Thermoresponsive organometallic arene ruthenium complexes for tumour targeting

Application of mild hyperthermia can increase the cytotoxicity of anticancer drugs in tumour cells. In this report, we describe low molecular weight thermoactive ruthenium-based drugs with fluorous chains that are selectively triggered by mild hyperthermia. The organometallic complexes were prepared, characterized, and evaluated for their in vitro cytotoxicity against a panel of human cancer cell lines and non-cancerous immortalized cells. The compounds show considerable chemo-thermal selectivity towards cancer cells (ca. 5 mu M versus >500 mu M for healthy cells) for the compound with the longest fluorous chain

Thermoresponsive fluorinated small-molecule drugs: a new concept for efficient localized chemotherapy

Hyperthermia is currently being explored as an adjuvant treatment to conventional therapies with chemotherapeutic agents based on thermoresponsive macromolecules. Although the concept of hyperthermia has existed for many years it has yet to become routinely used in the clinical management of cancer. The development of small thermoresponsive molecules could help to change this paradigm. Temperaturesensitive compounds have recently been developed by covalently modifying drug and drug-like molecules with thermomorphic perfluorinated appendages. Lead thermoresponsive compounds have been validated in a pre-clinical model, displaying high tumor growth inhibition, with strong synergies observed between hyperthermia and the thermomorphic compounds

Influence of Elemental Iodine on Imidazolium-Based Ionic Liquids: Solution and Solid-State Effects

Ionic liquids doped with I-2, usually resulting in the formation of polyiodide anions, are extensively used as electrolytes and in iodination reactions. Herein, NMR spectroscopy and single-crystal X-ray diffraction were used to rationalize the structures of imidazolium-based polyiodide ionic liquids in the liquid and solid states. Combined, these studies show that extensive interactions between the imidazolium cation and the resulting polyiodide anion are present, which have the net effect of lengthening, polarizing, and weakening the I-I bonds in the anion. This bond weakening rationalizes the high conductivity and reactivity of ionic liquids doped with I-2

Influence of the Linker Length on the Cytotoxicity of Homobinuclear Ruthenium(II) and Gold(I) Complexes

Dinudear metal complexes have emerged as a promising class of anticancer compounds with the ability to cross-link biomolecular targets. Here, we describe two novel series of phosphine-linked dinudear ruthenium(II) p-cyrnene and gold(I) complexes, in which the length of the connecting poly(ethylene glycol) chain has been systematically modified. The impact,Of the multinuclearity, lipophilicity, and linker length on the antiproliferative activity of the compounds-on tumorigenic,(A2780 and A2780cisR) and nonturnorigenic (HEK-293) cell lines was assessed. The dinuclear ruthenium(II) complexes were considerably more cytotoxic than their mononuclear : counterparts, and a correlation between the lipophilicity of the linker and the cytotoxicity was observed, whereas the cytotoxicity of the gold(I) series, is independent of these factors

In vivo evaluation of small-molecule thermoresponsive anticancer drugs potentiated by hyperthermia

Hyperthermia used as an adjuvant with chemotherapy is highly promising in the treatment of certain cancers. Currently, the small molecule drugs used in combination with hyperthermia were not designed for this application. Herein, we report the evaluation of a chlorambucil and a ruthenium compound modified with a long fluorous chain, which exhibit thermoresponsive activity in colorectal adenocarcinoma xenografts in athymic mice in combination with mild hyperthermia (42 degrees C). Intraperitoneal injection of the derivatives followed by local hyperthermia showed a synergistic tumor growth reduction by 79% and 90% for the chlorambucil and ruthenium-based derivatives, respectively, with the latter exhibiting a higher synergy in combination with hyperthermia compared to the monotherapies. Histological analysis shows that both derivatives in combination with hyperthermia significantly decrease the number of proliferating tumor cells

Organometallic Glutathione S-Transferase Inhibitors

A new family of organometallic p-cymene ruthenium(II) and osmium(II) complexes conjugated to ethacrynic acid, a glutathione transferase (GST) inhibitor, is reported. The ethacrynic acid moiety (either one or two) is tethered to the arene ruthenium(II) and osmium(II) fragments via strongly coordinating modified bipyridine ligands. The solid-state structure of one of the complexes, i.e. [Os(eta(6)-p-cymene)CI][(4'-methyl-[2,2'-bipyridin]-4-y1)methyl-2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetate]Cl, was established by single-crystal X-ray diffraction, corroborating the expected structure. The complexes are efficient inhibitors of GST P1-1, an enzyme expressed in cancer cells and implicated in drug resistance, and are cytotoxic to the GST-overexpressing chemoresistant A2780cisR ovarian cancer cell line

Design, synthèse, analyse structurale et activité antipaludique des nouveaux analogues de l'amodiaquine et l'amopyroquine

Une première direction de recherche a été centrée sur la conception, synthèse, analyse structurale et activité antipaludique de nouveaux analogues de l'amodiaquine et de l'amopyroquine. Après une introduction sur le paludisme, les mécanismes d'action des médicaments de la famille des 4-aminoquinoléiques, la structure et les propriétés thérapeutiques de ces composés, notre étude s'est focalisée sur l'amodiaquine et ses principaux dérivés. Notre approche stratégique ainsi que les produits cibles du projet sont présentés, mettant en évidence des fonctions d'intérêt, susceptibles d'apporter la diversité structurale. Les différentes voies de synthèse proposées et étudiées sont discutées et l'analyse structurale des dérivés obtenus est décrite. Les études biologiques d'inhibition de la croissance parasitaire et de cytotoxicité et les résultats physicochimiques des composés sont présentés. L'étude des relations structure-activité est ensuite détaillée, mettant en évidence les effets induits par la modification des groupements en position 4' de l'amodiaquine par des groupements hydrophobes (aryle, hétéroaryle ou alkyle) ou polaires (amines) et les modifications au niveau de la chaîne latérale amino (diéthylamine ou pyrrolidine). La deuxième direction de recherche abordée dans ce mémoire a été centrée sur la synthèse et l'analyse structurale des nouveaux podands contenants des unités structurales 4-aminoquinoléiques, comme précurseurs des produits de type cage.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF