- DNA damage and induction of apoptosis in pancreatic cancer cells by a new dinuclear bis(triazacyclonane) copper complex
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The dinuclear copper(II) complex [Cu2{bcmp(-H)}(μ-OH)](NO3)2·H2O (1, bcmp = 2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)-4-methylphenol) has been synthesized and characterized by electrospray ionization mass spectrometry, potentiometric titration and cyclovoltammetry. The X-ray structure of the analogous perchlorate salt [Cu2{bcmp(-H)}(μ-OH)](ClO4)2·2.5H2O (2) was determined. Cytotoxicity studies showed very promising activity of 1 against various pancreatic tumor cell lines with IC50 values comparable or even lower than those of cisplatin. The Cu complex displayed low toxicity against a human non-tumor cell line (HEK 293) demonstrating selectivity for cancer cells. 1 converts supercoiled pUC19 plasmid DNA into the nicked form at micromolar concentrations in the absence of added reductants. A detailed kinetic study on the hydrolysis of the DNA model bis(2,4-dinitrophenyl) phosphate (BDNPP) has been performed. 1 hydrolyses BDNPP with a second order rate constant of 0.047 M s- 1 at pH 8 and 40 °C. Finally, single cell electrophoresis (comet assay) and fluorescence microscopy analysis showed that 1 interacts with cellular DNA and induces apoptotic cell death of Capan-1 pancreatic cancer cells. Western blotting analysis indicated that the Cu complex activates the p53 dependent pathway of apoptosis.
- Montagner, Diego,Gandin, Valentina,Marzano, Cristina,Erxleben, Andrea
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- Self-assembly and selective exchange of oligoanions on the surface of monolayer protected Au nanoparticles in water
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Self-assembled monolayers on Au nanoparticles terminating with TACN·ZnII head groups are attractive scaffolds for the formation of multivalent supramolecular structures at submicromolar concentrations in water.
- Pieters, Gregory,Cazzolaro, Alessandro,Bonomi, Renato,Prins, Leonard J.
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- Phototoxic activity and DNA interactions of water-soluble porphyrins and their rhenium(I) conjugates
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In the search for alternative photosensitizers for use in photodynamic therapy (PDT), herein we describe two new water-soluble porphyrins, a neutral fourfold-symmetric compound and a +3-charged tris-methylpyridinium derivative, in which either four or one
- Mion, Giuliana,Gianferrara, Teresa,Bergamo, Alberta,Gasser, Gilles,Pierroz, Vanessa,Rubbiani, Riccardo,Vilar, Ramon,Leczkowska, Anna,Alessio, Enzo
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- Phosphodiester cleavage properties of copper(II) complexes of 1,4,7-triazacyclononane ligands bearing single alkyl guanidine pendants
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Three new metal-coordinating ligands, L1·4HCl [1-(2-guanidinoethyl)-1,4,7-triazacyclononane tetrahydrochloride], L 2·4HCl [1-(3-guanidinopropyl)-1,4,7-triazacyclononane tetrahydrochloride], and L3·4HCl [1-(4-guanidinobutyl)-1,4,7- triazacyclononane tetrahydrochloride], have been prepared via the selective N-functionalization of 1,4,7-triazacyclononane (tacn) with ethylguanidine, propylguanidine, and butylguanidine pendants, respectively. Reaction of L 1·4HCl with Cu(ClO4)2·6H 2O in basic aqueous solution led to the crystallization of a monohydroxo-bridged binuclear copper(II) complex, [Cu2L 12(μ-OH)](ClO4)3·H 2O (C1), while for L2 and L3, mononuclear complexes of composition [Cu(L2H)Cl2]Cl· (MeOH)0.5· (H2O)0.5 (C2) and [Cu(L 3H)Cl2]Cl· (DMF)0.5· (H 2O)0.5 (C3) were crystallized from methanol and DMF solutions, respectively. X-ray crystallography revealed that in addition to a tacn ring from L1 ligand, each copper(II) center in C1 is coordinated to a neutral guanidine pendant. In contrast, the guanidinium pendants in C2 and C3 are protonated and extend away from the Cu(II)-tacn units. Complex C1 features a single μ-hydroxo bridge between the two copper(II) centers, which mediates strong antiferromagnetic coupling between the metal centers. Complexes C2 and C3 cleave two model phosphodiesters, bis(p-nitrophenyl)phosphate (BNPP) and 2-hydroxypropyl-p-nitrophenylphosphate (HPNPP), more rapidly than C1, which displays similar reactivity to [Cu(tacn)(OH2)2] 2+. All three complexes cleave supercoiled plasmid DNA (pBR 322) at significantly faster rates than the corresponding bis(alkylguanidine) complexes and [Cu(tacn)(OH2)2]2+. The high DNA cleavage rate for C1 {kobs = 1.30 (±0.01) × 10-4 s-1 vs 1.23 (±0.37) × 10-5 s-1 for [Cu(tacn)(OH2)2]2+ and 1.58 (±0.05) × 10-5 s-1 for the corresponding bis(ethylguanidine) analogue} indicates that the coordinated guanidine group in C1 may be displaced to allow for substrate binding/activation. Comparison of the phosphate ester cleavage properties of complexes C1-C3 with those of related complexes suggests some degree of cooperativity between the Cu(II) centers and the guanidinium groups.
- Tjioe, Linda,Joshi, Tanmaya,Forsyth, Craig M.,Moubaraki, Boujemaa,Murray, Keith S.,Brugger, Joel,Graham, Bim,Spiccia, Leone
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- TACN-based cationic lipids with amino acid backbone and double tails: Materials for non-viral gene delivery
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Cationic lipids have become an efficient type of non-viral vectors for gene delivery. In this Letter, four cationic lipids containing 1,4,7- triazacyclononane (TACN) headgroup, glutamic/aspartic acid backbone and dioleyl tails were designed and synthesize
- Wang, Bing,Yi, Wen-Jing,Zhang, Ji,Zhang, Qin-Fang,Xun, Miao-Miao,Yu, Xiao-Qi
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- Phosphate diester cleavage, DNA interaction and cytotoxic activity of a bimetallic bis(1,4,7-triazacyclononane) zinc complex
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The dinuclear zinc complex [Zn2{bcmp(-H)}(μ-Cl)](ClO 4)2·H2O {bcmp = 2,6-bis(1,4,7- triazacyclonon-1-ylmethyl)-4-methylphenol} has been synthesized and structurally characterized. The DNA binding affinity was assessed by ethidium bromide fluorescence quenching experiments. The complex relaxes supercoiled pUC19 DNA into the nicked form at low micromolar concentration. Mechanistic studies were carried out using the DNA and RNA models bis(2,4-dinitrophenyl) phosphate (BDNPP) and 2-hydroxypropyl p-nitrophenyl phosphate (HPNP). A detailed kinetic analysis suggested that the bridging OH group of the solution species [Zn 2{bcmp(-H)}(μ-OH)]2+ acts as the nucleophile in the hydrolysis of BDNPP, while in the case of HPNP, the bridging OH group acts as a general base and seems to shift to a terminal position upon substrate coordination. Finally, the cytotoxicity profile of the dinuclear zinc(II) complex was assessed. The complex showed promising in vitro antitumour activity against pancreatic and lung cancers cell lines. A new bimetallic Zn complex with a phenolate scaffold ligand with two aza-crown binding sites has been synthesized and characterized. DNA binding, cleavage and cytotoxicity results are reported.
- Montagner, Diego,Gandin, Valentina,Marzano, Cristina,Erxleben, Andrea
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- Self-Assembled Multivalent Ag-SR Coordination Polymers with Phosphatase-Like Activity
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We show herein the phosphatase-like catalytic activity of coordination polymers obtained after adding Ag+-ions to thiols bearing hydrophobic alkyl chains terminated with a 1,4,7-triazacyclononane (TACN) group. The subsequent addition of Zn2+ -ions to the self-assembled polymers resulted in the formation of multivalent metal coordination polymers capable of catalysing the transphosphorylation of an RNA-model compound (2-hydroxypropyl-4-nitrophenyl phosphate, HPNPP) with high reactivity. Analysis of a series of metal ions showed that the highest catalytic activity was obtained when Ag+-ions were used as the first metal ions to construct the backbone of the coordination polymer through interaction with the -SH group followed by Zn2+-ions as the second metal ions complexed by the TACN-macrocycle. Furthermore, it was demonstrated that the catalytic activity could be modulated by changing the length of the hydrophobic alkyl chain.
- Cao, Ying-Juan,Yao, Mei-Xia,Prins, Leonard J.,Ji, Rui-Xue,Liu, Ning,Sun, Xiang-Ying,Jiang, Yun-Bao,Shen, Jiang-Shan
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- Toward supramolecular nanozymes for the photocatalytic activation of Pt(iv) anticancer prodrugs
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A supramolecular nanozyme for the photocatalytic conversion of a Pt(iv) anticancer complex to cisplatin is described herein. We employed 1.9 nm Au nanoparticles decorated with thiol ligands bearing a TACN (1,4,7-triazacyclononane) headgroup to encapsulate FMN (riboflavin-5′-phosphate). In the presence of an electron donor, flavin-loaded nanoparticles photocatalyzed the reductive activation of the prodrug cis,cis,trans-[Pt(NH3)2(Cl2)(O2CCH2CH2COOH)2] to cisplatin, achieving turnover frequency values of 7.4 min-1.
- Cortajarena, Aitziber L.,Mancin, Fabrizio,Martínez, álvaro,Mazzei, Laura F.,Rosa-Gastaldo, Daniele,Salassa, Luca,Trevisan, Lucia
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- Synthesis and evaluation of novel 1,4,7-triazacyclononane derivatives as Cu2+ and Ga3+ chelators
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Advances in chelator design are the cornerstone for the development of metals like copper and gallium based biomedical agents and radiopharmaceuticals. To develop optimal chelating ligands, we explored the synthesis and chelating properties of azaheterocycle pendant armed 1,4,7-triazacyclononane (TACN) dimethylcarboxylate derivatives and dimethylphosphonate derivatives. In the complexation kinetics test, dicarboxylate pendant armed TACN derivatives 2,2′-(7-((1H-imidazol-2-yl)methyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODA-Im), 2,2′-(7-((1-methyl-1H-imidazol-2-yl)methyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODA-MeIm), and 2,2′-(7-(thiazol-2-ylmethyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODA-Thia) exhibited fast complexation kinetics towards Cu (II) cations, which were comparable to the frequently explored ligand 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). And the diphosphonate pendant armed TACN derivative ((7-(thiazol-2-ylmethyl)-1,4,7-triazonane-1,4-diyl)bis(methylene))bis(phosphonic acid) (NODP-Thia) bound with Ga (III) cations at a much faster rate than NOTA. Density functional theory studies confirmed that the better complexation kinetics and metal chelating efficiency of NODA-Im, NODA-MeIm, NODA-Thia, and NODP-Thia could be ascribed to the lower Gibbs energies of corresponding chelator-metal complexes than NOTA-metal complexes. The kinetic inertness of the Cu (II) complex with NODA-Im, NODA-MeIm, and NODA-Thia was also demonstrated by cyclic voltammetry studies. Subsequently radiolabeling experiment demonstrated that these metal chelators could efficiently labeled with 64Cu or 68Ga in good radiochemical purities. These preliminary findings support NODA-Im, NODA-MeIm, NODA-Thia, and NODP-Thia as promising leading chelating agents for the development of bifunctional Cu2+ and Ga3+ chelators in biomedical applications.
- Wang, Sheng,Gai, Yongkang,Sun, Lingyi,Lan, Xiaoli,Zeng, Dexing,Xiang, Guangya,Ma, Xiang
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- Design, Synthesis, and Biological Evaluation of Boron-Containing Macrocyclic Polyamines and Their Zinc(II) Complexes for Boron Neutron Capture Therapy
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Boron neutron capture therapy (BNCT) is a binary therapeutic method for cancer treatment based on the use of a combination of a cancer-specific drug containing boron-10 (10B) and thermal neutron irradiation. For successful BNCT,10B-containing molecules need to accumulate specifically in cancer cells, because destructive effect of the generated heavy particles is limited basically to boron-containing cells. Herein, we report on the design and synthesis of boron compounds that are functionalized with 9-, 12-, and 15-membered macrocyclic polyamines and their Zn2+complexes. Their cytotoxicity, intracellular uptake activity into cancer cells and normal cells, and BNCT effect are also reported. The experimental data suggest that mono- and/or diprotonated forms of metal-free [12]aneN4- and [15]aneN5-type ligands are uptaken into cancer cells, and their complexes with intracellular metals such as Zn2+would induce cell death upon thermal neutron irradiation, possibly via interactions with DNA.
- Ueda, Hiroki,Suzuki, Minoru,Kuroda, Reiko,Tanaka, Tomohiro,Aoki, Shin
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p. 8523 - 8544
(2021/06/28)
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- DINUCLEATING LIGAND OR DINUCLEAR METAL COMPLEX
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To provide a dinuclear metal complex that can be synthesized simply and easily and has a proper anticancer action.SOLUTION: The present disclosure provides a dinucleating ligand represented by the following formula (I) and a dinuclear metal complex thereof (where X is H or a substituted carbamoyl group, R1, R2, R3, and R4 independently represent H or a C1-8 linear or branched alkyl group).SELECTED DRAWING: None
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Paragraph 0048; 0058-0059
(2021/03/19)
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- Host-Guest Allosteric Control of an Artificial Phosphatase
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The activity of many enzymes is regulated by associative processes. To model this mechanism, we report here that the conformation of an unstructured bimetallic Zn(II) complex can be controlled by its inclusion in the cavity of a γ-cyclodextrin. This resul
- Czescik, Joanna,Lyu, Yanchao,Neuberg, Samuele,Scrimin, Paolo,Mancin, Fabrizio
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supporting information
p. 6837 - 6841
(2020/05/19)
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- Factors influencing the activity of nanozymes in the cleavage of an RNA model substrate
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A series of 2-nm gold nanoparticles passivated with different thiols all featuring at least one triazacyclonanone-Zn(II) complex and different flanking units (a second Zn(II) complex, a triethyleneoxymethyl derivative or a guanidinium of arginine of a peptide) were prepared and studied for their efficiency in the cleavage of the RNA-model substrate 2-hydroxypropyl-p-nitrophenyl phosphate. The source of catalysis for each of them was elucidated from the kinetic analysis (Michaelis–Menten profiles, pH dependence and kinetic isotope effect). The data indicated that two different mechanisms were operative: One involving two Zn(II) complexes and the other one involving a single Zn(II) complex and a flanking guanidinium cation. The mechanism based on a dinuclear catalytic site appeared more efficient than the one based on the cooperativity between a metal complex and a guanidinium.
- Czescik, Joanna,Zamolo, Susanna,Darbre, Tamis,Mancin, Fabrizio,Scrimin, Paolo
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supporting information
(2019/08/08)
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- Optimized synthesis and indium complex formation with the bifunctional chelator NODIA-Me
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The bifunctional chelator NODIA-Me holds promise for radiopharmaceutical development. NODIA-Me is based on the macrocycle TACN (1,4,7-triazacyclononane) and incorporates two additional methylimidazole arms for metal chelation and an acetic acid residue fo
- Weinmann, Christian,Holland, Jason P.,L?ppchen, Tilman,Scherer, Harald,Maus, Stephan,Stemler, Tobias,Bohnenberger, Hendrik,Ezziddin, Samer,Kurz, Philipp,Bartholom?, Mark D.
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supporting information
p. 7503 - 7512
(2018/10/24)
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- Novel tinib-type compound, preparation method and application thereof
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The invention provides a novel tinib-type compound shown as a structural formula (I), wherein R1 is selected from aryl or ceteroary the aryl or ceteroary is substituted by one or more of alkyl, halogen, aryl, alkynyl, cyano, trifluoromethyl, methoxy and halogenated benzyl; R2 is 1,4,7,10-tetraazacyclododecane or 1,4,7-triazacyclononane. The invention also provides application of the compound in preparation of antitumor medicines. The novel tinib-type compound has an obvious inhibiting effect for A549 cell lines, apoptosis of A549 cells can be obviously enhanced, and the effect is obviously superior to that of gefitinib. (The structural formula is shown in the specification).
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Paragraph 0147; 0149; 0150
(2018/07/03)
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- Using iSUSTAIN to validate the chemical attributes of different approaches to the synthesis of tacn and bridged (bis)tacn ligands
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Using green chemistry principles, alternative approaches for the synthesis of commercially important aza-macrocyclic tacn and (bis)tacn derivatives have been investigated to determine the step average and overall efficiency of these synthetic methods. Based on analytical metrics derived from the iSUSTAIN toolkit, the Richman-Atkins route for the synthesis of tacn (1) was found to be the more efficient; however an alternate route was shown to be preferable for the synthesis of (bis)tacn (2) compounds. The outcome of this study documents the importance of rigorous analysis of synthetic procedures for such aza-macrocyclic compounds in terms of their green chemistry attributes, in order to delineate how alternative synthetic methods can be ranked, more innovative procedures selected to improve productivity and yield, and synthetic methods deployed to achieve greater levels of waste reduction, reduced use of hazardous chemicals and lower environmental impact.
- Coghlan,Campi,Jackson,Hearn
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supporting information
p. 5477 - 5484
(2016/10/21)
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- COMPOUNDS FOR POSITRON EMISSION TOMOGRAPHY
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Described herein are compounds, compositions, and methods for diagnosing and/or monitoring pathogenic disease using positron emission tomography. Also described are conjugates of the formula B-L-P, wherein B is a radical of a targeting agent selected from vitamin receptor binding ligands (such as folate), PSMA binding ligands, or PSMA inhibitors; L is a divalent linker comprising aspartic acid, lysine, or arginine, and P is a radical of an imaging agent or radiotherapy agent, such as a radionuclide or radionuclide containing group, or a radical of a compound capable of binding a radionuclide, such as a metal chelating group.
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Paragraph 0370-0372
(2016/12/26)
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- AMPHIPHILIC DERIVATIVES OF TRIAZAMACROCYCLIC COMPOUNDS, PRODUCTS AND COMPOSITIONS INCLUDING SAME, AND SYNTHESIS METHODS AND USES THEREOF
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The invention relates to amphiphilic derivatives of a triazamacrocyclic compound, as well as to said derivatives as active molecule transporters. The invention also relates to a nanodrug including at least one amphiphilic derivative of a triazamacrocyclic compound and at least one active molecule of a protein such as an antibody, in particular for the treatment of autoimmune diseases or for the treatment of cancer.
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Paragraph 0233; 0234; 0235; 0236; 0237
(2015/12/26)
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- Phosphate diester cleavage, DNA interaction and cytotoxic activity of a bimetallic bis(1,4,7-triazacyclononane) Zinc Complex
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The dinuclear zinc complex [Zn2{bcmp(-H)}(μ-Cl)](ClO4)2·H2O {bcmp = 2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)-4-methylphenol} has been synthesized and structurally characterized. The DNA binding affinity was assessed by ethidium bromide fluorescence quenching experiments. The complex relaxes supercoiled pUC19 DNA into the nicked form at low micromolar concentration. Mechanistic studies were carried out using the DNA and RNA models bis(2,4-dinitrophenyl) phosphate (BDNPP) and 2-hydroxypropyl p-nitrophenyl phosphate (HPNP). A detailed kinetic analysis suggested that the bridging OH group of the solution species [Zn2{bcmp(-H)}(μ-OH)]2+ acts as the nucleophile in the hydrolysis of BDNPP, while in the case of HPNP, the bridging OH group acts as a general base and seems to shift to a terminal position upon substrate coordination. Finally, the cytotoxicity profile of the dinuclear zinc(II) complex was assessed. The complex showed promising in vitro antitumour activity against pancreatic and lung cancers cell lines.
- Montagner, Diego,Gandin, Valentina,Marzano, Cristina,Erxleben, Andrea
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supporting information
p. 4084 - 4092
(2015/04/27)
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- Efficient phosphodiester cleaving nanozymes resulting from multivalency and local medium polarity control
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The self-organization of Zn(II) complexes on the surface of 1.6-nm diameter gold nanoparticles (nanozymes) allows the spontaneous formation of multiple bimetallic catalytic sites capable to promote the cleavage of a RNA model substrate. We show that by tu
- Diez-Castellnou, Marta,Mancin, Fabrizio,Scrimin, Paolo
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supporting information
p. 1158 - 1161
(2014/02/14)
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- Triostin A derived hybrid for simultaneous DNA binding and metal coordination
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The natural product triostin A is known as an antibiotic based on specific DNA recognition. Structurally, a bicyclic depsipeptide backbone provides a well-defined scaffold preorganizing the recognition motifs for bisintercalation. Replacing the intercalating quinoxaline moieties of triostin A by nucleobases results in a potential major groove binder. The functionalization of this DNA binding triostin A analog with a metal binding ligand system is reported, thereby generating a hybrid molecule with DNA binding and metal coordinating capability. Transition metal ions can be placed in close proximity to dsDNA by means of non-covalent interactions. The synthesis of the nucleobase-modified triostin A analog is described containing a propargylglycine for later attachment of the ligand by click-chemistry. As ligand, two [1,4,7] triazacyclononane rings were bridged by a phenol. Formation of the proposed binuclear zinc complex was confirmed for the ligand and the triostin A analog/ligand construct by high-resolution mass spectrometry. The complex as well as the respective hybrid led to stabilization of dsDNA, thus implying that metal complexation and DNA binding are independent processes.
- Sachs, Eike-F.,Nadler, Andre,Diederichsen, Ulf
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experimental part
p. 449 - 456
(2012/04/04)
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- Efficient plasmid DNA cleavage by copper(II) complexes of 1,4,7-triazacyclononane ligands featuring xylyl-linked guanidinium groups
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Three new metal-coordinating ligands, L1, L2, and L3, have been prepared by appending o-, m-, and p-xylylguanidine pendants, respectively, to one of the nitrogen atoms of 1,4,7-triazacyclononane (tacn). The copper(II) complexes of these ligands are able to accelerate cleavage of the P-O bonds within the model phosphodiesters bis(p-nitrophenyl) phosphate (BNPP) and [2-(hydroxypropyl)-p-nitrophenyl]phosphate (HPNPP), as well as supercoiled pBR 322 plasmid DNA. Their reactivity toward BNPP and HPNPP is not significantly different from that of the nonguanidinylated analogues, [Cu(tacn)(OH2)2]2+ and [Cu(1-benzyl-tacn) (OH2)2]2+, but they cleave plasmid DNA at considerably faster rates than either of these two complexes. The complex of L1, [Cu(L1H+)(OH2)2] 3+, is the most active of the series, cleaving the supercoiled plasmid DNA (form I) to the relaxed circular form (form II) with a k obs value of (2.7 ± 0.3) × 10-4 s -1, which corresponds to a rate enhancement of 22- and 12-fold compared to those of [Cu(tacn)(OH2)2]2+ and [Cu(1-benzyl-tacn)(OH2)2]2+, respectively. Because of the relatively fast rate of plasmid DNA cleavage, an observed rate constant of (1.2 ± 0.5) × 10-5 s-1 for cleavage of form II DNA to form III was also able to be determined. The X-ray crystal structures of the copper(II) complexes of L1 and L 3 show that the distorted square-pyramidal copper(II) coordination sphere is occupied by three nitrogen atoms from the tacn ring and two chloride ions. In both complexes, the protonated guanidinium pendants extend away from the metal and form hydrogen bonds with solvent molecules and counterions present in the crystal lattice. In the complex of L1, the distance between the guanidinium group and the copper(II) center is similar to that separating the adjacent phosphodiester groups in DNA (ca. 6 A). The overall geometry of the complex is also such that if the guanidinium group were to form charge-assisted hydrogen-bonding interactions with a phosphodiester group, a metal-bound hydroxide would be well-positioned to affect the nucleophilic attack on the neighboring phosphodiester linkage. The enhanced reactivity of the complex of L1 at neutral pH appears to also be, in part, due to the relatively low pKa of 6.4 for one of the coordinated water molecules.
- Tjioe, Linda,Meininger, Anja,Joshi, Tanmaya,Spiccia, Leone,Graham, Bim
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scheme or table
p. 4327 - 4339
(2011/06/23)
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- Histidine analog amino acids providing metal-binding sites derived from bioinorganic model systems
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Metalloproteins are of utmost importance for nearly all biological processes. Valuable information about their functionalities came from mutagenesis studies and led to the de novo design of artificial proteins. Advances in peptide chemistry enable the tot
- Nadler, Andre,Hain, Christina,Diederichsen, Ulf
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experimental part
p. 4593 - 4599
(2009/12/08)
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- Rational design and generation of a bimodal bifunctional ligand for antibody-targeted radiation cancer therapy
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An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of 212Bi, 213Bi, and 177Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. 177Lu-C-NETA and 205/6Bi-C-NETA possess an excellent or acceptable in vivo biodistribution profile.
- Chong, Hyun-Soon,Ma, Xiang,Le, Thien,Kwamena, Baidoo,Milenic, Diane E.,Brady, Erik D.,Song, Hyun A.,Brechbiel, Martin W.
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p. 118 - 125
(2008/09/18)
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- Synthesis and binding properties of hybrid cyclophane - Azamacrocyclic receptors
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(Chemical Equation Presented). Three new azamacrocyclic-cyclophane hybrid receptors L1, L2, and L3 have been synthesized that incorporate either 1,4,7,10-tetraazacyclododecane (cyclen) or 1,4,7-triazacyclononane (tacn) uni
- Benniston, Andrew C.,Gunning, Patrick,Peacock, Robert D.
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p. 115 - 123
(2007/10/03)
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- Solid-Phase Assisted N-1 Functionalization of Azamacrocycles
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A simple solid-phase assisted strategy for the N-1 functionalization of azamacrocycles is described. Compounds such as cyclen, cyclam and piperazine can be selectively modified by temporary attachment to solid-phase resins providing an efficient and clean method to prepare biomedically interesting moieteies.
- Oliver, Morag,Jorgensen, Michael R.,Miller, Andrew D.
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p. 453 - 456
(2007/10/03)
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- Phenylthiyl radical complexes of gallium(III), iron(III), and cobalt(III) and comparison with their phenoxyl analogues
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Three hexadentate, asymmetric pendent arm macrocycles containing a 1,4,7-triazacyclononane-1,4-diacetate backbone and a third, N-bound phenolate or thiophenolate arm have been synthesized. In [L1]3- the third arm is 3,5-di-tert-butyl
- Kimura,Bill,Bothe,Weyhermueller,Wieghardt
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p. 6025 - 6039
(2007/10/03)
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