Graham E. Jackson

METAL ION COORDINATION BY SOME PENICILLIN AND CEPHALOSPORIN ANTIBIOTICS

Abstract We describe the application of an NMR line broadening technique to the study of complexation between Cu(II), Mn(II) and some antibiotics. The site of complexation is observed to be a function of the side chain and also of pH. The overall time-averaged conformations of the complexes are determined.

Metal-ion speciation in blood plasma incorporating the tetraphosphonate, N,N-dimethylenephosphonate-1-hydroxy-4-aminopropilydenediphosphonate (APDDMP), in therapeutic radiopharmaceuticals

In a quest for more effective radiopharmaceuticals for pain palliation of metastatic bone cancer, this paper relates results obtained with 166Ho and 153Sm complexed to the bone seeking phosphonate, N,N-dimethylenephosphonate-1-hydroxy-4-aminopropylidenediphosphonate (APDDMP). APDDMP is synthesised from the known bone cancer pain palliation agent 1-hydroxy-3-aminopropylidenediphosphonate (APD) and was complexed to lanthanide trivalent metal ions. This work is performed to utilise the idea that the energetic beta-particle emitter, 166 Ho, coupled with phosphonate ligands such as APD and APDDMP could afford a highly effective radiopharmaceutical in the treatment of bone cancer. Complex-formation constants of APDDMP with the important blood plasma metal-ions, Ca2+, Mg2+, and Zn2+ and the trivalent lanthanides Ho3+ and Sm3+ were measured by glass electrode potentiometry at 37 degrees C and I = 150 mM. Blood plasma models were constructed using the computer code ECCLES and the results compared with those gathered from animal tests. The 166Ho-APDDMP complex was found to have little liver or bone uptake while 153Sm-APDDMP had a moderate bone uptake. This was primarily due to the high affinity of APDDMP for Ca(II). Clinical observations could be explained by the blood plasma modelling.

Spectra-structure correlations from the infrared spectra of some transition metal complexes of 8-hydroxyquinoline

Abstract The IR spectra of twenty-one transition metal complexes of 8-hydroxyquinoline over the range 700-50 cm −1 are discussed in relation to their known or inferred structures. The complexes are of three types: (a) the bis (aquo) complexes of the 3 d metal(II) ions trans -[M(ox) 2 (H 2 O) 2 ] (M = Mn, Fe, Co, Ni, Cu, Zn); (b) the corresponding anhydrous complexes, [M(ox) 2 ] (M = Mn, Co, Ni, Cu, Zn); and (c) the complexes of the metal(III) ions, [M(ox) 3 ] (M = Sc, V, Cr, Mn, Fe, Co, Ga). 8-Hydroxyquinoline- d 7 has been synthesized and used to assist in the metal-ligand assignments which are further based on 64,68 Zn labelling of the bis (aquo) zinc complex and on the effects of metal ion substitution in relation to expectations based on crystal field theory. The effects of Jahn-Teller distortion on the spectra of the complexes of Cu(II) and Mn(III) are discussed. The spectra of the bis (aquo) adducts support the previously proposed trans -octahedral structure. The spectra of the anhydrous complexes are consistent with tetrahedral Mn, Ni and Zn but suggest that the Co complex has polymeric octahedral coordination rather than the previously-proposed tetrahedral structure. The six-coordinate α-Cu complex and five-coordinate β-Cu complex exhibit distinctive differences in their spectra which support the elongated axial Cu-O bonds observed in crystal structure determinations. The spectra of the metal(III) tris (oxinates) are consistent with the facial ( cis-cis ) coordination previously proposed. The spectra of these complexes are discussed in relation to bonding considerations based on crystal field theory.

Aluminium, gallium and indium in biological fluids—a computer model of blood plasma

Abstract A computer model of the solution equilibria involving Al 3+ , Ga 3+ and In 3+ in blood plasma has been constructed and used to investigate the in vivo fate of these metal ions. The effect of a series of chelating agents on the species distribution of Al 3+ is reported. Chemical explanations are given for a number of clinical observations on the use of 67 Ga 3+ and 111 In 3+ in nuclear medicine.

Metal-ion speciation in blood plasma incorporating the bisphosphonate, 1-hydroxy-4-aminopropilydenediphosphonate (APD), in therapeutic radiopharmaceuticals.

In the quest for more effective pain palliation radiopharmaceuticals for metastatic bone cancer, this paper relates results obtained with 166Ho complexed to the bone-seeking bisphosphonate, 1-hydroxy-4-aminopropililydenediphosphonate (APD). APD is itself a bone cancer pain palliation agent and this work was therefore driven by the idea that the energetic beta-particle emitter, 166Ho, coupled with APD could afford a highly effective radiopharmaceutical in the treatment of bone cancer. Complex-formation constants for important blood plasma metal-ions were measured by potentiometry or polarography at 37 degrees C and I = 150 mmol dm-3. The latter technique was used for systems where precipitates formed at ligand-to-metal ratios appropriate for potentiometry. For trivalent lanthanides, neither electrochemical technique could be used. Animal tests showed that the 166Ho-APD complex was taken up primarily by the liver due to precipitation or colloid formation.

Quinolinone alkaloids from an Agathosma species

Abstract The aerial parts of a new species from the genus Agathosma yielded skimmianine and two new alkaloids which were identified by means of spectral data and synthesis as 4,6-dimethoxy-1-methyl-2(1H)-quinolinone and 2,6-dihydro-9-methoxy-2,2,6-trimethyl-5H-pyrano[3,2 c ]quinolin-5-one. Further related structures were synthesized and a 2D NMR study on the eight synthetic structures enabled us to correct some of the data appearing in the literature.

The existence of AlF4− in aqueous solution and its relevance to phosphorylase reactions

Abstract The discovery that trace amounts of aluminium are necessary for fluoride to exert its biological influence has lead to numerous investigations into the nature of the active fluoroaluminate complex. Many workers have postulated AlF4− to be this species. In this study we show that in the presence of inorganic phosphate or ADP, fluoride is not able to complex aluminium(III), but rather the species [Al(PO4)2H]2− and [Al(ADP)OH]− are formed. In the absence of completing ligands, 27Al NMR reveals that octahedral, hydrated aluminium fluoride complexes are formed, the most likely one being [AlF4(H2O)2]−.

The chemistry of uranium. Part 23. Isomorphous tetrachlorobis(hexamethylphosphoramide)uranium(IV) and tetrabromobis(hexamethylphosphoramide)uranium(IV)

The structures of UCl 4 ·2hmpa and UBr 4 ·2hmpa have been determined by Fourier methods from single-crystal X-ray diffraction data Full-matrix least-squares refinement yielded final conventional R factors of 0.062 and 0.059 respectively. The complexes are isomorphout and crystallise in the space group P2 1 /n with a = 14.141(5), b = 10.530(5), c = 9.076(5) A , β = 93.33° and a = 14.348(5), b = 10.698 (5), c = 9.304(5), β = 91.95 respectively. The hmpa moieties are in trans-octahedral arrangement about the uranium atom. The principal bond lengths are U—X (X = Cl, Br) = 2.615, 2.78; U—O = 2.23, 2.18; O—P = 1.50, 1.53 A respectively.

Quercetin encapsulation in modified silica nanoparticles: potential use against Cu(II)-induced oxidative stress in neurodegeneration.

Neurodegenerative diseases entail deeply complex processes, intimately associated with progressive brain damage reflecting cellular demise. Biochemical reactivity linked to such processes in Alzheimers disease involves, among others, metal-induced oxidative stress contributing to neuronal cell death. Prominent among redox active metals inducing oxidative stress is Cu(II). Poised to develop molecular technology counteracting oxidative stress, efforts were launched to prepare bioactive hybrid nanoparticles, capable of working as host-carriers of potent antioxidants, such as the natural flavonoid quercetin. Employing synthetic protocols consistent with the assembly of silica nanoparticles, PEGylated and CTAB-modified materials were synthesized. Subsequent concentration-dependent loading of quercetin led to well-defined molecular carriers, the antioxidant efficiency of which was determined through drug release studies using UV-visible spectroscopy. The physicochemical characterization (elemental analysis, particle size, z-potential, FT-IR, thermogravimetric analysis, scanning electron microscopy) of the empty and loaded silica nanoparticles led to the formulation of optimized material linked to the delivery of the encapsulated antioxidant to primary rat hippocampal cultures under oxidative stress. Entrapment and drug release studies showed a) the competence of hybrid nanoparticles as far as the loading capacity in quercetin (concentration dependence), b) congruence with the physicochemical features determined, and c) the release profile of the nanoparticle load under oxidative stress in neuronal cultures. The bio-activity profile of quercetin nanoparticles in a neurodegenerative environment brought on by Cu(II) a) denotes the improved specificity of antioxidant reactivity counteracting oxidative stress, and b) sets the stage for the development of molecular protection and preventive medical nanotechnology of relevance to neurodegenerative Alzheimers disease.

Conformational study of insect adipokinetic hormones using NMR constrained molecular dynamics.

Mem-CC (pGlu-Leu-Asn-Tyr-Ser-Pro-Asp-Trp-NH2), Tem-HrTH (pGlu-Leu-Asn-Phe-Ser-Pro-Asn-Trp-NH2) and Del-CC (pGlu-Leu-Asn-Phe-Ser-Pro-Asn-Trp-Gly-Asn-NH2) are adipokinetic hormones, isolated from the corpora cardiaca of different insect species. These hormones regulate energy metabolism during flight and so are intimately involved in an insects mobility. Secondary structural elements of these peptides and the N7 analogue, [N7]-Mem-CC (pGlu-Leu-Asn-Tyr-Ser-Pro-Asn-Trp-NH2), have been determined in dimethylsulfoxide solution using NMR restrained molecular mechanic simulations. The neuropeptides were all found to have an extended structure for the first 4 residues and a β-turn between residues 4–8. For Tem-HrTH and Del-CC, asparagine (N7) which is postulated to be involved in receptor binding and/or activation, projects outward form the β-turn. Mem-CC does not have an asparagine at position 7 while, for [N7]-Mem-CC, the N7 sidechain folds inside the β-turn preventing its interaction with the receptor.