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 calixarene 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 calixarenes 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 calixarene 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 calixarene ligand 5 a, which possesses the highest corresponding properties. Analyses of molecular dynamics simulations performed on the two calixarenes provide three-dimensional structures of the complexes and proved 5 a to be the most stable upon complexation.