Osmium | EPFL Graph Search

L'osmium est l'élément chimique de numéro atomique 76, de symbole Os. Son corps simple est un métal platinoïde lourd, de couleur grise, dur et cassant. Découverte Du grec osme qui signifie « odeur », l'osmium a été découvert en 1803 par Smithson Tennant à Londres, avec l'iridium dans les résidus de la dissolution du platine dans de l'eau régale. Ce premier résidu de fabrication industrielle est principalement de l'osmiure d'iridium, un corps dur inaltéré dans l'attaque du minerai de platine par l'eau régale. Les chimistes français Antoine-François Fourcroy et Louis-Nicolas Vauquelin l'identifient également dans des résidus de platine qu'ils nomment ptène. Description C'est un métal de transition appartenant au groupe du platine. Il est l'élément naturel le plus dense sur Terre. Il est le plus souvent trouvé nativement en alliage avec le platine ou l'iridium. Les alliages d'osmium sont employés notamment dans les pointes de stylo-plume, les contacts électriques

Computational characterisation of the selectivity and binding mode of mono- and binuclear transition metal based anticancer compounds

Thibaud Edouard Alistair von Erlach

The rising resistance and the severe side effects associated with classical anticancer drugs such as cisplatin or mercaptopurines has triggered the development of novel antitumourous agents based on transition metal (e.g. ruthenium, osmium, and gold) organometallic complexes. In parallel, the tools of computational biochemistry have become more and more powerful and can nowadays provide important insights into the mechanistic origins of many systems of medicinal relevance creating a synergetic working environment between experimental and theoretical approaches. In this dissertation, a range of computational methods to study molecules from a quantum mechanical and/or classical mechanical point of view have been applied to characterise key properties of biological drug-target complexes. All of the computational research presented herein has been performed in tight collaboration with experimental groups, which determined X-ray structures of drug-target adducts and characterised the anticancer properties of the synthesised novel anticancer drugs studied here. In particular, the interactions of a small ruthenium-based complex acting as an DNA semi-intercalator,[(eta^6-5,8,9,10-tetrahydroanthracene)Ru(II)(ethylenediamine)X] with X representing a leaving group such as Cl-, were characterised exposing different binding modes of the compounds with free vs. nucleosomal DNA. Additionally, classical molecular dynamics simulations were used to complete a characterisation of the localisation of the linker of a novel binuclear antitumourous compound, that was designed in such a way as to take advantage of newly discovered allosteric pathways present in the nucleosome core particle with the aim of creating a synergistic effect in the uptake the two moieties. In addition to the localisation of the linker, the effects of the bound compound on the allostery of the nucleosome core particle has been explored to compare the mode of action of the newly synthesised binuclear compound with that of non-linked analogue with synergistic properties. Moreover, a similar study has been performed on a herpes virus peptide, (Met-Ala-Pro-Pro-Gly-Met-Arg-Leu-Arg-Ser-Gly-Arg-Ser-Thr-Gly-Ala-Pro-Leu-Thr-Arg- Gly-Ser), binding to the nucleosome core particle to observe whether or not it would be able to trigger allosteric pathways. Finally, some fundamental issues related to the selectivity of transition metal based anticancer compounds for specific binding sites on the nucleosome core particle were tackled by simulating the approach of three different ruthenium and osmium-based complexes, [(eta^6-cymene)Ru(II)(1,3,5-triaza-7-phosphoadamantane)X_2], [(eta^6-cymene)Ru(II)(N-phenylpyridine-2-carbothioamide)X] and [(eta^6-cymene)Os(II)( N-phenylpyridine-2-carbothioamide)X], from the bulk solvent to their bound state with the histone proteins with the help of classical and mixed quantum mechanical/molecular mechanical molecular dynamics simulations. A determination and analysis of the corresponding free energy profiles were used to provide some rationalisation of the observed preference of different compounds for specific binding sites. All the computational studies performed here and the insights gained can provide some guidance for the rational design of anticancer compounds with specific binding properties.

EPFL2020

Potent and selective anticancer activity of half-sandwich ruthenium and osmium complexes with modified curcuminoid ligands

Paul Joseph Dyson, Mouna Hadiji

We have recently reported a series of half-sandwich ruthenium(ii) complexes with curcuminoid ligands showing excellent cytotoxic activities (particularly ionic derivatives containing PTA (PTA = 1,3,5-triaza-7-phosphaadamantane). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of a long hydrophobic chain obtained by replacing the OH-groups, present in curcumin and bisdemethoxycurcumin, with the palmitic acid ester. We report the synthesis of ruthenium(ii) and osmium(ii) p-cymene derivatives containing palmitic acid curcumin ester ligands ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene)dipalmitate (p-curcH) and ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(4,1-phenylene)dipalmitate (p-bdcurcH). Complexes [M(ii)(cym)(p-curc)/(p-bdcurc)(Cl)] 1-4 (M = Ru or Os) are neutral, whereas [M(ii)(cym)(p-curc)/(p-bdcurc)(PTA)][SO3CF3] 5-8 are salts obtained when the chloride ligand is replaced by the PTA ligand. Stability studies performed on 1-8 in DMSO-PBS under physiological conditions (pH = 7.4) indicate that the complexes remain intact. The complexes exhibit potent and selective cytotoxic activity against an ovarian carcinoma cell line and its cisplatin-resistant form (A2780 and A2780cis), and non-cancerous human embryonic kidney (HEK293T) cells. To define the structure-activity relationships (SAR), the compounds have been compared with other Ru(ii) and Os(ii) complexes with curcuminoid ligands previously reported. SAR data reveal that the bisdemethoxycurcumin complexes are generally more active and selective than analogous curcumin-containing complexes.

ROYAL SOC CHEMISTRY2022

Ru(II), Os(II) and RH(III) complexes of PTA

Antoine Dorcier

A series of ruthenium, osmium and rhodium complexes utilizing pta, (1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane) and pta-Me+, its N-methyl derivative, have been synthesized. Their characterization by 1H and 31P NMR spectroscopy, ESI-MS and single crystal X-Ray diffraction are described. The mechanism of hydrolysis for [Ru(η6-C10H14)Cl2(pta)] has been studied and two watertype adducts, [Ru(η6-C10H14)Cl(OH2)(pta)][Cl] and [Ru(η6-C10H14)(OH2)2(pta)][Cl]2, have been characterized by 1H and 31P NMR spectroscopy and ESI-MS. The pKa of the pta moiety for the mono-aqua complex has been determined to be 2.33 ± 0.07, and the one of bis-aqua estimated to be between 2 and 2.1 units of pH. Although it was not possible to measure the pKa of the coordinated water, it is expected to be higher than 8 for the mono-aqua and 6.5 for the bis-qua complexes. The reactivity of the above described complexes towards guanine and adenine in which N9 position is blocked by a methyl or ribose substituent, has been investigated. The coordination of the complexes through the N7 center has been demonstrated by 1H NMR spectroscopy, and ESI-MS, which has also shown the formation of η2-(N6,N7) coordination mode for the adenine derivatives. The pKa for [Ru(η6-C10H14)Cl2(guanosine)(pta)] has been determined as 2.54 ± 0.03. A second model was devised based on a 14-mer strand (5'-ATACATGGTACATA-3') and ESI-MS has been used to demonstrate specific reactivity of the complexes. The interaction of pta and pta derivatives has been confirmed, however, no correlation between the reactivity toward the DNA strand and antineoplastic activity was found. Ruthenium, especially with hydrogen bonding capable substituents, is able to dissociate the arene group, which is not observed for the osmium cases, and it is believed that the water solubility of the arene, rather the strength of the arene – ruthenium bond plays more of a role.

EPFL2006

Computational characterisation of the selectivity and binding mode of mono- and binuclear transition metal based anticancer compounds

Thibaud Edouard Alistair von Erlach

EPFL2020