Développement de nouveaux ligands polyaminés du fer pour la vectorisation anticancéreuse (synthèse, caractérisation et évaluation biologique)

The aim of this work is the development of new and selective iron (III) chelators bearing polyamine moieties to target the PTS and to induce specifically an iron depletion into tumor cells. These hybrid molecules, named Quilamines, are based on the association of 8-hydroxyquinoline with different polyamine chains. Synthesis and biological studies of different polyamine moieties, analogues of spermidine and spermine, showed that the homospermidine chain was the best choice for an efficient vectorization. Biological analysis highlighted a great PTS selectivity and a promising antiproliferative activity for some Quilamines. Structural modifications of the ligands allowed to modulate the iron complexation properties and to increase the selectivity and efficiency. Finally, for one compound, potentiometric titrations showed a high iron affinity constant and a good selectivity toward other biological metals such as cooper and zinc.L'objectif de ce travail de thèse est de développer de nouveaux ligands, spécifiques du fer (III), comportant une partie polyaminée pour la vectorisation par le STP afin d'induire spécifiquement une déplétion en fer dans les cellules tumorales et inhiber leur prolifération. Ces molécules chimères, appelées Quilamines, sont basées sur l'association de la 8-hydroxyquinoléine avec différentes chaînes polyaminées. La synthèse et l'étude biologique de différents motifs polyaminés dérivant de la sperdimine et de la spermidine ont montré que la chaîne homospermidine apparaît comme un vecteur de choix. De plus, des tests cellulaires de cytotoxicité ont mis en avant une forte sélectivité pour le STP ainsi qu'une activité antiproliférative prometteuse de certaines Quilamines. Des modifications structurales des ligands ont permis de changer le mode de coordination du fer et moduler leur efficacité ainsi que leur sélectivité pour le STP. Enfin, pour un des composés, l'analyse potentiométrique a mis en évidence une forte constante d'affinité pour le fer ainsi qu'une sélectivité vis-à-vis des autres métaux d'intérêt biologique comme le cuivre et le zinc.NANTES-BU Sciences (441092104) / SudocSudocFranceF

TUMORAL VECTORIZATION OF NEW IRON CHELATORS FOR ANTIPROLIFERATIVE ACTIVITY: BIOLOGICAL PROPERTIES OF POLYAMINOQUINOLINES

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THE POLYAMINOQUINOLINE HQ1-44, A NEW IRON CHELATOR VECTORIZED BY POLYAMINE INHIBITS THE TUMOR GROWTH IN XENOGRAFTED IMUNODEPRESSED MICE

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Synthesis and Biological Properties of Quilamines II, New Iron Chelators with Antiproliferative Activities

International audienceTo 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