New approach of delivering cytotoxic drugs towards CAIX expressing cells: A concept of dual-target drugs

Simon J. A. van Kuijk*, Nanda Kumar Parvathaneni*, Raymon Niemans, Marilee W. van Gisbergen, Fabrizio Carta, Daniela Vullo, Silvia Pastorekova, Ala Yaromina, Claudiu T. Supuran, Ludwig J. Dubois, Jean-Yves Winurn, Philippe Lambin

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

Abstract

Carbonic anhydrase IX (CAIX) is a hypoxia-regulated and tumor-specific protein that maintains the pH balance of cells. Targeting CAIX might be a valuable approach for specific delivery of cytotoxic drugs, thereby reducing normal tissue side-effects. A series of dual-target compounds were designed and synthesized incorporating a sulfonamide, sulfamide, or sulfamate moiety combined with several different anti-cancer drugs, including the chemotherapeutic agents chlorambucil, tirapazamine, and temozolomide, two Ataxia Telangiectasia and Rad3-related protein inhibitors (ATRi), and the anti-diabetic biguanide agent phenformin. An ATRi derivative (12) was the only compound to show a preferred efficacy in CAIX overexpressing cells versus cells without CAIX expression when combined with radiation. Its efficacy might however not solely depend on binding to CAIX, since all described compounds generally display low activity as carbonic anhydrase inhibitors. The hypothesis that dual target compounds specifically target CAIX expressing tumor cells was therefore not confirmed. Even though dual-target compounds remain an interesting approach, alternative options should also be investigated as novel treatment strategies. (C) 2016 The Authors.

Original languageEnglish
Pages (from-to)691-702
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume127
DOIs
Publication statusPublished - 15 Feb 2017

Keywords

  • Tumor
  • Hypoxia
  • Carbonic anhydrase IX
  • Dual-target drugs
  • CAIX inhibitors
  • Cytotoxic drugs
  • CARBONIC-ANHYDRASE-IX
  • HYPOXIA-INDUCED EXPRESSION
  • IN-VIVO
  • TUMOR HYPOXIA
  • BIOLOGICAL EVALUATION
  • CANCER-CELLS
  • INHIBITORS
  • THERAPY
  • RADIATION
  • RESPONSES

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