Synthesis and biological activities of polyquinoline derivatives: new Bcl-2 family protein modulators

Eur J Med Chem. 2012 Nov;57:112-25. doi: 10.1016/j.ejmech.2012.09.012. Epub 2012 Sep 17.

Abstract

The synthesis of quinoline derivatives, designed to interact with Bcl-x(L), and to inhibit its interaction with pro-apoptotic partners, is described and their biological effects investigated. We showed that 5 out of 28 synthetized compounds restored cell death of 3T3 cells overexpressing Bcl-x(L) following serum starvation. Active compounds were further characterized for their binding capacity to the anti-apoptotic member of the Bcl-2 family, Bcl-x(L) as well as Bcl-2, Bfl-1 and Mcl-1, and for their pro-apoptotic activities toward lymphoid tumor cells and peripheral blood mononuclear cells. Altogether our results indicate that dimeric, rather than trimeric quinoline derivatives, represent a new attractive class of BH3 mimetics for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Dimerization
  • Gene Expression / drug effects*
  • Humans
  • Inhibitory Concentration 50
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Minor Histocompatibility Antigens
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Binding
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Quinolines / chemical synthesis*
  • Quinolines / pharmacology
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism*

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2-related protein A1
  • BCL2L1 protein, human
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Mcl1 protein, mouse
  • Membrane Proteins
  • Minor Histocompatibility Antigens
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Quinolines
  • bcl-2-Associated X Protein
  • bcl-X Protein