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

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- (<b>5a</b>) or disubstituted (<b>5b</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 anti-angiogenic results were obtained with calix[4]arene ligand <b>5a</b>, 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 <b>5a</b> to be the most stable upon complexation.