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Eur J Med Chem. 2017 Feb 15;127:691-702. doi: 10.1016/j.ejmech.2016.10.037. Epub 2016 Oct 19.

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

Author information

1
Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, 6229 ER Maastricht, The Netherlands. Electronic address: s.vankuijk@maastrichtuniversity.nl.
2
Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, 6229 ER Maastricht, The Netherlands; Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS, ENSCM, Université de Montpellier, Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France. Electronic address: nanda-kumar.parvathaneni@etu.umontpellier.fr.
3
Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, 6229 ER Maastricht, The Netherlands.
4
University of Florence, NEUROFARBA Department, Via Ugo Schiff 6, Polo Scientifico, 50019 Sesto Fiorentino (Firenze), Italy.
5
University of Florence, Department of Chemistry, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
6
Department of Molecular Medicine, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia.
7
Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS, ENSCM, Université de Montpellier, Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.

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.

KEYWORDS:

CAIX inhibitors; Carbonic anhydrase IX; Cytotoxic drugs; Dual-target drugs; Hypoxia; Tumor

PMID:
27823879
DOI:
10.1016/j.ejmech.2016.10.037
[Indexed for MEDLINE]
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