title: Polyaminoquinoline iron chelators for vectorization of antiproliferative agents: design, synthesis, and validation.
abstract: 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.
authors.affiliation: LUNAM Université, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 NANTES Cedex 3, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Corcé
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Morin
authors.forename: Solène
authors.initials: S
authors.lastname: Guihéneuf
authors.forename: Eric
authors.initials: E
authors.lastname: Renault
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Renaud
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cannie
authors.forename: Raphaël
authors.initials: R
authors.lastname: Tripier
authors.forename: Luís M P
authors.initials: LM
authors.lastname: Lima
authors.forename: Karine
authors.initials: K
authors.lastname: Julienne
authors.forename: Sébastien G
authors.initials: SG
authors.lastname: Gouin
authors.forename: Olivier
authors.initials: O
authors.lastname: Loréal
authors.forename: David
authors.initials: D
authors.lastname: Deniaud
authors.forename: François
authors.initials: F
authors.lastname: Gaboriau
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D015195:Drug Design; D007502:Iron Chelating Agents / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013055:Spectrophotometry, Infrared
chemical_list: D000634:Aminoquinolines; D007502:Iron Chelating Agents