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51.
Serum Albumin Binding Inhibits Nuclear Uptake of Luminescent Metal‐Complex‐Based DNA Imaging Probes
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Dr. Ashley Wragg Dr. Martin R. Gill Luke McKenzie Caroline Glover Rachel Mowll Dr. Julia A. Weinstein Dr. Xiaodi Su Prof. Carl Smythe Prof. Jim A. Thomas 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(33):11865-11871
The DNA binding and cellular localization properties of a new luminescent heterobimetallic IrIIIRuII tetrapyridophenazine complex are reported. Surprisingly, in standard cell media, in which its tetracationic, isostructural RuIIRuII analogue is localized in the nucleus, the new tricationic complex is poorly taken up by live cells and demonstrates no nuclear staining. Consequent cell‐free studies reveal that the IrIIIRuII complex binds bovine serum albumin, BSA, in Sudlow’s Site I with a similar increase in emission and binding affinity to that observed with DNA. Contrastingly, in serum‐free conditions the complex is rapidly internalized by live cells, where it localizes in cell nuclei and functions as a DNA imaging agent. The absence of serum proteins also greatly alters the cytotoxicity of the complex, where high levels of oncosis/necrosis are observed due to this enhanced uptake. This suggests that simply increasing the lipophilicity of a DNA imaging probe to enhance cellular uptake can be counterproductive as, due to increased binding to serum albumin protein, this strategy can actually disrupt nuclear targeting. 相似文献
52.
A Cytostatic Ruthenium(II)–Platinum(II) Bis(terpyridyl) Anticancer Complex That Blocks Entry into S Phase by Up‐regulating p27KIP1
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Vadde Ramu Dr. Martin R. Gill Paul J. Jarman Dr. David Turton Prof. Jim A. Thomas Dr. Amitava Das Prof. Carl Smythe 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(25):9185-9197
Cytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear RuII–PtII complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)]3+ (tpy=2,2′:6′,2′′‐terpyridine and tpypma=4‐([2,2′:6′,2′′‐terpyridine]‐4′‐yl)‐N‐(pyridin‐2‐ylmethyl)aniline), VR54, which employs the extended terpyridine tpypma ligand to link the two metal centres. In cell‐free conditions, VR54 binds DNA by non‐intercalative reversible mechanisms (Kb=1.3×105 M ?1) and does not irreversibly bind guanosine. Cellular studies reveal that VR54 suppresses proliferation of A2780 ovarian cancer cells with no cross‐resistance in the A2780CIS cisplatin‐resistant cell line. Through the preparation of mononuclear RuII and PtII structural derivatives it was determined that both metal centres are required for this anti‐proliferative activity. In stark contrast to cisplatin, VR54 neither activates the DNA‐damage response network nor induces significant levels of cell death. Instead, VR54 is cytostatic and inhibits cell proliferation by up‐regulating the cyclin‐dependent kinase inhibitor p27KIP1 and inhibiting retinoblastoma protein phosphorylation, which blocks entry into S phase and results in G1 cell cycle arrest. Thus, VR54 inhibits cancer cell growth by a gain of function at the G1 restriction point. This is the first metal‐coordination compound to demonstrate such activity. 相似文献
53.
Tuning the Cellular Uptake Properties of Luminescent Heterobimetallic Iridium(III)–Ruthenium(II) DNA Imaging Probes
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Dr. Ashley Wragg Dr. Martin R. Gill Dr. David Turton Harry Adams Thomas M. Roseveare Prof. Carl Smythe Dr. Xiaodi Su Dr. Jim A. Thomas 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(43):14004-14011
The synthesis of two new luminescent dinuclear IrIII–RuII complexes containing tetrapyrido[3,2‐a:2′,3′‐c:3′′,2′′‐h:2′′′,3′′′‐j]phenazine (tpphz) as the bridging ligand is reported. Unlike many other complexes incorporating cyclometalated IrIII moieties, these complexes display good water solubility, allowing the first cell‐based study on IrIII–RuII bioprobes to be carried out. Photophysical studies indicate that emission from each complex is from a RuII excited state and both complexes display significant in vitro DNA‐binding affinities. Cellular studies show that each complex is rapidly internalised by HeLa cells, in which they function as luminescent nuclear DNA‐imaging agents for confocal microscopy. Furthermore, the uptake and nuclear targeting properties of the complex incorporating cyclometalating 2‐(4‐fluorophenyl)pyridine ligands around its IrIII centre is enhanced in comparison to the non‐fluorinated analogue, indicating that fluorination may provide a route to promote cell uptake of transition‐metal bioprobes. 相似文献
54.
The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides. 总被引:1,自引:0,他引:1
G T Bourne S W Golding R P McGeary W D Meutermans A Jones G R Marshall P F Alewood M L Smythe 《The Journal of organic chemistry》2001,66(23):7706-7713
Cyclic peptides are appealing targets in the drug-discovery process. Unfortunately, there currently exist no robust solid-phase strategies that allow the synthesis of large arrays of discrete cyclic peptides. Existing strategies are complicated, when synthesizing large libraries, by the extensive workup that is required to extract the cyclic product from the deprotection/cleavage mixture. To overcome this, we have developed a new safety-catch linker. The safety-catch concept described here involves the use of a protected catechol derivative in which one of the hydroxyls is masked with a benzyl group during peptide synthesis, thus making the linker deactivated to aminolysis. This masked derivative of the linker allows BOC solid-phase peptide assembly of the linear precursor. Prior to cyclization, the linker is activated and the linear peptide deprotected using conditions commonly employed (TFMSA), resulting in deprotected peptide attached to the activated form of the linker. Scavengers and deprotection adducts are removed by simple washing and filtration. Upon neutralization of the N-terminal amine, cyclization with concomitant cleavage from the resin yields the cyclic peptide in DMF solution. Workup is simple solvent removal. To exemplify this strategy, several cyclic peptides were synthesized targeted toward the somatostatin and integrin receptors. From this initial study and to show the strength of this method, we were able to synthesize a cyclic-peptide library containing over 400 members. This linker technology provides a new solid-phase avenue to access large arrays of cyclic peptides. 相似文献
55.
56.
Smythe NC Butler DP Moore CE McGowan WR Rheingold AL Beauvais LG 《Dalton transactions (Cambridge, England : 2003)》2012,41(26):7855-7858
A technique for preparing heterobimetallic frameworks with tunable metal sites is demonstrated by the synthesis of a new two-dimensional metal-organic framework that is constructed from tetra(4-carboxyphenyl)porphyrin and Cd(II) species. The solid can be prepared in the presence of other divalent transition metals to yield the same framework with the smaller metal ions occupying the porphyrin ligands. 相似文献
57.
Baker RT Gordon JC Hamilton CW Henson NJ Lin PH Maguire S Murugesu M Scott BL Smythe NC 《Journal of the American Chemical Society》2012,134(12):5598-5609
Ammonia-borane (NH(3)BH(3), AB) has garnered interest as a hydrogen storage material due to its high weight percent hydrogen content and ease of H(2) release relative to metal hydrides. As a consequence of dehydrogenation, B-N-containing oligomeric/polymeric materials are formed. The ability to control this process and dictate the identity of the generated polymer opens up the possibility of the targeted synthesis of new materials. While precious metals have been used in this regard, the ability to construct such materials using earth-abundant metals such as Fe presents a more economical approach. Four Fe complexes containing amido and phosphine supporting ligands were synthesized, and their reactivity with AB was examined. Three-coordinate Fe(PCy(3))[N(SiMe(3))(2)](2) (1) and four-coordinate Fe(DEPE)[N(SiMe(3))(2)](2) (2) yield a mixture of (NH(2)BH(2))(n) and (NHBH)(n) products with up to 1.7 equiv of H(2) released per AB but cannot be recycled (DEPE = 1,2-bis(diethylphosphino)ethane). In contrast, Fe supported by a bidentate P-N ligand (4) can be used in a second cycle to afford a similar product mixture. Intriguingly, the symmetric analogue of 4 (Fe(N-N)(P-P), 3), only generates (NH(2)BH(2))(n) and does so in minutes at room temperature. This marked difference in reactivity may be the result of the chemistry of Fe(II) vs Fe(0). 相似文献
58.
We study the joint probability distribution of the number of nodes of outdegree 0, 1, and 2 in a random recursive tree. We complete the known partial list of exact means and variances for outdegrees up to two by obtaining exact combinatorial expressions for the remaining means, variances, and covariances. The joint probability distribution of the number of nodes of outdegree 0, 1, and 2 is shown to be asymptotically trivariate normal and the asymptotic covariance structure is explicitly determined. It is also shown how to extend the results (at least in principle) to obtain a limiting multivariate normal distribution for nodes of outdegree 0, 1, …, k. 相似文献
59.
The reaction of Co(II), pyridine-2-aldehyde-2-pyridyl hydrazone (PAPHY) and eosin at pH 5.6 produces the ternary complex Co(L)(HL)E(2) (where HL represents the protonated form of the ligand and E represents the eosinate anion). This complex is extracted by a chloroform-acetone mixture to give a strongly coloured and highly fluorescent extract. Spectrophotometric and fluorometric methods for the determination of Co have been developed with detection limits of 0.017 and 0.008 ppm respectively. Cu(II), Ni, Fe(II), Pd(II) and Hg(II) interfere. The Spectrophotometric method has been successfully applied to the analysis of steels, following ion-exchange separation of Co. 相似文献
60.
Development of small molecules that mimic the binding of ω-conotoxins at the N-type voltage-gated calcium channel 总被引:2,自引:0,他引:2
Cone snails (Conidae) are marine predators with some extraordinary features. Their venom contains a hundred or more peptides that target numerous ion channels and receptors in mammals, including several that are involved in disease. omega-Conotoxins from fish hunting snails are 24-27 residue peptides with a rigid 4-loop cysteine framework that target the N-type voltage-gated calcium channel (VGCC). Two omega-conotoxins, MVIIA and CVID are currently in clinical development for chronic pain management (Ziconotide or Prialt, and AM336, respectively). In an attempt to develop small molecule equivalents of CVID, we defined the Calpha-Cbeta vectors of the residues believed to be important for binding to the N-type VGCC. Using these vectors, we undertook a virtual screening of virtual libraries approach to identify compounds that matched the pharmacophore. Cyclic pentapeptides containing residues of loop 2 of CVID, with one or more being a D-amino acid were designed and synthesised and were found to be active at the N-type VGCC (IC50 approximately 20 microM). Agreeing with the specificity profile of CVID, molecules were inactive at the P/Q-type VGCC. 相似文献