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Tris(2-pyridylmethyl)amine (TPA) as a membrane-permeable chelator for interception of biological mobile zinc.

ABSTRACT: We report the characterization of tris(2-pyridylmethyl)amine (TPA) as a membrane-permeable zinc chelator for intercepting biological mobile zinc. Compared to N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), TPA chelates zinc with faster kinetics in cuvettes, live cells, and brain slices. TPA also is generally less toxic than TPEN in cell culture. Mechanistic analysis indicates that these improvements arise from both the electronic and steric properties of TPA including weaker metal-binding affinity, lower pKa, and smaller size. These results demonstrate that TPA chelation is a valuable addition to the methodologies available for investigating mobile zinc in biology.

SUBMITTER: Huang Z

PROVIDER: S-EPMC3730853 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Tris(2-pyridylmethyl)amine (TPA) as a membrane-permeable chelator for interception of biological mobile zinc.

Huang Zhen Z Zhang Xiao-an XA Bosch Miquel M Smith Sarah J SJ Lippard Stephen J SJ

Metallomics : integrated biometal science 20130601 6

We report the characterization of tris(2-pyridylmethyl)amine (TPA) as a membrane-permeable zinc chelator for intercepting biological mobile zinc. Compared to N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), TPA chelates zinc with faster kinetics in cuvettes, live cells, and brain slices. TPA also is generally less toxic than TPEN in cell culture. Mechanistic analysis indicates that these improvements arise from both the electronic and steric properties of TPA including weaker metal-bin ...[more]

PMID: 23715510

Similar Datasets

Phenylamino derivatives of tris(2-pyridylmethyl)amine: hydrogen-bonded peroxodicopper complexes.

Project description:A series of copper complexes bearing new 6-substituted tris(2-pyridylmethyl)amine ligands (LR) appended with NH(p-R-C6H4) groups (R = H, CF3, OMe) were prepared. These ligands are electronically tunable (ΔE1/2 = 160 mV) and CuI(LR)+ complexes react with oxygen to form hydrogen bonded (trans-1,2-peroxo)dicopper species.

| S-EPMC5780194 | biostudies-literature

Effects of Methyl Substitution in Ruthenium Tris(2-pyridylmethyl)amine Photocaging Groups for Nitriles.

Project description:Four complexes of the general formula [Ru(L)(CH3CN)2](PF6)2, [L = TPA (5), MeTPA (6), Me2TPA (7), and Me3TPA (8)] [TPA = tris[(pyridin-2-yl)methyl]amine, where methyl groups were introduced consecutively onto the 6-position of py donors of TPA, were prepared and characterized by various spectroscopic techniques and mass spectrometry. While 5 and 8 were isolated as single stereoisomers, 6 and 7 were isolated as mixtures of stereoisomers in 2:1 and 1.5:1 ratios, respectively. Steric effects on ground state stability and thermal and photochemical reactivities were studied for all four complexes using (1)H NMR and electronic absorption spectroscopies and computational studies. These studies confirmed that the addition of steric bulk accelerates photochemical and thermal nitrile release.

| S-EPMC4966558 | biostudies-literature

Selective Release of Aromatic Heterocycles from Ruthenium Tris(2-pyridylmethyl)amine with Visible Light.

Project description:Three complexes of the general formula [Ru(TPA)L2](PF6)2 [TPA = tris(2-pyridylmethyl)amine], where L = pyridine (1), nicotinamide (2), and imidazole (3), were prepared and characterized spectroscopically. X-ray crystallographic data were obtained for 1 and 3. Complexes 1-3 show strong absorption in the visible region and selective release of heterocycles upon irradiation with visible light. Time-dependent density functional theory calculations are consistent with the presence of singlet metal-to-ligand charge-transfer bands in the visible region in 1-3. Caged heterocycles 1-3 are highly stable in solution in the dark, including in cell growth media. Cell viability data show no signs of toxicity of 1-3 against PC-3 cells at concentrations up to 100 μM under light and dark conditions, consistent with Ru(TPA) acting as a nontoxic and effective photocaging group for aromatic heterocycles.

| S-EPMC4864085 | biostudies-literature

μ-Oxido-bis-{chlorido[tris-(2-pyridylmethyl)amine]manganese(III)} bis-(hexa-fluorido-phosphate).

Project description:In the title compound, [Mn(2)O(C(18)H(18)ClN(4))(2)](PF(6))(2), the Mn atom is chelated by a tetra-dentate ligand via four N atoms, and further bonded to one chloride ion and one bridging oxide, to give a centrosymmetric cation and distorted octa-hedral coordination geometry.

| S-EPMC2915134 | biostudies-literature

(Dicyanamido)[tris-(2-pyridylmeth-yl)amine]zinc(II) perchlorate.

Project description:In the title complex, [Zn(C(2)N(3))(C(18)H(18)N(4))]ClO(4), the Zn(II) ion has a slightly distorted trigonal-bipyramidal ZnN(5) coordination geometry. The crystal structure is stabilized by weak inter-molecular C-H?O and C-H?N hydrogen bonds. In addition, there are relatively close contacts between the O atoms of the perchlorate anion and symmetry-related pyridine rings [O?Cg = 3.179?(3) and 3.236?(3)?Å, where Cg is the centroid of a pyridine ring], and between the terminal N atom of the dicyanamide ligand and pyridine rings [N?Cg = 3.381?(4)-3.761?(3)?Å]. The central N atom of the dicyanamide ligand is disordered over two sites in an approximately 0.6:0.4 ratio.

| S-EPMC2960752 | biostudies-literature

Hyperpolarized 15N-labeled, deuterated tris (2-pyridylmethyl)amine as an MRI sensor of freely available Zn2.

Project description:Dynamic nuclear polarization (DNP) coupled with 15N magnetic resonance imaging (MRI) provides an opportunity to image quantitative levels of biologically important metal ions such as Zn2+, Mg2+ or Ca2+ using appropriately designed 15N enriched probes. For example, a Zn-specific probe could prove particularly valuable for imaging the tissue distribution of freely available Zn2+ ions, an important known metal ion biomarker in the pancreas, in prostate cancer, and in several neurodegenerative diseases. In the present study, we prepare the cell-permeable, 15N-enriched, d6-deuterated version of the well-known Zn2+ chelator, tris(2-pyridylmethyl)amine (TPA) and demonstrate that the polarized ligand had favorable T1 and linewidth characteristics for 15N MRI. Examples of how polarized TPA can be used to quantify freely available Zn2+ in homogenized human prostate tissue and intact cells are presented.

| S-EPMC8244538 | biostudies-literature

Ruthenium tris(2-pyridylmethyl)amine as an effective photocaging group for nitriles.

Project description:Ruthenium(II) tris(2-pyridylmethyl)amine (TPA) is an effective caging group for nitriles that provides high levels of control over the enzyme activity with light. Two caged nitriles were prepared, [Ru(TPA)(MeCN)2](PF6)2 (1) and [Ru(TPA)(3)2](PF6)2 (2), where 3 is the cathepsin K inhibitor Cbz-Leu-NHCH2CN, and characterized by various spectroscopic techniques and mass spectrometry. Both 1 and 2 show the release of a single nitrile within 20 min of irradiation with 365 nm light. Complex 2 acts as a potent, photoactivated inhibitor of human cathepsin K. IC50 values were determined for 2 and 3. Enzyme inhibition for 2 was enhanced by a factor of 89 upon exposure to light, with IC50 values of 63 nM (light) and 5.6 ?M (dark).

| S-EPMC3993900 | biostudies-other

[(2-Morpholinoeth-yl)(2-pyridylmethyl-ene)amine]dithio-cyanato-zinc(II).

Project description:The title compound, [Zn(NCS)(2)(C(12)H(17)N(3)O)], was prepared by the reaction of zinc acetate with pyridine-2-carbaldehyde, 2-morpholinoethyl-amine and ammonium thio-cyanate in an ethanol solution. The Zn(II) atom is five coordinate with a distorted trigonal-bipyramidal geometry, coordinating with three N atoms of the Schiff base (2-morpholinoeth-yl)(2-pyridylmethyl-idene)amine and two N atoms from two thio-cyanate ligands. The morpholine ring adopts a chair configuration.

| S-EPMC2968346 | biostudies-other

N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine, a zinc chelator, inhibits biofilm and hyphal formation in Trichosporon asahii.

Project description:OBJECTIVE:Trichosporon asahii is the major causative fungus of disseminated or deep-seated trichosporonosis and forms a biofilm on medical devices. Biofilm formation leads to antifungal drug resistance, so biofilm-related infections are relatively difficult to treat and infected devices often require surgical removal. Therefore, prevention of biofilm formation is important in clinical settings. In this study, to identify metal cations that affect biofilm formation, we evaluated the effects of cation chelators on biofilm formation in T. asahii. RESULTS:We evaluated the effect of cation chelators on biofilm formation, since microorganisms must assimilate essential nutrients from their hosts to form and maintain biofilms. The inhibition by N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) was greater than those by other cation chelators, such as deferoxamine, triethylenetetramine, and ethylenediaminetetraacetic acid. The inhibitory effect of TPEN was suppressed by the addition of zinc. TPEN also inhibited T. asahii hyphal formation, which is related to biofilm formation, and the inhibition was suppressed by the addition of zinc. These results suggest that zinc is essential for biofilm formation and hyphal formation. Thus, zinc chelators have the potential to be developed into a new treatment for biofilm-related infection caused by T. asahii.

| S-EPMC7063706 | biostudies-literature

Phosphorescent sensor for biological mobile zinc.

Project description:A new phosphorescent zinc sensor (ZIrF) was constructed, based on an Ir(III) complex bearing two 2-(2,4-difluorophenyl)pyridine (dfppy) cyclometalating ligands and a neutral 1,10-phenanthroline (phen) ligand. A zinc-specific di(2-picolyl)amine (DPA) receptor was introduced at the 4-position of the phen ligand via a methylene linker. The cationic Ir(III) complex exhibited dual phosphorescence bands in CH(3)CN solutions originating from blue and yellow emission of the dfppy and phen ligands, respectively. Zinc coordination selectively enhanced the latter, affording a phosphorescence ratiometric response. Electrochemical techniques, quantum chemical calculations, and steady-state and femtosecond spectroscopy were employed to establish a photophysical mechanism for this phosphorescence response. The studies revealed that zinc coordination perturbs nonemissive processes of photoinduced electron transfer and intraligand charge-transfer transition occurring between DPA and phen. ZIrF can detect zinc ions in a reversible and selective manner in buffered solution (pH 7.0, 25 mM PIPES) with K(d) = 11 nM and pK(a) = 4.16. Enhanced signal-to-noise ratios were achieved by time-gated acquisition of long-lived phosphorescence signals. The sensor was applied to image biological free zinc ions in live A549 cells by confocal laser scanning microscopy. A fluorescence lifetime imaging microscope detected an increase in photoluminescence lifetime for zinc-treated A549 cells as compared to controls. ZIrF is the first successful phosphorescent sensor that detects zinc ions in biological samples.

| S-EPMC3212631 | biostudies-literature

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