Dataset Information

Similar biological activities of two isostructural ruthenium and osmium complexes.

ABSTRACT: In this study, we probe and verify the concept of designing unreactive bioactive metal complexes, in which the metal possesses a purely structural function, by investigating the consequences of replacing ruthenium in a bioactive half-sandwich kinase inhibitor scaffold by its heavier congener osmium. The two isostructural complexes are compared with respect to their anticancer properties in 1205 Lu melanoma cells, activation of the Wnt signaling pathway, IC(50) values against the protein kinases GSK-3beta and Pim-1, and binding modes to the protein kinase Pim-1 by protein crystallography. It was found that the two congeners display almost indistinguishable biological activities, which can be explained by their nearly identical three-dimensional structures and their identical mode of action as protein kinase inhibitors. This is a unique example in which the replacement of a metal in an anticancer scaffold by its heavier homologue does not alter its biological activity.

SUBMITTER: Maksimoska J

PROVIDER: S-EPMC2753370 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Similar biological activities of two isostructural ruthenium and osmium complexes.

Maksimoska Jasna J Williams Douglas S DS Atilla-Gokcumen G Ekin GE Smalley Keiran S M KS Carroll Patrick J PJ Webster Richard D RD Filippakopoulos Panagis P Knapp Stefan S Herlyn Meenhard M Meggers Eric E

Chemistry (Weinheim an der Bergstrasse, Germany) 20080101 16

In this study, we probe and verify the concept of designing unreactive bioactive metal complexes, in which the metal possesses a purely structural function, by investigating the consequences of replacing ruthenium in a bioactive half-sandwich kinase inhibitor scaffold by its heavier congener osmium. The two isostructural complexes are compared with respect to their anticancer properties in 1205 Lu melanoma cells, activation of the Wnt signaling pathway, IC(50) values against the protein kinases ...[more]

PMID: 18425743

Similar Datasets

Project description:Ruthenium nitrosyl complexes of the general formulas (cation)(+)[cis-RuCl4(NO)(Hazole)](-), where (cation)(+) = (H2ind)(+), Hazole = 1H-indazole (Hind) (1c), (cation)(+) = (H2pz)(+), Hazole = 1H-pyrazole (Hpz) (2c), (cation)(+) = (H2bzim)(+), Hazole = 1H-benzimidazole (Hbzim) (3c), (cation)(+) = (H2im)(+), Hazole = 1H-imidazole (Him) (4c) and (cation)(+)[trans-RuCl4(NO)(Hazole)](-), where (cation)(+) = (H2ind)(+), Hazole = 1H-indazole (1t), (cation)(+) = (H2pz)(+), Hazole = 1H-pyrazole (2t), as well as osmium analogues of the general formulas (cation)(+)[cis-OsCl4(NO)(Hazole)](-), where (cation)(+) = (n-Bu4N)(+), Hazole =1H-indazole (5c), 1H-pyrazole (6c), 1H-benzimidazole (7c), 1H-imidazole (8c), (cation)(+) = Na(+); Hazole =1H-indazole (9c), 1H-benzimidazole (10c), (cation)(+) = (H2ind)(+), Hazole = 1H-indazole (11c), (cation)(+) = H2pz(+), Hazole = 1H-pyrazole (12c), (cation)(+) = (H2im)(+), Hazole = 1H-imidazole (13c), and (cation)(+)[trans-OsCl4(NO)(Hazole)](-), where (cation)(+) = n-Bu4N(+), Hazole = 1H-indazole (5t), 1H-pyrazole (6t), (cation)(+) = Na(+), Hazole = 1H-indazole (9t), (cation)(+) = (H2ind)(+), Hazole = 1H-indazole (11t), (cation)(+) = (H2pz)(+), Hazole = 1H-pyrazole (12t), have been synthesized. The compounds have been comprehensively characterized by elemental analysis, ESI mass spectrometry, spectroscopic techniques (IR, UV-vis, 1D and 2D NMR) and X-ray crystallography (1c·CHCl3, 1t·CHCl3, 2t, 3c, 6c, 6t, 8c). The antiproliferative activity of water-soluble compounds (1c, 1t, 3c, 4c and 9c, 9t, 10c, 11c, 11t, 12c, 12t, 13c) in the human cancer cell lines A549 (nonsmall cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon adenocarcinoma) has been assayed. The effects of metal (Ru vs Os), cis/trans isomerism, and azole heterocycle identity on cytotoxic potency and cell line selectivity have been elucidated. Ruthenium complexes (1c, 1t, 3c, and 4c) yielded IC50 values in the low micromolar concentration range. In contrast to most pairs of analogous ruthenium and osmium complexes known, they turned out to be considerably more cytotoxic than chemically related osmium complexes (9c, 9t, 10c, 11c, 11t, 12c, 12t, 13c). The IC50 values of Os/Ru homologs differ by factors (Os/Ru) of up to ~110 and ~410 in CH1 and SW480 cells, respectively. ESI-MS studies revealed that ascorbic acid may activate the ruthenium complexes leading to hydrolysis of one M-Cl bond, whereas the osmium analogues tend to be inert. The interaction with myoglobin suggests nonselective adduct formation; i.e., proteins may act as carriers for these compounds.

Project description:The experimental electron-density distribution in two isostructural complexes, tetrakis(?2-acetato)diaquadicopper(II) [H2OCu(ac)2Cu(ac)2H2O] and tetrakis(?2-acetato)diaquadichromium(II) [H2OCr(ac)2Cr(ac)2H2O], has been studied and compared. The experimental electron density distribution in two isostructural and isomorphous complexes, tetrakis(?2-acetato)diaquadicopper(II) [H2OCu(ac)2Cu(ac)2H2O] (I) and tetrakis(?2-acetato)diaquadichromium(II), [H2OCr(ac)2Cr(ac)2H2O] (II), has been obtained from high-resolution X-ray diffraction data in order to shed light on the bonding properties in the compounds studied. It has been shown that from accurate X-ray data it is possible to discuss the bonding capability of the metal atom (Cu/Cr) and the ligands in these complexes. A comparison of results obtained from averaged and non-averaged X-ray data demonstrates that using the non-averaged data and introducing an anisotropic correction for secondary extinction errors provides a more detailed distribution of the electron density in the area of the metal atoms. In both complexes studied, the bonding of the acetate oxygen atom to the central metal atom is significantly affected by the formation of hydrogen bonds. The electron density and its Laplacian at the bond critical point of metal–oxygen coordination bonds for those oxygen atoms not involved in the intermolecular hydrogen bonds are approximately 10% larger compared with the case when oxygen atoms take part in hydrogen bonds with the neighboring water molecules. It is shown that metal–oxygen bonds in a quasi-equatorial plane are typical coordination bonds and differ significantly from the apical metal–oxygen bond. Metal–metal interaction with a small positive value of the electron density Laplacian at this bond critical point is mainly of electrostatic character. The metal–metal interaction is definitely not a bond according to the classical definition. Based on a search of the Cambridge Structural Database, it can be argued that there are four typical coordination bonds in the [CuO6] chromophore, similar to the four Cu—O coordination bonds in the basal plane of the CuO5 pyramid in one of the complexes under study.

Dataset Information

Similar biological activities of two isostructural ruthenium and osmium complexes.

Publications

Similar biological activities of two isostructural ruthenium and osmium complexes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets