title: Synthesis, Physicochemical Studies, Molecular Dynamics Simulations, and Metal-Ion-Dependent Antiproliferative and Antiangiogenic Properties of Cone ICL670-Substituted Calix[4]arenes.
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 FeIIIchelator, have been synthesized. Physicochemical properties and antiproliferative, angiogenesis, and tumorigenesis effects of two calix[4]arenes mono- (5a) or disubstituted (5b) with ICL670 have been studied. These compounds form metal complexes in a ratio of one to two ligands per FeIIIatom 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 anti-angiogenic results were obtained with calix[4]arene ligand5a, 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 proved5ato be the most stable upon complexation.
authors.affiliation: Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France).
authors.forename: Pascal
authors.initials: P
authors.lastname: Rouge
authors.affiliation: Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France).
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dassonville-Klimpt
authors.affiliation: Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France).
authors.forename: Christine
authors.initials: C
authors.lastname: Cézard
authors.affiliation: Institut de Chimie Moléculaire de Reims (ICMR), UMR CNRS 7312, UFR des Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims (France).
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boudesocque
authors.affiliation: Hémostase et remodelage vasculaire post-ischémique, EA3801, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France).
authors.forename: Roger
authors.initials: R
authors.lastname: Ourouda
authors.affiliation: Hémostase et remodelage vasculaire post-ischémique, EA3801, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France) ; Laboratoire d'Oncobiologie Moléculaire, CHU d'Amiens, Amiens (France).
authors.forename: Carole
authors.initials: C
authors.lastname: Amant
authors.affiliation: Inserm U991 (EA/MDC), Université de Rennes I, Hôpital Pontchaillou, Rennes (France).
authors.forename: François
authors.initials: F
authors.lastname: Gaboriau
authors.affiliation: CNRS FRE 3396 (Pharmacochimie), UFR de Pharmacie, Université de Bordeaux Segalen, Bordeaux (France).
authors.forename: Isabelle
authors.initials: I
authors.lastname: Forfar
authors.affiliation: CNRS FRE 3396 (Pharmacochimie), UFR de Pharmacie, Université de Bordeaux Segalen, Bordeaux (France).
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
authors.affiliation: Institut de Chimie Moléculaire de Reims (ICMR), UMR CNRS 7312, UFR des Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims (France).
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guillon
authors.affiliation: Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France).
authors.forename: Enguerran
authors.initials: E
authors.lastname: Vanquelef
authors.affiliation: Sandford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 (USA).
authors.forename: Piotr
authors.initials: P
authors.lastname: Cieplak
authors.affiliation: Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France).
authors.forename: François-Yves
authors.initials: FY
authors.lastname: Dupradeau
authors.affiliation: Institut de Chimie Moléculaire de Reims (ICMR), UMR CNRS 7312, UFR des Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims (France).
authors.forename: Laurent
authors.initials: L
authors.lastname: Dupont
authors.affiliation: Laboratoire des Glucides, CNRS FRE 3517, UFR de Pharmacie, Université de Picardie Jules Verne, 1, rue des Louvels, 80037 Amiens cedex 1 (France).
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
keywords: calixarenes; chelates; iron; lipophilicity; molecular dynamics