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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
Author(s) -
Rouge Pascal,
DassonvilleKlimpt Alexandra,
Cézard Christine,
Boudesocque Stéphanie,
Ourouda Roger,
Amant Carole,
Gaboriau François,
Forfar Isabelle,
Guillon Jean,
Guillon Emmanuel,
Vanquelef Enguerran,
Cieplak Piotr,
Dupradeau FrançoisYves,
Dupont Laurent,
Sonnet Pascal
Publication year - 2012
Publication title -
chempluschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.801
H-Index - 61
ISSN - 2192-6506
DOI - 10.1002/cplu.201200141
Subject(s) - lipophilicity , chemistry , ribonucleotide reductase , chelation , stereochemistry , metal , molecular dynamics , ligand (biochemistry) , molecule , small molecule , combinatorial chemistry , inorganic chemistry , organic chemistry , computational chemistry , biochemistry , receptor , protein subunit , gene
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 Fe III 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 Fe III 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.