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 FeIII chelator, 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 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 anti-angiogenic results were obtained with calix[4]arene ligand 5a, 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 5a to be the most stable upon complexation.

β-Hematin Crystal Formation: New Insights from Molecular Dynamics Simulations of Small Clusters in Condensed Phase

“…On the contrary different theoretical works involving DFT methods have considered FPD as a preformed entity. ,, Indeed defining a topology for a bioinorganic complex with coordinate bonds between the metal center and its different ligands is a strategy widely adopted in structural studies involving MD simulations. Examples of such an approach are legion in the literature. − This empirical strategy is the one we have chosen in this work.…”

Study of Iron Piperazine-Based Chelators as Potential Siderophore Mimetics

“…The complex and ligand insolubility in a water/DMSO medium for x DMSO < 0.2 renders such a methodology irrelevant to the pFe determination in the case of Fe-1 and Fe-2 systems. This problem can be overcome by performing pFe calculations with data collected in a H 2 O/DMSO medium (x DMSO = 0.2) at a pH corresponding to the same [OH − ]/[H 3 O + ] ratio as that in pure water (pH 7.45) [47]. For x DMSO equal to 0.2, the pH scale is extended from 0 to 16.0, and a neutral solution has a pH value of 8.05.…”

A Deferasirox Derivative That Acts as a Multifaceted Platform for the Detection and Quantification of Fe3+

“…As a consequence, tight control over the pH is required if 1 is to be used for the quantitative determination of Fe 3+ in water [36]. Further complicating matters is the hydrophobicity of 1 (logP = 3.8); this results in poor water solubility and further limits its utility as a Fe 3+ chemosensor [37]. Recognizing these limitations, we focused our efforts on evaluating the sulfonic acid-bearing deferasirox derivative, 2, as a potential Fe 3+ chemosensor.…”