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Synthesis, Physicochemical Studies, Molecular Dynamics Simulations, and Metal-Ion-Dependent Antiproliferative and Antiangiogenic Properties of Cone ICL670-Substituted Calix[4]arenes

Authors

  • Dr. Pascal Rouge,

    1. Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France), Fax: (+33) 322827469
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  • Dr. Alexandra Dassonville-Klimpt,

    1. Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France), Fax: (+33) 322827469
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  • Dr. Christine Cézard,

    1. Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France), Fax: (+33) 322827469
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  • Dr. Stéphanie Boudesocque,

    1. Institut de Chimie Moléculaire de Reims (ICMR), UMR CNRS 7312, UFR des Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims (France)
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  • Dr. Roger Ourouda,

    1. Hémostase et remodelage vasculaire post-ischémique, EA3801, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France)
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  • Dr. Carole Amant,

    1. Hémostase et remodelage vasculaire post-ischémique, EA3801, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France)
    2. Laboratoire d'Oncobiologie Moléculaire, CHU d'Amiens, Amiens (France)
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  • Dr. François Gaboriau,

    1. Inserm U991 (EA/MDC), Université de Rennes I, Hôpital Pontchaillou, Rennes (France)
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  • Dr. Isabelle Forfar,

    1. CNRS FRE 3396 (Pharmacochimie), UFR de Pharmacie, Université de Bordeaux Segalen, Bordeaux (France)
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  • Prof. Dr. Jean Guillon,

    1. CNRS FRE 3396 (Pharmacochimie), UFR de Pharmacie, Université de Bordeaux Segalen, Bordeaux (France)
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  • Prof. Dr. Emmanuel Guillon,

    1. Institut de Chimie Moléculaire de Reims (ICMR), UMR CNRS 7312, UFR des Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims (France)
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  • Dr. Enguerran Vanquelef,

    1. Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France), Fax: (+33) 322827469
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  • Dr. Piotr Cieplak,

    1. Sandford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 (USA)
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  • Prof. Dr. François-Yves Dupradeau,

    1. Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France), Fax: (+33) 322827469
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  • Prof. Dr. Laurent Dupont,

    1. Institut de Chimie Moléculaire de Reims (ICMR), UMR CNRS 7312, UFR des Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims (France)
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  • Prof. Dr. Pascal Sonnet

    Corresponding author
    1. Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France), Fax: (+33) 322827469
    • Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France), Fax: (+33) 322827469
    Search for more papers by this author

Abstract

Iron chelators, through their capacity to modulate the iron concentration in cells, are promising molecules for cancer chemotherapy. Chelators with high lipophilicity easily enter into cells and deplete the iron intracellular pool. Consequently, iron-dependent enzymes, such as ribonucleotide reductase, which is over-expressed in cancer cells, become nonfunctional. A series of calix[4]arene derivatives substituted at the lower rim by ICL670, a strong FeIII chelator, have been synthesized. Physicochemical properties and antiproliferative, angiogenesis, and tumorigenesis effects of two calix[4]arenes mono- (5 a) or disubstituted (5 b) with ICL670 have been studied. These compounds form metal complexes in a ratio of one to two ligands per FeIII atom as shown by combined analyses of the protometric titration curves and ESIMS spectra. The grafting of an ICL670 group on a calix[4]arene core does not significantly alter the acid–base properties, but improves the iron-chelating and lipophilicity properties. The best antiproliferative and antiangiogenic results were obtained with calix[4]arene ligand 5 a, which possesses the highest corresponding properties. Analyses of molecular dynamics simulations performed on the two calix[4]arenes provide three-dimensional structures of the complexes and proved 5 a to be the most stable upon complexation.

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