Structure-based design, structure-activity relationship analysis, and antitumor activity of diaryl ether derivatives

Arch Pharm Res. 2015 Oct;38(10):1761-73. doi: 10.1007/s12272-015-0578-7. Epub 2015 Feb 28.

Abstract

To identify novel therapeutic agents to treat cancer, we synthesized a series of diaryl ether derivatives. Structure-activity relationship studies revealed that the presence of a chlorine or hydroxyl at the para-position on the phenyl ring (5h or 5k) significantly enhanced antitumor activity. Compound 5h had stronger growth inhibitory activity in HepG2, A549, and HT-29 cells than compound 5k, with IC50 values of 2.57, 5.48, and 30.04 μM, respectively. Compound 5h also inhibited the growth of other cells lines, including Hep3B, PLC/PRF5, SMMC-7721, HeLa, and A375, with IC50 values of 2.76, 4.26, 29.66, 18.86, and 10.21 μM, respectively. The antitumor activity of compound 5h was confirmed by a colony forming assay. Further, our results indicated that the antitumor activity of compound 5h may be mediated by enhancing expression of p21 and cl-caspase3, and leading to apoptosis of cancer cells.

Keywords: Antitumor; Diaryl ethers; Structural modification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / genetics
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Ethers / chemical synthesis
  • Ethers / chemistry
  • Ethers / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • HT29 Cells
  • HeLa Cells
  • Humans
  • Inhibitory Concentration 50
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p21
  • Ethers
  • Caspase 3