Search PubMed⌕ Search

Biomedical subjects

A J White

Publications and source records attributed to A J White.

At least 19 recordsLinked to original sources
PubMed2001

Heterometallic network complexes of the ambidentate, extended-reach linear ligand 1-(4'-pyridyl)pyridin-4-one.

An investigation into the ability of the ambidentate, "extended-reach" ligand 1-(4'-pyridyl)pyridin-4-one (pypyd) to form polymeric network complexes has resulted in the X-ray characterization of the compounds [Cu(pypyd)(2)(H2O)(2)](ClO(4))(2).pypyd 1, [Co(2)Dy(2)(pypyd)(8)(H2O)(2)(NCS)(4)(NO(3))(4)][Co(NCS)(4)] 2, and [NiYb(pypyd)(4)(NCS)(2)(NO(3))(2)](NO(3)) 3. The homometallic copper complex, 1, forms a (4,4) sheet polymer with additional intrasheet cross-linking via hydrogen bonding of noncoordinated pypyd molecules to the aqua ligands on the Cu centers. The heterometallic Co/Dy complex, 2, also produces a contiguous (4,4) sheet but without the hydrogen bonded pypyd cross-link. The heterometallic Ni/Yb compound, 3, forms a more complex array comprised of mutually interpenetrating networks each of three-dimensional (6,4) topology. The crystal structure of an acetic acid adduct of pypyd, 4, is also reported.

Journal Article↗
PubMed2001

Synthesis and characterization of gallium silylamido complexes.

The reaction between GaCl(3) and 1 equiv of HN(SiMe(2)Ph)(2) in CH(2)Cl(2) solution affords colorless crystals of [Cl(2)Ga[mu-N(H)SiMe(2)Ph]](2) (1). The related reaction between GaCl(3) and 1 equiv of LiN(SiMe(2)Ph)(2) in hexane solution results in the isolation of colorless crystals of [PhGa[N(SiMe(2)Ph)(2)](mu-Cl)](2) (2). In contrast, treatment of GaCl(3) with 1 equiv of N(SiMe(3))(3) in CH(2)Cl(2) solutions affords colorless crystals of [MeGaCl(2)](2) (4). Compounds 2 and 4 are the result of monochloride substitution and transfer of a phenyl and methyl ligand, respectively, from the silyl group of the amine to the Ga center. All the complexes have been characterized by X-ray crystallography.

Journal Article↗
PubMed2001

Spatial properties of koniocellular cells in the lateral geniculate nucleus of the marmoset Callithrix jacchus.

1. The receptive field dimensions, contrast sensitivity and linearity of spatial summation of koniocellular (KC), parvocellular (PC) and magnocellular (MC) cells in the lateral geniculate nucleus (LGN) of 11 adult marmosets were measured using achromatic sinusoidal gratings. 2. The receptive field centre diameter of cells in each (PC, KC and MC) class increases with distance from the fovea. There is substantial overlap in centre size between the three cell classes at any eccentricity, but the PC cells have, on average, the smallest centres and the KC cells have the largest. Some PC and KC cells did not respond at all to the grating stimulus. 3. The contrast sensitivity of the receptive field centre mechanism in KC cells decreases in proportion to the centre area. A similar trend was seen for the surround mechanism. These characteristics are common to PC and MC cells, suggesting that they originate at an early stage of visual processing in the retina. 4. The KC cells showed, in general, lower peak evoked discharge rates than PC or MC cells. The spontaneous discharge rate of KC cells was lower than that of PC cells and similar to that of MC cells. 5. The majority of cells in all divisions of the LGN show linear spatial summation. A few cells did show non-linear spatial summation; these cells were predominantly located in the MC and ventral KC layers. 6. The ventral KC layers below and between the MC layers contain cells with larger and more transiently responding receptive fields than cells in the more dorsal KC layers. 7. We conclude that many of the contrast-dependent spatial properties of cells in the marmoset LGN are common to PC, MC and KC cells. The main difference between KC cells and the other two classes is that there is more variability in their response properties, and they are less responsive to high spatial frequencies.

Animals↗
PubMed2001

Chromatic sensitivity of ganglion cells in the peripheral primate retina.

Visual abilities change over the visual field. For example, our ability to detect movement is better in peripheral vision than in foveal vision, but colour discrimination is markedly worse. The deterioration of colour vision has been attributed to reduced colour specificity in cells of the midget, parvocellular (PC) visual pathway in the peripheral retina. We have measured the colour specificity (red-green chromatic modulation sensitivity) of PC cells at eccentricities between 20 and 50 degrees in the macaque retina. Here we show that most peripheral PC cells have red-green modulation sensitivity close to that of foveal PC cells. This result is incompatible with the view that PC pathway cells in peripheral retina make indiscriminate connections ('random wiring') with retinal circuits devoted to different spectral types of cone photoreceptors. We show that selective cone connections can be maintained by dendritic field anisotropy, consistent with the morphology of PC cell dendritic fields in peripheral retina. Our results also imply that postretinal mechanisms contribute to the psychophysically demonstrated deterioration of colour discrimination in the peripheral visual field.

Animals↗
PubMed2001

Synthesis and characterization of coronanes: multicyclopropane-fused macrocyclic arrays.

Stepwise macrocyclization of the all syn-trans-1,15-quinquecyclopropanedimethanol (4) with iso- and terephthaloyl chlorides and 4,4'-methanediyl-dibenzoic acid (28) gave the corresponding coronanes 22, 23, and 32. The same protocol was used with all syn-trans-1,21-septecyclopropanedimethanol (5) and 2,3-naphthalenedicarboxylic acid to obtain the macrolide 27. Direct macrocyclization of diol 4 and 1,10-phenanthroline-2,9-dicarbonyl chloride (33) and 2,2'-bipyridine-4,4'-dicarbonyl chloride (35) gave the coronanes 34 and 36, respectively. Ring closing metathesis (RCM) of the diene 42 using Cl2(Cy3P)2Ru=CHPh (48) (Grubbs's catalyst) gave the macrocyclic lactone 45. The structures of coronanes 22, 23, 32, 34, 36, and 45 were confirmed by X-ray crystallographic studies which showed the cyclopropyl chain to adopt very differing conformations throughout the series. Several of the macrocycles have significant free pathways through their ring centers, and in the case of compound 34 there is a water molecule hydrogen bonded within the ring. This latter compound has the potential to act as a chiral ligand to metal centers.

Crystallography, X-Ray↗
PubMed2001

Synthesis of near-IR absorbing/emitting porphyrazine derivatives with tunable solubility.

We report the synthesis of porphyrazines (pzs), or tetraazaporphyrins, of the form H2[pz(An;B4-n)], where A is [S(CH2)3COOR]2 (R = n-Pr,H) and B is a fused beta,beta'-diisopropyloxybenzo group, including the compounds with n = 4 (6), n = 3 (7) and the trans compound with n = 2 (8) (Scheme 1). The synthesis employs Linstead crossover macrocyclization of dimethyl 6,7-dicyano-5,8-dithia-6(Z)-dodecenedioate, MNT(C4O2Me)2 (2), with 1-imino-4,7-bis(1-methylethoxy)-1H-isoindole-3-amine (4). These pigments were characterized by 1H NMR, 13C NMR, absorbance/fluorescence spectroscopy, mass spectrometry, and microanalysis. An X-ray crystal structure of 8 is presented. Of particular note, 6-8 display intense near-IR absorbance and dual UV-visible/near-IR emission which are very important in potential biomedical applications, both for cancer therapy (photodynamic therapy, PDT) and cancer diagnosis (optical tumor imaging). For example, the trans-porphyrazine 8 has an intense long-wavelength absorption at ca. 800 nm (log epsilon = 4.18) and S1 fluorescence at approximately 820 nm, where mammalian tissue is effectively penetrated by light. Transformation of the ester group permits a wide range of functionality and solubility to be generated without change in optical properties. As an example, hydrolysis of these compounds by LiOH in THF/H2O gives the corresponding carboxylato-functionalized pigments 9-11, which are described. The last of these dissolves without aggregation in fetal calf serum.

Journal Article↗
PubMed2001

Influence of the counteranion on the formation of polymeric networks by metal complexes of hexamethylenebis(acetamide).

An investigation into the anion dependence of the network-forming ability of metal complexes of hexamethylenebis(acetamide), CH3CONH(CH2)6NHCOCH3 (HMBA), has resulted in the X-ray characterization of the compounds [Co(HMBA)3][Co(NCS)4], 1, [Nd(HMBA)3][Nd(NO3)6].2CHCl3, 2, [Co(HMBA)3][HgCl4], 3, and [Mn(HMBA)3][HgBr4].3CHCl3, 4. The structures of compounds 1, 3, and 4 each comprise cationic frameworks formed by the bridging action of HMBA ligands binding octahedrally to the cobalt or manganese centers and, in the cases of 3 and 4, the formation of tetrahedral HgX4(2-) anions by transfer of the respective halide ions from Co or Mn to Hg. Complete anion (NO3-) transfer between Nd centers is also a key factor in the structure of 2, which forms a cationic 3-D network of HMBA-bridged octahedrally coordinated Nd centers with occluded [Nd(NO3)6]3- anions. These types of inter-metal-anion transfer, with consequent complex counteranion formation, appear to facilitate the network-forming ability of the metal-HMBA cationic arrays.

Journal Article↗
PubMed2001

Metabolic complications associated with antiretroviral therapy.

Mortality rates in the HIV-infected patient population have decreased with the advent of highly active antiretroviral therapy (HAART) for the treatment of AIDS. Due to the chronic nature of HAART, long-term metabolic complications are associated with therapy, such as hyperlipidemia, fat redistribution and diabetes mellitus. Currently, all of these symptoms are classified as the lipodystrophy (LD) syndrome(s). However, hyperlipidemia and fat redistribution occur independently, indicating there may be multiple syndromes associated with HAART. Although fat gain/loss and dyslipidemia occur in protease inhibitor (PI) naïve patients treated with nucleoside reverse transcriptase inhibitors (NRTIs), combination therapies (PI and NRTI) accelerate the syndrome. Recent clinical trials, cell culture and animal studies indicate that these effects are not drug class specific and select PIs, NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) can be associated with metabolic complications. Moreover, the effects can vary between various members of the same class of antiretroviral agents (i.e. not all PIs cause the same adverse reactions) and may be influenced by duration of infection, genetics and environmental factors. Although HAART increases the risk of metabolic complications, this does not outweigh the benefits of survival. In this review, we summarize the latest clinical and scientific information on these metabolic complications, examine current hypotheses explaining the syndromes and comment on the existing methods available to manage these metabolic side effects.

Antiretroviral Therapy, Highly Active↗
PubMed2001

Mitochondrial toxicity and HIV therapy.

Nucleoside reverse transcriptase inhibitors (NRTIs) remain the cornerstone of highly active antiretroviral therapy (HAART) combination regimens. However, it has been known for some time that these agents have the potential to cause varied side effects, many of which are thought to be due to their effects on mitochondria. Mitochondria, the key energy generating organelles in the cell, are unique in having their own DNA, a double stranded circular genome of about 16 000 bases. There is a separate enzyme present inside the cell that replicates mitochondrial DNA, polymerase gamma. NRTIs can affect the function of this enzyme and this may lead to depletion of mitochondrial DNA or qualitative changes. The study of inherited mitochondrial diseases has led to further understanding of the consequences of mutations or depletion in mitochondrial DNA. Key among these is the realisation that there may be substantial heteroplasmy among mitochondria within a given cell, and among cells in a particular tissue. The unpredictable nature of mitochondrial segregation during cellular replication makes it difficult to predict the likelihood of dysfunction in a given tissue. In addition, there is a threshold effect for the expression of mitochondrial dysfunction, both at the mitochondrial and cellular level. Various clinical and in vitro studies have suggested that NRTIs are associated with mitochondrial dysfunction in different tissues, although the weight of evidence is limited in many cases. The heterogeneity in the tissues affected by the different drugs raises interesting questions, and possible explanations include differential distribution or activation of these agents. This article reviews the major recognised toxicities associated with NRTI therapy and evidence for mitochondrial dysfunction in these complications. Data were identified through searching of online databases including Medline and Current Contents for relevant articles, along with abstracts and posters from recent conferences in the HIV and mitochondrial fields.

Acidosis, Lactic↗
PubMed2000

Synthesis and structures of polymeric Mn, Co, Cu, and Zn complexes of 3-diphenylamino-4-hydroxycyclobut-3-ene-1,2-dione (diphenylaminosquarate) and of the salt [Ni(H2O)6][(C6H5)2NC4O3]2.2H2O.

Reaction of M(NO3)2.xH2O (M = Mn, Co, Ni, Cu, Zn) with 3-diphenylamino-4-hydroxycyclobut-3-ene-1,2-dione (diphenylaminosquarate) produces the neutral polymeric species (M[mu-(C6H5)2NC4O3]2[H2O]2)n [M = Mn (1), Cu (2)]; (M[mu-(C6H5)2NC4O3][(C6H5)2NC4O3][H2O]3)n [M = Co (3), Zn (4)]; and in the case of Ni, the salt [Ni(H2O)6][(C6H5)2NC4O3]2.2H2O (5). Complexes 1 and 2 are isomorphous and crystallize in the monoclinic space group P2(1)/c with, for 1, a = 13.138(1) A, b = 10.900(2) A, c = 9.269(2) A, beta = 96.07(1) degrees, and Z = 2. Complexes 3 and 4 are also isomorphous and crystallize in the space group P2(1)/c with, for 3, a = 13.211(1) A, b = 11.038(1) A, c = 18.748(1) A, beta = 97.75(1) degrees, and Z = 4. The nickel salt, 5, crystallizes in the triclinic space group P1 with a = 6.181(1) A, b = 9.417(1) A, c = 15.486(1) A, alpha = 101.37(1) degrees, beta = 95.51(1) degrees, gamma = 107.57(1) degrees, and Z = 1. In 1 and 2, the metal coordination is octahedral, comprising four mu-1,3-bridging diphenylaminosquarate ligands and two trans aqua ligands. In 3 and 4, the metal coordination is again octahedral, comprising two mu-1,3-bridging and one pendant diphenylaminosquarate ligands, the octahedron being completed by three aqua ligands in a meridional configuration. In 5, the hexaaquanickel(II) ion is linked by O-H...O hydrogen bonds to a pair of diphenylaminosquarate anions. These anion-cation units are linked via included water molecules to form hydrogen-bonded chains. The diphenylaminosquarate ligands in the polymeric complexes 1-4 display multiple-bond localization, a feature which is absent in 5. Complex 1 exhibits weak antiferromagnetic coupling, whereas 2 shows no significant magnetic interactions.

Journal Article↗
PubMed2000

Ammonium ion binding with pyridine-containing crown ethers.

Dipyrido[24]crown-8 (DP24C8) has been synthesized and shown to form [2]pseudorotaxanes spontaneously with dibenzylammonium ions. These complexes, which have been demonstrated by (1)H NMR spectroscopy to form faster in solution than when the macrocyclic polyether is dibenzo[24]crown-8 (DB24C8), are also stronger than their DB24C8 counterparts. One of the [2]pseudorotaxanes has been used to construct a [2]rotaxane (see above) comprising a dumbbell-shaped component based on a dibenzylammonium ion which is encircled by a DP24C8 macrocycle and terminated by (triphenylphosphonium)methyl stoppers.

Journal Article↗
PubMed2000

Tandem ireland-claisen rearrangement ring-closing alkene metathesis in the construction of bicyclic beta-lactam carboxylic esters.

4-Alkenyl-2-azetidinone systems were converted to the corresponding ethyl 2-¿4-alkenyl-2-oxo-1-azetidinyl-4-pentenoates. In addition, 4-(2-propenyl-1-oxy)-, 4-(2-propenyl-1-thio)-, 4-¿N-(2-propenyl)-(4-toluenesulfonyl)- and (3S, 4R)-4-(2-propenyl)-3-¿(1R)-1-(tert-butyldimethylsilyloxy)ethyl-++ +azeti din-2-one were converted into beta-lactam dienes via sequential N-alkylation, Ireland-Claisen ester enolate rearrangement and esterification. Ring-closing metathesis using the Schrock ¿(CF(3))(2)MeCO(2)Mo(=CHCMe(2)Ph)(=NC(6)H(3)-2,6-iso-Pr(2)) (1) or Grubbs Cl(2)(Cy(3)P)(2)Ru=CHPh (2) carbenes gave a series of ¿5.2.0 and ¿6.2.0 bicycles. Subsequent elaboration of the analogous (2R,7R, 8S)-tert-butyl 8-¿(1R)-(tert-butyldimethylsilyloxy)ethyl-1-aza-9-oxobicyclo++ +¿5.2. 0non-4-ene-2-carboxylate (15), via selenation and desilylation, gave (+)-(2S,7R,8S)-tert-butyl 8-¿(1R)-hydroxyethyl-1-aza-9-oxobicyclo¿5.2.0nona-2, 4-diene-2-carboxylate (18), a novel type of bicyclic beta-lactam. Diels-Alder cycloaddition further afforded tetracyclic systems exemplified by tert-butyl (1R,4S,5R,7S)-4-¿(1R)-1-hydroxyethyl-3,9, 11-trioxo-10-phenyl-2,8,10,12-tetraazatetracyclo¿5.5.2.0.(2, 5)0(8, 12)tetradec-13-ene-1-carboxylate (19).

Alkenes↗
PubMed2000

Bis(dimethylamino)porphyrazines: synthetic, structural, and spectroscopic investigations.

The synthesis and isolation of unsymmetrical porphyrazines bearing two, four, and six bis-(dimethylamino) functionalities has been achieved via the base-catalyzed cross-condensation of 1,2-dicyanobenzene 8 and bis(dimethylamino)maleonitrile 7. In addition, the benzo-fused hexaaminoporphyrazine dimer 10 was prepared from condensation of dinitrile 7 (in excess) with benzenebis(1,3-diiminopyrroline) 9. Electrochemical studies reveal that all porphyrazines may be readily oxidized. The X-ray structures of porphyrazines 2b and 5a and the cis isomer 3a are presented. The latter is the first structure of a porphyrazine having a cis-type substitution pattern. The extended pi-conjugation in dimer 10 causes a approximately 100 nm red-shifted Q-band in the electronic absorption spectrum.

Crystallography, X-Ray↗
PubMed2000

Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate-nitric oxide neurotransmission.

Poly(ADP-ribose) polymerase (PARP) transfers ADP ribose groups from NAD(+) to nuclear proteins after activation by DNA strand breaks. PARP overactivation by massive DNA damage causes cell death via NAD(+) and ATP depletion. Heretofore, PARP has been thought to be inactive under basal physiologic conditions. We now report high basal levels of PARP activity and DNA strand breaks in discrete neuronal populations of the brain, in ventricular ependymal and subependymal cells and in peripheral tissues. In some peripheral tissues, such as skeletal muscle, spleen, heart, and kidney, PARP activity is reduced only partially in mice with PARP-1 gene deletion (PARP-1(-/-)), implicating activity of alternative forms of PARP. Glutamate neurotransmission involving N-methyl-d-aspartate (NMDA) receptors and neuronal nitric oxide synthase (nNOS) activity in part mediates neuronal DNA strand breaks and PARP activity, which are diminished by NMDA antagonists and NOS inhibitors and also diminished in mice with targeted deletion of nNOS gene (nNOS(-/-)). An increase in NAD(+) levels after treatment with NMDA antagonists or NOS inhibitors, as well as in nNOS(-/-) mice, indicates that basal glutamate-PARP activity regulates neuronal energy dynamics.

Animals↗