1,721,242 research outputs found
Synthesis, structural characterization and in vitro cytotoxicity of gold complexes with 2-(2-pyridyl)benzimidazole. Gold)III) vs. cold(I), mono- vs. binuclear derivatives
No full textGold compounds are attracting much interest because of their promising pharmacological activity against a series of diseases. Some of these complexes are reported to posses a great potential for cancer treatment, 1 showing important anti proliferative activity both in vitro and in vivo, probably involving thioredoxin reductase inhibition. 2 In this framework, a variety of gold(III) and gold(I) derivatives of 2-(2-pyridyl)benzimidazole (pbiH), both mono- and binuclear, have been synthesized, fully characterized and their biological properties investigated. All complexes show from good to excellent cytotoxic activity in vitro toward the human carcinoma cell line A2780, both sensitive, A2780/S, and resistant, A2780/R, to cisplatin, with IC50 values falling in the low micromolar, and in some case nanomolar, range. In general, the binuclear derivatives were found more active than the corresponding mononuclear ones. Particularly beneficial was joining into the same compound a gold(III) and a gold(I) centre. Reactivity with model proteins (Cytochrome C and Lysozyme) was also studied by ESI MS and UV-visible spectrometry. Methods and results of this study will be presented. Literature [1] Nbili S., Mini E., Landini I., Gabbiani C., Casini A., Messori L., med. Res. Rev., 2010, 30, 550-580. [2] Pratesi A., Gabbiani C., Ginanneschi M., Messori L., Chem. Common., 2010, 46, 7001-700
John Bates Clark’s view on the Treaty of Versailles as the origin of both World War II and the idea of a European Union
No full textThe aim of this paper is to highlight the position of John Bates Clark about the Treaty of Versailles and the U.S. approach to Foreign Policy in the aftermath of World War I. To achieve this goal, we analyze some unpublished manuscripts from the Rare Book & Manuscript Library of Columbia University and four published articles written by Clark between 1918 and 1919 about the consequences of the Treaty and, more generally, the future of Europe. The main ideas emerging from this material are that Clark supported the Treaty because he thought that given the threat of a resurgent Germany, only a League of Nations including the U.S. could be able to maintain world peace. On the other hand, he also criticized it because he shared with Keynes the view that the very harsh provisions imposed on Germany would generate another World War in the near future. Finally, Clark saw the union among European countries as a tool for preventing another war
John Bates Clark: The first American marginalist as a social economist
No full textWe analyze the content of four articles by John Bates Clark published between 1878 and 1887, during his Christian Socialist period in order to show that next to the marginalist Clark and beyond the neoclassical principles outlined in The Distribution of Wealth, the whole Clark's work is a strongly coherent body, deeply rooted in positions less extreme than the ones held by more reformer-minded economists like Richard T. Ely or John R. Commons containing an array of different contributions to political economy displaying a certain originality and coherence, and enrolling in a thematic environment that today would be broadly defined as social economy. In particular, the main ideas emerging from this selection of papers are his organismic idea of society, the role of moral forces in shaping economic activity, and his promotion of profit sharing and cooperation as better regimes for production and distribution with respect to competition
A Role for Metal-Based Drugs in Fighting COVID-19 Infection? The Case of Auranofin
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Ruthenium metalation of proteins: the X-ray structure of the complex formed between NAMI-A and hen egg white lysozyme.
No full textA crystallographic study of the adduct formed between hen egg white lysozyme (HEWL) and NAMI-A, an established ruthenium(iii) anticancer agent in clinical trials, is presented here. The X-ray structure reveals that NAMI-A coordinates the protein, as a naked ruthenium ion, at two distinct sites (namely Asp101 or Asp119) after releasing all its original ligands (DMSO, imidazole and Cl-). Structural data of the HEWL/NAMI-A adduct are compared with those previously obtained for the HEWL adduct of AziRu, a NAMI-A analogue bearing a pyridine in place of imidazole. The present results further support the view that NAMI-A exerts its biological effects acting as a classical "prodrug" first undergoing activation and then causing extensive metalation of relevant protein targets. It is also proposed that the original Ru-ligands, although absent in the final adduct, play a major role in directing the ruthenium center to its ultimate anchoring site on the protein surface
Protein Recognition of Gold-Based Drugs: 3D Structure of the Complex Formed When Lysozyme Reacts with Aubipyc
No full textThe structure of the adduct formed in the reaction between Aubipyc,
a cytotoxic organogold(III) compound, and the model protein hen egg white
lysozyme (HEWL) has been solved by X-ray crystallography. It emerges that
Aubipyc, after interaction with HEWL, undergoes reduction of the gold(III) center followed by detaching of the cyclometalated ligand; the resulting naked gold(I) ion is found bound to the protein at Gln121. A direct comparison between the present structure and those previously solved for the lysozyme adducts with other gold(III) compounds demonstrates that coordinated ligands play a key role in the protein−metallodrug recognition process. Structural data support the view that gold(III)-based antitumor prodrugs are activated through metal reduction
ESI MS studies highlight the selective interaction of Auranofin with protein free thiols
Full text linkThe clinically established gold drug Auranofin was reacted individually with a group of representative proteins, namely ubiquitin, ribonuclease A, carbonic anhydrase, haemoglobin and superoxide dismutase, and adduct formation was monitored in the various cases by ESI-MS analysis. We found that the reaction is highly selective for solvent exposed free cysteines that are modified through coordination of the AuPEt3+ fragment. Indeed, ESI-Q-TOF MS spectra carried out on protein samples incubated with a three fold molar excess of Auranofin allowed direct detection of the native proteins bearing bound AuPEt3+ fragments in the cases of carbonic anhydrase and haemoglobin. At variance, the two proteins that do not possess any free cysteine residue, i.e. ubiquitin and ribonuclease A, were unable to bind the gold fragment. In the case of superoxide dismutase, adduct formation is hindered by the scarce solvent accessibility of the free cysteine residue. These findings were further confirmed by a series of competition binding experiments with ebselen, a potent and selective cysteine-modifying reagent; we observed that pre-treatment with ebselen prevents the binding of the AuPEt3+ fragment to both carbonic anhydrase and haemoglobin
The X-ray structure of the primary adducts formed in the reaction between cisplatin and cytochrome c.
No full textIn the present study, the interactions between cisplatin and cytochrome c are investigated. Based on high-resolution X-ray diffraction data, two monometalated species, i.e. cyt c-Pt(NH3)2 and cyt c-Pt(NH3)2Cl, are found to be the main adducts that form in the reaction between the protein and the drug. Both monodentate and bidentate platinum coordination to the protein is observed, with platinum binding either to Met65 or to Met65 and Glu61, simultaneously
Protein metalation by metal-based drugs: X-ray crystallography and mass spectrometry studies
No full textThe combined use of X-ray Crystallography and Mass Spectrometry represents a valuable strategy to investigate and characterize protein metalation induced by anticancer metal-based drugs. Here, we summarize a series of significant results recently obtained by our laboratories in the examination of the structures of several adducts of proteins with representative metallodrugs (mostly containing ruthenium, gold and platinum). The general mechanisms of protein metalation that emerge from a careful comparative analysis of these structures are illustrated and their mechanicistic implications discussed. Possible directions for future work in the field are delineate
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