School of Chemistry - Research Publications
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ItemCellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-03-11)The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [Co(III)(salen)(acac)] complexes capable of up-regulating the ubiquitin ligase adaptor protein Ndfip1. Ndfip1 is a neuroprotective protein that is up-regulated in the brain after injury and functions in combination with Nedd4 ligases to ubiquitinate harmful proteins for removal. We previously showed that Ndfip1 can be increased in human neurons using CoCl(2) that is toxic at high concentration. Here we demonstrate a similar effect can be achieved by low concentrations of synthetic Co(III) complexes that are non-toxic and designed to be activated following cellular entry. Activation is achieved by intracellular reduction of Co(III) to Co(II) leading to release of Co(II) ions for Ndfip1 up-regulation. The cellular benefit of Ndfip1 up-regulation by Co(III) complexes includes demonstrable protection against cell death in SH-SY5Y cells during stress. In vivo, focal delivery of Co(III) complexes into the adult mouse brain was observed to up-regulate Ndfip1 in neurons. These results demonstrate that a cellular response pathway can be advantageously manipulated by chemical modification of metal complexes, and represents a significant step of harnessing low concentration metal complexes for therapeutic benefit.
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ItemGuest‐induced Assembly of Bis(thiosemicarbazonato) Zinc(II) Coordination Nanotubes(Wiley, 2017-07-10)Abstract A ZnII complex of the dianionic tetradentate ligand formed by deprotonation of glyoxal‐bis(4‐phenyl‐3‐thiosemicarbazone) (H2gtsp) is a [3+3] trinuclear triangular prism. Recrystallization of this complex in the presence of either CO2, CS2, or CH3CN leads to the formation of [4+4] open‐ended charge‐neutral tetranuclear coordination nanotubes, approximately 2 nm in length and with internal dimensions large enough to accommodate linear guest molecules, which serve to template their formation. Upon removal of the templating molecules the nanotubes demonstrated reversible sorption of CO2 with an isosteric enthalpy of sorption of 28 kJ mol−1 at low loading.
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ItemGuest-induced Assembly of Bis(thiosemicarbazonato) Zinc(II) Coordination Nanotubes(Wiley, 2017-07-10)A ZnII complex of the dianionic tetradentate ligand formed by deprotonation of glyoxal‐bis(4‐phenyl‐3‐thiosemicarbazone) (H2gtsp) is a [3+3] trinuclear triangular prism. Recrystallization of this complex in the presence of either CO2, CS2, or CH3CN leads to the formation of [4+4] open‐ended charge‐neutral tetranuclear coordination nanotubes, approximately 2 nm in length and with internal dimensions large enough to accommodate linear guest molecules, which serve to template their formation. Upon removal of the templating molecules the nanotubes demonstrated reversible sorption of CO2 with an isosteric enthalpy of sorption of 28 kJ mol−1 at low loading.
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ItemSynthesis of Homochiral Co-III- and Mn-IV-[2.2]Paracyclophane Schiff Base Complexes with Predetermined Chirality at the Metal Centre(WILEY-V C H VERLAG GMBH, 2016-08-01)The planar chiral Schiff base ligand 2, derived from (Rp)‐5‐formyl‐4‐hydroxy‐[2.2]paracyclophane (FHPC) (1), was utilised to form a Λ‐CoIII cis‐β‐octahedral metal complex 3 with complete control of the metal‐centred chirality. In addition, a di‐µ‐oxo Λ,Λ‐MnIV complex 4 was synthesised with control of both metal‐centred and (P)‐helical chirality.
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ItemRhenium and technetium complexes of thioamide derivatives of pyridylhydrazine that bind to amyloid-β plaques(SPRINGER, 2018-10)Age-associated deposition of amyloid-β in cerebral blood vessels, a condition referred to as cerebral amyloid angiopathy, can contribute to stroke and dementia. This research aimed to design new radioactive technetium-99 m complexes that bind to amyloid-β plaques that have the potential to assist in diagnosis of cerebral amyloid angiopathy using single-photon-emitted computed tomography (SPECT) imaging. Six new pyridylthiosemicarbazide ligands containing either benzofuran or styrylpyridyl functional groups that are known to selectively bind to amyloid plaques were prepared. Non-radioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. The new ligands were used to prepare well-defined [Re-oxo]3+ complexes where two pyridylthiosemicarbazide ligands were coordinated to a single metal ion to give bivalent complexes with two amyloid-β targeting functional groups. The interaction of the [Re-oxo]3+ complexes with synthetic amyloid-β1-42 and with amyloid plaques in human brain tissue was investigated. Two ligands were selected to develop methods to prepare their [99mTc-oxo]3+ complexes at the tracer level. These technetium-99 m complexes are likely to be isostructural to their rhenium-oxo analogues.
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ItemNo Preview AvailableRhenium and Technetium-oxo Complexes with Thioamide Derivatives of Pyridylhydrazine Bifunctional Chelators Conjugated to the Tumour Targeting Peptides Octreotate and Cyclic-RGDfK(AMER CHEMICAL SOC, 2017-08-21)This research aimed to develop new tumor targeted theranostic agents taking advantage of the similarities in coordination chemistry between technetium and rhenium. A γ-emitting radioactive isotope of technetium is commonly used in diagnostic imaging, and there are two β- emitting radioactive isotopes of rhenium that have the potential to be of use in radiotherapy. Variants of the 6-hydrazinonicotinamide (HYNIC) bifunctional ligands have been prepared by appending thioamide functional groups to 6-hydrazinonicotinamide to form pyridylthiosemicarbazide ligands (SHYNIC). The new bidentate ligands were conjugated to the tumor targeting peptides Tyr3-octreotate and cyclic-RGD. The new ligands and conjugates were used to prepare well-defined {M═O}3+ complexes (where M = 99mTc or natRe or 188Re) that feature two targeting peptides attached to the single metal ion. These new SHYNIC ligands are capable of forming well-defined rhenium and technetium complexes and offer the possibility of using the 99mTc imaging and 188/186Re therapeutic matched pairs.
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ItemVersatile New Bis(thiosemicarbazone) Bifunctional Chelators: Synthesis, Conjugation to Bombesin(7-14)-NH2, and Copper-64 Radiolabeling(AMER CHEMICAL SOC, 2010-02-15)New bifunctional derivatives of diacetyl-bis(4-methylthiosemicarbazone) (H(2)atsm) have been prepared by a selective transamination reaction of a new dissymmetric bis(thiosemicarbazone) precursor H(2)L(1). The new derivatives contain an aliphatic carboxylic acid (H(2)L(2) and H(2)L(3)), t-butyl carbamate (H(2)L(4)), or ammonium ion (H(2)L(5)) functional group. The new ligands and copper(II) complexes have been characterized by NMR spectroscopy, mass spectrometry, and microanalysis. The complex Cu(II)(L(4)) was structurally characterized by X-ray crystallography and shows the metal center to be in an N(2)S(2) distorted square planar coordination geometry. Electrochemical measurements show that the copper(II) complexes undergo a reversible reduction attributable to a Cu(II)/Cu(I) process. The ligands and the copper(II) complexes featuring a carboxylic acid functional group have been conjugated to the tumor targeting peptide bombesin(7-14)-NH(2). The bifunctional peptide conjugates were radiolabeled with copper-64 in the interest of developing new positron emission tomography (PET) imaging agents. The conjugates were radiolabeled with copper-64 rapidly in high radiochemical purity (>95%) at room temperature under mild conditions and were stable in a cysteine and histidine challenge study.
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ItemGallium-68 Complex of a Macrobicyclic Cage Amine Chelator Tethered to Two Integrin-Targeting Peptides for Diagnostic Tumor Imaging(AMER CHEMICAL SOC, 2011-10)Tumor-targeting peptides radiolabeled with positron-emitting (68)Ga are promising candidates as new noninvasive diagnostic agents for positron emission tomography (PET). The targeting peptides are tethered to a chelator that forms a stable coordination complex with Ga(3+) that is inert to dissociation of Ga(3+)in vivo. Metal complexes of macrobicyclic hexaamine "sarcophagine" (sar = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) ligands exhibit remarkable stability as a result of the encapsulating nature of the cage amine ligand. A Ga(3+) sarcophagine complex, [Ga-(1-NH(3)-8-NH(2)-sar)](4+), has been characterized using X-ray crystallography, demonstrating that Ga(3+) is coordinated to six nitrogen atoms in a distorted octahedral complex. A bifunctional derivative of (NH(2))(2)sar, possessing two aliphatic linkers with carboxylic acid functional groups has been attached to two cyclic-RGD peptides that target the α(v)β(3) integrin receptor that is overexpressed in some types of tumor tissue. This dimeric species can be radiolabeled with (68)Ga(3+) in >98% radiochemical yield and (68)Ga(3+) does not dissociate from the ligand in the presence of transferrin, an endogenous protein with high affinity for Ga(3+). Biodistribution and micro-PET imaging studies in tumor-bearing mice indicate that the tracer accumulates specifically in tumors with high integrin expression. The high tumor uptake is coupled with low nonspecific uptake and clearance predominantly through the kidneys resulting in high-quality PET images in animal models.
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ItemNo Preview AvailableRhenium and technetium tricarbonyl complexes of 1,4-substituted pyridyl-1,2,3-triazole bidentate ‘click’ ligands conjugated to a targeting RGD peptide(Wiley, 2014)New 1,4‐substituted pyridyl‐1,2,3‐triazole ligands with pendent phenyl isothiocyanate functional groups linked to the heterocycle through a short methylene or longer polyethylene glycol spacers were prepared and conjugated to a peptide containing the arginine–glycine–aspartic acid peptide motif. Rhenium and technetium carbonyl complexes, [M(CO)3Lx(py)]+ (where M = ReI or 99mTcI; Lx = 1,4‐substituted pyridyl‐1,2,3‐triazole ligands and py = pyridine) were prepared. One rhenium complex has been characterized by X‐ray crystallography, and the luminescent properties of [M(CO)3Lx(py)]+ are reported.
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ItemRhenium and technetium complexes that bind to amyloid-β plaques(ROYAL SOC CHEMISTRY, 2015)Alzheimer's disease is associated with the presence of insoluble protein deposits in the brain called amyloid plaques. The major constituent of these deposits is aggregated amyloid-β peptide. Technetium-99m complexes that bind to amyloid-β plaques could provide important diagnostic information on amyloid-β plaque burden using Single Photon Emission Computed Tomography (SPECT). Tridentate ligands with a stilbene functional group were used to form complexes with the fac-[M(I)(CO)3](+) (M = Re or (99m)Tc) core. The rhenium carbonyl complexes with tridentate co-ligands that included a stilbene functional group and a dimethylamino substituent bound to amyloid-β present in human frontal cortex brain tissue from subjects with Alzheimer's disease. This chemistry was extended to make the analogous [(99m)Tc(I)(CO)3](+) complexes and the complexes were sufficiently stable in human serum. Whilst the lipophilicity (log D7.4) of the technetium complexes appeared ideally suited for penetration of the blood-brain barrier, preliminary biodistribution studies in an AD mouse model (APP/PS1) revealed relatively low brain uptake (0.24% ID g(-1) at 2 min post injection).