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Polyaminoquinoline Iron Chelators for Vectorization of Antiproliferative Agents: Design, Synthesis, and Validation

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posted on 2012-09-19, 00:00 authored by Vincent Corcé, Emmanuelle Morin, Solène Guihéneuf, Eric Renault, Stéphanie Renaud, Isabelle Cannie, Raphaël Tripier, Luís M. P. Lima, Karine Julienne, Sébastien G. Gouin, Olivier Loréal, David Deniaud, François Gaboriau
Iron chelation in tumoral cells has been reported as potentially useful during antitumoral treatment. Our aim was to develop new polyaminoquinoline iron chelators targeting tumoral cells. For this purpose, we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, which we named Quilamines, based on an 8-hydroxyquinoline (8-HQ) scaffold linked to linear polyamine vectors. These were designed to target tumor cells expressing an overactive polyamine transport system (PTS). A set of Quilamines bearing variable polyamine chains was designed and assessed for their ability to interact with iron. Quilamines were also screened for their cytostatic/cytotoxic effects and their selective uptake by the PTS in the CHO cell line. Our results show that both the 8-HQ moiety and the polyamine part participate in the iron coordination. HQ1–44, the most promising Quilamine identified, presents a homospermidine moiety and was shown to be highly taken up by the PTS and to display an efficient antiproliferative activity that occurred in the micromolar range. In addition, cytotoxicity was only observed at concentrations higher than 100 μM. We also demonstrated the high complexation capacity of HQ1–44 with iron while much weaker complexes were formed with other cations, indicative of a high selectivity. We applied the density functional theory to study the binding energy and the electronic structure of prototypical iron­(III)-Quilamine complexes. On the basis of these calculations, Quilamine HQ1–44 is a strong tridentate ligand for iron­(III) especially in the form of a 1:2 complex.