title: Synthesis and biological properties of Quilamines II, new iron chelators with antiproliferative activities.
abstract: To selectively target tumor cells expressing an overactive Polyamine Transport System (PTS), we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, derived from the lead compound HQ1-44, which we named Quilamines II. The structures of four new antiproliferative agents were developed. They differ in the size of the linker (HQ0-44 and HQ2-44) or in the nature of the linker (HQCO-44 and HQCS-44) between a hydroxyquinoline moiety (HQ) and a homospermidine (44) chain, the best polyamine vector. The Quilamines II were obtained after 6 to 9 steps by Michael addition, peptide linkage, and reductive amination or by using the Willgerodt-Kindler reaction. The biological evaluation of these second-generation Quilamines showed that modifying the size of the linker increased the selectivity of these compounds for the PTS. In addition, measurement of the toxicity of Quilamines HQ0-44 and HQ2-44 highlighted their marked antiproliferative nature on several cancerous cell lines as well as a differential activity on nontransformed cells (fibroblasts). In contrast, Quilamines HQCO-44 and HQCS-44 presented low selectivity for the PTS, probably due to a loss of electrostatic interaction. We also demonstrated that the HCT116 cell line, originating from a human colon adenocarcinoma, was the most responsive to the various Quilamines. As deduced from the calcein and HVA assays, the higher iron chelating capacity of HQ1-44 could explain its higher antiproliferative efficiency.
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: Stéphanie
authors.initials: S
authors.lastname: Renaud
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cannie
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: François
authors.initials: F
authors.lastname: Gaboriau
authors.forename: David
authors.initials: D
authors.lastname: Deniaud
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000588:Amines; D007502:Iron Chelating Agents