Showing papers by "Paul S. Donnelly published in 2007"

Functionalized bis(thiosemicarbazonato) complexes of zinc and copper: synthetic platforms toward site-specific radiopharmaceuticals.

Abstract: Two new types of unsymmetrical bis(thiosemicarbazone) proligands and their neutral zinc(II) and copper(II) complexes have been synthesized. These bifunctional ligands both chelate the metal ions and provide pendent amino groups that can be readily functionalized with biologically active molecules. Functionalization has been demonstrated by the synthesis of three water-soluble glucose conjugates of the new zinc(II) bis(thiosemicarbazonato) complexes, and their copper(II) analogues have been prepared in aqueous solution via transmetalation. A range of techniques including NMR, electron paramagnetic resonance, cyclic voltammetry, high-performance liquid chromatography (HPLC), UV/vis, and fluorescence emission spectroscopy have been used to characterize the complexes. Four compounds, including two zinc(II) complexes, have been characterized by X-ray crystallography. The connectivity and conformation of the glucose conjugates have been assigned by NMR spectroscopy. Time-dependent density functional theory calculations have been used to assign the electronic transitions of the copper(II) bis(thiosemicarbazonato) chromophore. Two copper-64-radiolabeled complexes, including one glucose conjugate, have been prepared and characterized using radio-HPLC, and transmetalation is shown to be a viable method for radiolabeling compounds with copper radionuclides. Preliminary cell washout studies have been performed under normoxic conditions, and the uptake and intracellular distribution have been studied using confocal fluorescence microscopy.

Bifunctional chelators for copper radiopharmaceuticals: the synthesis of [Cu(ATSM)–amino acid] and [Cu(ATSM)–octreotide] conjugates

Abstract: Two new bifunctional chelators that are derivatives of the bis(thiosemicarbazone) ATSMH(2) proligand have been prepared, one with two phenyl carboxylate substituents on the exocyclic nitrogens (L(1)H(2)) and one with a single phenyl carboxylate (L(2)H(2)). The new ligands have been characterised by NMR spectroscopy, mass spectrometry and in the case of L(1)H(2) by X-ray crystallography. The copper, nickel and zinc complexes of the new ligands have been synthesised and characterised. Electrochemical measurements show that the copper(II) complexes undergo a reversible reduction attributable to a Cu(II)/Cu(I) process. The new proligands have been tethered to the N-alpha-Boc-protected amino acids lysine and ornithine using solution and solid phase methods. The new amino acid conjugates form copper complexes and the complexes have been characterised by mass spectrometry and electronic spectroscopy. The bifunctional chelator L(2)H(2) has been conjugated to the tumour targeting peptide octreotide and the new ATSMH(2)-octreotide conjugate and its copper complex have been characterized by mass spectrometry. These new systems have the potential to be used for new targeted copper radiopharmaceuticals for imaging and therapy.

New bimetallic compounds based on the bis(thiosemicarbazonato) motif.

Abstract: Zinc and copper bis(thiosemicarbazonato) complexes containing more than one metal centre have been prepared with a view to examining their application for molecular imaging. The zinc complexes are fluorescent with excitation and emission at relatively long wavelengths. The dinuclear copper complex undergoes two sequential, quasi-reversible reductions.

Rhenium diazenide ternary complexes with dithiocarbamate ligands: towards new rhenium radiopharmaceuticals

Abstract: The reaction of the mono-diazenide core, [ReCl2(NNC6H4-4-OCH3)(NCCH3)(PPh3)2], with four equivalents of the sodium or potassium salts of dithiocarbamate (dtc) ligands gives neutral complexes of the formula [Re(NNC6H4-4-OCH3)(dtc)2(PPh3)]. It is possible to use a wide range of dithiocarbamate ligands (S2CNRR′) with a variety of R groups (R = R′ = methyl, phenyl or ethyl; R = methyl, R′ = phenyl and R = R′ = morpholino). Substitution reactions with dtc ligands on the mono-diazenide derived from 2-hydrazinopyridine, [ReCl2(NNC5H4N)(PPh3)2, give the analogous complexes, [Re(NNC6H5N)(dtc)2(PPh3)]. The new complexes have been characterised by a combination of NMR spectroscopy, mass spectrometry and X-ray crystallography. Cyclic voltammetry measurements in dimethyl formamide show that the rhenium diazenido-dtc complexes undergo a quasi-reversible oxidation tentatively assigned to a ReIII/ReIV oxidation. Since the parent complex, [ReCl2(NNC6H4-4-R)(NCCH3)(PPh3)2] can be prepared directly from perrhenate and readily derivatised with dtc ligands these complexes have potential relevance to the development of new therapeutic rhenium radiopharmaceuticals.

Metal delivery agents and therapeutic uses of the same

Abstract: The present invention relates to metal complexes, processes for their preparation and their use as pharmaceutical or veterinary agents, in particular for the treatment of conditions in which metal delivery can prevent, alleviate or ameliorate the condition There are a number of clinical conditions which are caused by or associated with abnormal levels of metals (typically low metal levels) Conditions in of this type include cancer and conditions characterised by or associated with oxidative damage, more specifically neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease or Huntington's disease The invention also relates to ligands useful in the preparation of metal complexes of this type

Alzheimer's disease and the chemistry of copper

Abstract: Modified copper metabolism seems to be an important factor in Alzheimer's disease and is a promising target for new therapies.