Design and synthesis of novel 4'-demethyl-4-deoxypodophyllotoxin derivatives as potential anticancer agents

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1360-4. doi: 10.1016/j.bmcl.2015.06.089. Epub 2015 Jul 4.

Abstract

A group of podophyllotoxin (PPT) derivatives (7a-j) were synthesized by conjugating aryloxyacetanilide moieties to the 4'-hydroxyl of 4'-demethyl-4-deoxypodophyllotoxin (DDPT), and their anticancer activity was evaluated. It was found that the most potent compound 7d inhibited the proliferation of three cancer cell lines with sub to low micromolar IC50 values. Furthermore, it was demonstrated that 7d induced cell cycle arrest in G2/M phase in MGC-803 cells, and regulated the expression of cell cycle check point proteins, such as cyclin A, cyclin B, CDK1, cdc25c, and p21. Finally, 4 mg/kg of 7d reduced the weights and volumes of HepG2 xenografts in mice. Our findings suggest that 7d might be a potential anticancer agent.

Keywords: Anticancer; Aryloxyacetanilide; Cell cycle; Cyclin; Podophyllotoxin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Drugs, Chinese Herbal
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / drug therapy
  • M Phase Cell Cycle Checkpoints / drug effects
  • Mice
  • Mice, Nude
  • Podophyllotoxin / analogs & derivatives*
  • Podophyllotoxin / chemistry
  • Podophyllotoxin / pharmacology
  • Podophyllotoxin / therapeutic use
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Drugs, Chinese Herbal
  • deoxypodophyllotoxin
  • Podophyllotoxin