1,721,023 research outputs found
Using coordination chemistry to design new medicines
No full textThe rich diversity of coordination chemistry provides exciting prospects for the design of novel therapeutic agents with unique mechanisms of action. Central to such discovery is the understanding of both the kinetics and thermodynamics of reactions of metal complexes under conditions of biological relevance, and consideration of the roles of both the metal and its ligands in recognition processes. Examples from our recent work are reported here and discussed. Xylylbicyclam is a potent anti-HIV agent and is in clinical use as a stem-cell-mobilizing drug (AMD3100, "Mozobil"). Its target is the 7-helix membrane receptor CXCR4. Specific metallomacrocycle configurations can be recognized by proteins via metal coordination to specific amino acid side-chains, H-bonding and hydrophobic interactions, allowing optimisation of drug design. Photoactivation of octahedral cis and trans diam(m)ino diazido Pt(IV) complexes can lead to unusual redox and substitution reactions. Such activated complexes can kill cancer cells by novel mechanisms of action, providing a basis for a novel form of photochemotherapy. Substitution and redox reactions and the anticancer activity of Ru(II) arene complexes of the type [(η6-arene)Ru(X)(YZ)] are highly dependent on the nature of the arene, and monodentate (X) and chelated (YZ) ligands. Understanding of the factors which control such reactions has led to the rational design of analogous osmium anticancer complexes
Unprecedented carbon–carbon bond formation induced by photoactivation of a platinum(iv)-diazido complex
No full textUVA-induced photodecomposition of a PtIV-diazido complex involves not only reduction to PtII and N2 release, but also O2 evolution and formation of nitrene intermediates, whose trapping with (CH3)2S gives rise to an unusual N,N′-bis(ethyl)sulfurousdiamide ligand in an apparently unprecedented process involving C–C bond formation
Applications of heteronuclear NMR spectroscopy in biological and medicinal inorganic chemistry
No full textThere is a wide range of potential applications of inorganic compounds, and metal coordination complexes in particular, in medicine but progress is hampered by a lack of methods to study their speciation. The biological activity of metal complexes is determined by the metal itself, its oxidation state, the types and number of coordinated ligands and their strength of binding, the geometry of the complex, redox potential and ligand exchange rates. For organic drugs a variety of readily observed spin I = 1/2 nuclei can be used (H-1, C-13, N-15, F-19, P-31), but only a few metals fall into this category. Most are quadrupolar nuclei giving rise to broad lines with low detection sensitivity (for biological systems). However we show that, in some cases, heteronuclear NMR studies can provide new insights into the biological and medicinal chemistry of a range of elements and these data will stimulate further advances in this area. (C) 2008 Elsevier B.V. All rights reserved
Photoreaction pathways for the anticancer complex trans,trans,trans-[Pt(N3)2(OH)2(NH3)2]
No full textThe photodecomposition of the anticancer complex trans,trans,trans-[Pt(N3)2(OH)2(NH3)2] in acidic aqueous solution, as well as in phosphate-buffered saline (PBS), induced by UVA light (centred at λ = 365 nm) has been studied by multinuclear NMR spectroscopy. We show that the photoreaction pathway in PBS, which involves azide release, differs from that in acidic aqueous conditions, under which N2 is a major product. In both cases, a number of trans-{N–Pt(II/IV)–NH3} species were also observed as photoproducts, as well as the evolution of O2 and release of free ammonia with a subsequent increase in pH. The results from this study illustrate that photoinduced reactions of Pt(IV)-diazido derivatives can lead to novel reaction pathways, and therefore potentially to new cytotoxic mechanisms in cancer cells
Insights into photoreduction mechanisms for Pt(IV)-diazido anticancer agents from multinuclear NMR spectroscopy
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Insights into the photoreduction mechanisms for Pt(IV)-diazido anticancer agents from multinuclear NMR spectroscopy
No full textPhotoactivatable platinum(IV)-diazide complexes: a new generation of platinum-based anticancer agents
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Photoinduced reactions of cis,trans,cis-[Pt-IV(N-3)(2)(OH)(2)(NH3)(2)] with 1-methylimidazole
No full textLighting up new platinum anticancer complexes: Photoactivation of a platinum(IV) diazido anticancer complex in the presence of a derivative of imidazole, an important constituent of biomolecules, gives surprising photoproducts, including a tetrakis imidazole platinum(II) adduct (see figure), together with free azide, dioxygen and ammonia.
The photodecomposition of cis,trans,cis-[PtIV(N3)2(OH)2(NH3)2] in phosphate buffered saline (PBS), as well as in the presence of 1-methylimidazole (1-MeIm), induced by UVA light (centred at λ=365 nm) has been studied by multinuclear NMR spectroscopy. We show that photoreduction, photoisomerisation and trans-labilisation pathways are involved. The photodecomposition pathway in PBS, which involves azide release, as detected by 14N NMR spectroscopy, appears to differ from that in acidic aqueous conditions, under which N2 is a product. A number of trans-{N-PtII-NH3} species were also observed as photoproducts, as well as the release of free ammonia with a corresponding increase in pH. Oxygen was also detected as a product in solution. In the presence of 1-methylimidazole, surprisingly the major photoproduct was the tetra-substituted PtII complex [PtII(1-MeIm-N3)4]2+ (structure confirmed by crystallography), even at a Pt/1-MeIm molar ratio of 1:1, together with cis- and trans-[PtII(NH3)2(1-MeIm-N3)2]2+ as minor products. In these photoinduced 1-MeIm reactions, free ammonia, azide and oxygen were also detected. The results from this study illustrate that photoinduced reactions of platinum complexes can lead to novel reaction pathways, and therefore to new cytotoxic mechanisms in cancer cells
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