Synthesis and anticancer activity of new 1-[(5 or 6-substituted 2-alkoxyquinoxalin-3-yl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives

Bioorg Med Chem. 2010 Nov 15;18(22):7966-74. doi: 10.1016/j.bmc.2010.09.028. Epub 2010 Sep 19.


A series of novel quinoxalinyl-piperazine compounds, 1-[(5 or 6-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives were synthesized and evaluated as an anticancer agent. From screening of quinoxalinyl-piperazine compound library, we identified that many compounds inhibited proliferation of various human cancer cells at nanomolar concentrations. Among them, one of the fluoro quinoxalinyl-piperazine derivatives showed its IC(50) values ranging from 11 to 21nΜ in the growth inhibition of cancer cells. This compound also displayed a more potent effect than paclitaxel against paclitaxel resistant HCT-15 colorectal carcinoma cells. The potency of this novel compound was further confirmed with the synergistic cytotoxic effect with several known cancer drugs such as paclitaxel, doxorubicin, cisplatin, gemcitabine or 5-fluorouracil in cancer cells. This strong cell killing effect was derived from the induction of apoptosis. Mechanistic studies have shown that this quinoxalinyl-piperazine compound is a G2/M-specific cell cycle inhibitor and inhibits anti-apoptotic Bcl-2 protein with p21 induction. Thus the results suggest that our compound has potential use in the growth inhibition of drug resistant cancer cells and the combination therapy with other clinically approved anticancer agents as well.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / toxicity
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • G2 Phase / drug effects
  • Humans
  • Molecular Conformation
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / toxicity
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p21
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2