Karine Julienne

Synthesis and biological properties of Quilamines II, new iron chelators with antiproliferative activities.

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.

A Simple C 2 Symmetric Sulfide for a One Pot Ylide Mediated Asymmetric Conversion of Aldehydes into Epoxides

The use of sulfur ylides in their reaction with aldehydes offers an attractive synthesis of oxiranes. Though it was developed in the early 60s, asymmetric versions only appeared in the 90s.1-5 A major practical advantage of this route to enantioenriched oxiranes is that they are obtained in one step from aldehydes and organic halides whereas the oxidation of alkenes adds one step, i.e. the synthesis of the alkenes by a Wittig reaction which starts from the same substrates.

Asymmetric synthesis of epoxides from aldehydes mediated by (+)-(2R,5R)-2,5-dimethylthiolane

Nonracemic epoxides were prepared by reaction of (+)-(2R,5R)-2,5-dimethylthiolane, benzyl bromide and a mineral base with an aldehyde. Various parameters (solvent, base, aldehyde, sulfide) have been investigated. These studies led to the optimisation of a practical and simple procedure. Acetonitrile or tert-butyl alcohol were used in the presence of water and potassium or sodium hydroxide at room temperature. These conditions gave 87–93% yields with aromatic or branched aliphatic aldehydes and enantiomeric excesses ranged from 66 to 96%. Kinetic studies and stereochemical analyses have been carried out and a transition state was suggested to rationalize the observed stereochemistry.

Lanthanide(III) complexes of pyridine–tetraacetic acid-glycoconjugates: Synthesis and luminescence studies of mono and divalent derivatives

A potent lanthanide chelate, fulfilling the requirements for the development of MRI contrast agents or luminescent probes, was armed with alkyne groups. We then implemented a click methodology to graft the bifunctional ligand to azide-containing glucoside and maltoside scaffolds. The resulting hydrophilic glycoconjugates retained the ligand binding capacity for Eu(3+) or Tb(3+) ion as evidenced by the number of bound water molecules to the lanthanide ion. Divalent Eu(3+) and Tb(3+) complexes were shown to double the brightness of the emitted fluorescent signal compared to its monovalent derivatives. Designing multivalent lanthanide luminescent probes would enable the fluorescent signal of labeled biomolecules to be enhanced.

Efficient synthesis of new tetradentate ligands with potential applications for 64Cu PET-imaging.

We wish to report the synthesis of new tetradentate ligands in less than 3h in good to excellent yields from a commercially available compound using microwave-assisted technology. First tests of complexation showed a high ability of these ligands to chelate (64)Cu(II) in very diluted medium. These new systems have the potential to be used for nuclear medicine and particularly for PET-imaging.