4β-[(4-Alkyl)-1,2,3-triazol-1-yl] podophyllotoxins as anticancer compounds: design, synthesis and biological evaluation

Eur J Med Chem. 2011 Jun;46(6):1983-91. doi: 10.1016/j.ejmech.2011.02.016. Epub 2011 Feb 24.

Abstract

A series of 4β-[(4-alkyl)-1,2,3-triazol-1-yl] podophyllotoxin derivatives were designed in silico, synthesised by employing click chemistry approach, and evaluated for cytotoxicity against a panel of human cancer cell lines (SF-295, A-549, PC-3, Hep-2, HCT-15 and MCF-7). Majority of the compounds proved to be more potent than etoposide and select compounds exhibited significant anticancer activity with IC50 values in the range of 0.001-1 μM. DNA fragmentation and flow-cytometric results reveals that 4β-[(4-alkyl)-1,2,3-triazol-1-yl] podophyllotoxin derivatives induce dose dependent apoptosis. Docking experiments showed a good correlation between their calculated interaction energies with the topoisomerase-II and the observed IC50 values of all these compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • DNA Fragmentation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Podophyllotoxin / chemical synthesis
  • Podophyllotoxin / chemistry
  • Podophyllotoxin / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Podophyllotoxin