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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ItemSynthesis of glycoconjugate fragments of mycobacterial phosphatidylinositol mannosides and lipomannan(BEILSTEIN-INSTITUT, 2011-03-28)Mycobacterium tuberculosis, the causitive agent of tuberculosis (TB), possesses a complex cell wall containing mannose-rich glycophospholids termed phosphatidylinositol mannosides (PIMs), lipomannan (LM), and lipoarabinomannan (LAM). These glycophospholipids play important roles in cell wall function and host-pathogen interactions. Synthetic PIM/LM/LAM substructures are useful biochemical tools to delineate and dissect the fine details of mannose glycophospholipid biosynthesis and their interactions with host cells. We report the efficient synthesis of a series of azidooctyl di- and trimannosides possessing the following glycan structures: α-Man-1,6-α-Man, α-Man-1,6-α-Man-1,6-α-Man, α-Man-1,2-α-Man-1,6-α-Man and 2,6-di-(α-Man)-α-Man. The synthesis includes the use of non-benzyl protecting groups compatible with the azido group and preparation of the branched trisaccharide structure 2,6-di-(α-Man)-α-Man through a double glycosylation of a 3,4-butanediacetal-protected mannoside. The azidooctyl groups of these synthetic mannans were elaborated to fluorescent glycoconjugates and squaric ester derivatives useful for further conjugation studies.
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Item4-Chloroanilinium 2-carboxy-4,5-dichlorobenzoate(WILEY-BLACKWELL, 2009-09)The structure of the 1:1 proton-transfer compound of 4-chloro-aniline with 4,5-dichloro-phthalic acid (DCPA), viz. C(6)H(7)ClN(+)·C(8)H(3)Cl(2)O(4) (-), has been determined at 130 K. The non-planar hydrogen phthalate anions and the 4-chloro-anilinium cations form two-dimensional O-H⋯O and N-H⋯O hydrogen-bonded substructures which have no peripheral extension. Between the sheets there are weak π-π associations between alternating cation-anion aromatic ring systems [shortest centroid-centroid separation = 3.735 (4) Å].
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Item2-(4-Aminophenyl)-1-phenyldiazenium 2,4,6-trinitrophenolate(WILEY-BLACKWELL, 2011-04)In the title salt, C(12)H(12)N(3) (+)·C(6)H(2)N(3)O(7) (-), the diazenyl group of the 4-(phenyl-diazen-yl)aniline mol-ecule is protonated and forms a hydrogen bond with the phenolate O-atom acceptor of the picrate anion. Structure extension occurs through two symmetrical inter-ion three-centre amine N-H⋯O,O'(nitro) hydrogen-bonding associations [graph set R(1) (2)(4)], giving a convoluted two-dimensional network structure.
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Item1,10-Phenanthrolin-1-ium 2-carboxy-4,5-dichlorobenzoate(WILEY-BLACKWELL, 2009-10)In the structure of the 1:1 proton-transfer compound of 1,10-phenanthroline with 4,5-dichloro-phthalic acid, C(12)H(9)N(2) (+)·C(8)H(3)Cl(2)O(4) (-), determined at 130 K, the 1,10-phenanthrolinium cation and the hydrogen 4,5-dichloro-phthalate anion associate through a single N-H⋯O(carbox-yl) hydrogen bond giving discrete units which have no extension except through a number of weak cation C-H⋯O(anion) associations and weak cation-anion aromatic ring π-π inter-actions [minimum centroid-centroid separation = 3.6815 (12) Å]. The anions are essentially planar "[maximum deviation 0.214 (1) Å (a carboxyl O)] with the syn-related H atom of the carboxyl group, forming a short intra-molecular O-H⋯O(carbox-yl) hydrogen bond.
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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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Item2-carboxyquinolinium-2,4,6-trinitro-benzenesulfonate -quinolinium-2-carboxylate (1/1/1)(BLACKWELL PUBLISHING, 2008-01)The structure of the title adduct compound, C(10)H(8)NO(2) (+)·C(6)H(2)N(3)O(9)S(-)·C(10)H(7)NO(2), from the reaction of 2,4,6-trinitro-benzene-sulfonic acid (picrylsulfonic acid) with quinoline-2-carboxylic acid (quinaldic acid) in 2-propanol-water, has been determined at 130 (2) K. The cation and the adduct species form a twisted cyclic hydrogen-bonded R(2) (2)(10) pseudo-dimer which is extended into a one-dimensional chain structure through short head-to-tail carboxylic acid O-H⋯O(carbox-yl) associations [O⋯O = 2.4711 (19) Å]. The picrylsulfonate anions are attached peripherally by single N-H⋯O(sulfonate) hydrogen bonds [N⋯O = 2.8643 (19) Å].
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ItemMacrobicyclic Cage Amine Ligands for Copper Radiopharmaceuticals: A Single Bivalent Cage Amine Containing Two Lys3-bombesin Targeting Peptides(AMER CHEMICAL SOC, 2011-07-18)The synthesis of new cage amine macrobicyclic ligands with pendent carboxylate functional groups designed for application in copper radiopharmaceuticals is described. Reaction of [Cu((NH(2))(2)sar)](2+) (sar = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) with either succinic or glutaric anhydride results in selective acylation of the primary amine atoms of [Cu((NH(2))(2)sar)](2+) to give derivatives with either one or two aliphatic carboxylate functional groups separated from the cage amine framework by either a four- or five-atom linker. The Cu(II) serves to protect the secondary amine nitrogen atoms from acylation, and can be removed to give the free ligands. The newly appended carboxylate functional groups can be used as sites of attachment for cancer-targeting peptides such as Lys(3)-bombesin. The synthesis of the first dimeric sarcophagine-peptide conjugate, possessing two Lys(3)-bombesin peptides tethered to a single cage amine, is presented. This species has been radiolabeled with copper-64 at ambient temperature and there is minimal dissociation of Cu(II) from the conjugate even after two days of incubation in human serum.