Synthesis of a new 4-aza-2,3-didehydropodophyllotoxin analogues as potent cytotoxic and antimitotic agents

Bioorg Med Chem. 2011 Apr 1;19(7):2349-58. doi: 10.1016/j.bmc.2011.02.020. Epub 2011 Feb 24.

Abstract

A series of novel conjugates of 4-aza-2,3-didehydropodophyllotoxins (11a-w) were synthesized by a straightforward one-step multicomponent synthesis that demonstrated cytotoxicity against five human cancer cell lines (breast, oral, colon, lung and ovarian). All the twenty three compounds (11a-w) have been examined for the inhibition of tubulin polymerization. Among these compounds, 11a, 11k and 11p exhibited inhibition of polymerization tubulin comparable to podophyllotoxin apart from disruption of microtubule organization within the cells. Flow cytometric analysis showed that these compounds (11a, 11k and 11p) arrested the cell cycle in the G2/M phase of cell cycle leading to caspase-3 dependent apoptotic cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimitotic Agents / chemical synthesis*
  • Antimitotic Agents / chemistry
  • Antimitotic Agents / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Enzyme Activation
  • Flow Cytometry
  • Humans
  • Podophyllotoxin / analogs & derivatives*
  • Podophyllotoxin / chemical synthesis
  • Podophyllotoxin / chemistry
  • Podophyllotoxin / pharmacology
  • Structure-Activity Relationship
  • Tubulin / metabolism

Substances

  • 4-aza-2,3-didehydropodophyllotoxin
  • Antimitotic Agents
  • Antineoplastic Agents
  • Tubulin
  • Caspase 3
  • Podophyllotoxin