Synthesis and structural characterization of copper-cuprizone complexes.

Copper(II) coordination by bis(cyclohexanone)oxalyldihydrazone (also known as cuprizone), resulting in the formation of an intensely coloured blue complex, was first reported over 70 years ago. The cuprizone reaction has been employed in colourimetric tests for the presence of trace levels of copper. Cuprizone administration in C57BL/6 mice also leads to demyelination over time - a consequence that appears to be due to copper dyshomeostasis - and this has led to use of cuprizone as the leading method for toxicant-induced generation of an animal model of demyelination since its first use in the 1960s.

X-ray-Induced Photoreduction of Hg(II) in Aqueous Frozen Solution Yields Nearly Monatomic Hg(0).

We use X-ray-induced photochemistry, which is well known to cause changes in a number of systems, to reduce Hg(II) to Hg(0) in frozen aqueous solution with added glycerol maintained at 10 K. X-ray absorption spectroscopy was used to monitor the extent of the reaction and to characterize the species. An analysis of the extended X-ray absorption fine structure (EXAFS) of the photochemical product indicated a nearly monatomic Hg(0) species bound only by long, weak bonds to oxygens at ∼3.

Cryoprotectants Severely Exacerbate X-ray-Induced Photoreduction.

Approximately 11% of enzymes contain a transition metal ion that is essential for catalytic function. Such metalloenzymes catalyze much of the most chemically challenging and biologically essential chemistry carried out by life. X-ray-based methods, predominantly macromolecular crystallography (MX) and also X-ray absorption spectroscopy (XAS), have proved essential for determining structures of transition metal ion-containing active sites in order to deduce enzyme catalytic mechanisms.

Binding of Copper and Cisplatin to Atox1 Is Mediated by Glutathione through the Formation of Metal-Sulfur Clusters.

Copper is an essential nutrient required for many biological processes involved in primary metabolism, but free copper is toxic due to its ability to catalyze formation of free radicals. To prevent toxic effects, in the cell copper is bound to proteins and low molecular weight compounds, such as glutathione, at all times. The widely used chemotherapy agent cisplatin is known to bind to copper-transporting proteins, including copper chaperone Atox1.

Combined EXAFS and DFT structure calculations provide structural insights into the 1:1 multi-histidine complexes of Cu(II) , Cu(I) , and Zn(II) with the tandem octarepeats of the mammalian prion protein.

The metal-coordinating properties of the prion protein (PrP) have been the subject of intense focus and debate since the first reports of its interaction with copper just before the turn of the century. The picture of metal coordination to PrP has been improved and refined over the past decade, but structural details of the various metal coordination modes have not been fully elucidated in some cases. In the present study, we have employed X-ray absorption near-edge spectroscopy as well as extended X-ray absorption fine structure (EXAFS) spectroscopy to structurally characterize the dominant 1:1 coordination modes for Cu(II) , Cu(I) , and Zn(II) with an N-terminal fragment of PrP.

The solution structure of the copper clioquinol complex.

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) recently has shown promising results in the treatment of Alzheimer's disease and in cancer therapy, both of which also are thought to be due to clioquinol's ability as a lipophilic copper chelator. Previously, clioquinol was used as an anti-fungal and anti-protozoal drug that was responsible for an epidemic of subacute myelo-optic neuropathy (SMON) in Japan during the 1960s, probably a myeloneuropathy arising from a clioquinol-induced copper deficiency. Previous X-ray absorption spectroscopy of solutions of copper chelates of clioquinol suggested unusual coordination chemistry.

X-ray-induced photo-chemistry and X-ray absorption spectroscopy of biological samples.

As synchrotron light sources and optics deliver greater photon flux on samples, X-ray-induced photo-chemistry is increasingly encountered in X-ray absorption spectroscopy (XAS) experiments. The resulting problems are particularly pronounced for biological XAS experiments. This is because biological samples are very often quite dilute and therefore require signal averaging to achieve adequate signal-to-noise ratios, with correspondingly greater exposures to the X-ray beam.

Structural, functional and calorimetric investigation of MosA, a dihydrodipicolinate synthase from Sinorhizobium meliloti l5-30, does not support involvement in rhizopine biosynthesis.

MosA is an enzyme from Sinorhizobium meliloti L5-30, a beneficial soil bacterium that forms a symbiotic relationship with leguminous plants. MosA was proposed to catalyze the conversion of scyllo-inosamine to 3-O-methyl-scyllo-inosamine (compounds known as rhizopines), despite the MosA sequence showing a strong resemblance to dihydrodipicolinate synthase (DHDPS) sequences rather than to methyltransferases. Our laboratory has already shown that MosA is an efficient catalyst of the DHDPS reaction.

E,E,E-1-(4-Arylamino-4-oxo-2-butenoyl)-3,5-bis(arylidene)-4-piperidones: a topographical study of some novel potent cytotoxins.

A series of E,E,E-3,5-bis(arylidene)-1-(4-arylamino-4-oxo-2-butenoyl)-4-piperidones 4 (phenylidene) and 5 (4-nitrophenylidene) were prepared in order to explore the structural features of the N-acyl group which affects the cytotoxic potency. Evaluation toward human Molt 4/C8 and CEM T-lymphocytes revealed that many of the IC(50) figures were submicromolar and lower than melphalan. Marked inhibitory potencies toward murine leukemia L1210 cells were also noted.

Cytotoxic 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienes mounted on alicyclic scaffolds.

The 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienyl pharmacophore was incorporated into four series of compounds 1-4. Compounds 1a-g comprised a cluster of 3-arylidene-1-(4-nitrophenylmethylene)-2-oxo-3,4-dihydro-1H-naphthalenes while the analogues 2a-g consisted of a group of 6-arylidene-2-(4-nitrophenylmethylene)cyclohexanones. Three other compounds prepared in this study were 1-(4-nitrophenylmethylene)-3-(3,4,5-trimethoxyphenylmethylene)-2-oxo-2,3-dihydro-1H-indene 3a as well as two 5-arylidene-2-(4-nitrophenylmethylene)cyclopentanones 4a,b.

Crystallization, preliminary X-ray diffraction and structure solution of MosA, a dihydrodipicolinate synthase from Sinorhizobium meliloti L5-30.

The structure of MosA, a dihydrodipicolinate synthase and reported methyltransferase from Sinorhizobium meliloti, has been solved using molecular replacement with Escherichia coli dihydrodipicolinate synthase as the model. A crystal grown in the presence of pyruvate diffracted X-rays to 2.3 A resolution using synchrotron radiation and belonged to the orthorhombic space group C222(1), with unit-cell parameters a = 69.

Cytotoxic and anticonvulsant aryloxyaryl Mannich bases and related compounds.

A series of 1-(4-aryloxyphenyl)-3-diethylamino-1-propanone hydrochlorides 3a-3e and related compounds 3f, 3g and 4a-4d were synthesised. In addition, a group of 4-(4-aryloxyphenyl)-3-(4-aryloxyphenylcarbonyl)-1-ethyl-4-piperidinol hydrochlorides 6a-6e were prepared which incorporated most of the structural features of 3a-3e. All of these compounds displayed cytotoxic properties towards murine L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes.

Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones and related compounds.

A series of 4-carboxychalcones 1 were prepared and coupled to 3,5-bis(phenylmethylene)-4-piperidone (2) giving rise to a novel series of N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones (3). Molecular simplification of the amides 3 led to the formation of the corresponding N-(3-aryl-1-oxo-2-propenyl)-3,5-bis(phenylmethylene)-4-piperidones (4). A cytotoxic evaluation of the compounds in series 1-4 utilized murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes.

Cytotoxic analogues of 2,6-bis(arylidene)cyclohexanones.

A series of 2,6-bis(arylidene)cycloalkanones (1) and related compounds containing one or two substituents at the four position of the cyclohexyl ring were prepared and shown to display cytotoxic activity towards murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In some of the series of compounds, positive correlations were noted between the potencies of the enones and the magnitude of the Hammett sigma values of the aryl substituents. Four representative compounds were cytotoxic to a number of human tumours in vitro, particularly towards colon cancer and leukemic cells.