruzi; Triazole ring.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Click Chemistry
  • Dendrimers / chemical synthesis
  • Dendrimers / chemistry
  • Dendrimers / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Lymphocytes / drug effects
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Polyamines / chemistry
  • Polyamines / pharmacology*
  • Steroids / chemical synthesis
  • Steroids / chemistry
  • Steroids / pharmacology*
  • Structure-Activity Relationship
  • Trypanosoma cruzi / drug effects*
  • Trypanosoma cruzi / growth & development

Substances

  • Dendrimers
  • Poly(amidoamine)
  • Polyamines
  • Steroids