Synthesis and iron binding studies of myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate, and iron binding studies of all myo-inositol tetrakisphosphates

The first syntheses of the natural products myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate are described. The protected key intermediates 4,5,6-tri-O-benzoyl-myo-inositol and (+/-)-3,4,5,6-tetra-O-benzyl-myo-inositol were phosphorylated with dibenzyl N,N-di-isopropylphosphoramidite in the presence of 1H-tetrazole and subsequent oxidation of the phosphite. The crystal structures of the synthetic intermediates (+/-)-1-O-(tert-butyldiphenylsilyl)-2,3,O-cyclohexylidene-myo-inos itol and (+/-)-4,5,6-tri-O-benzoyl-1-O-(tert-butyldiphenylsilyl)-2,3-O-cycl ohexylidene- myo-inositol are reported. myo-Inositol 1,2,3-trisphosphate (+/-)-myo-inositol 1,2-bisphosphate, and all isomeric myo-inositol tetrakisphosphates were evaluated for their ability to alter HO. production in the iron-catalysed Haber-Weiss reaction. The results demonstrated that a 1,2,3-grouping of phosphates in myo-inositol was necessary for inhibition also that (+/-)-myo-inositol 1,2-bisphosphate potentiated HO. production. myo-Inositol 1,2,3-trisphosphate resembled myo-inositol hexakisphosphate (phytic acid) in its ability to act as a siderophore by promoting iron-uptake into Pseudomonas aeruginosa.

Synthetic studies of thymosin alpha-1 fragments

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Bifunctional role for VEGF-induced heme oxygenase-1 in vivo:induction of angiogenesis and inhibition of leukocytic infiltration

Heme-oxygenases (HOs) catalyze the conversion of heme into carbon monoxide and biliverdin. HO-1 is induced during hypoxia, ischemia/reperfusion, and inflammation, providing cytoprotection and inhibiting leukocyte migration to inflammatory sites. Although in vitro studies have suggested an additional role for HO-1 in angiogenesis, the relevance of this in vivo remains unknown. We investigated the involvement of HO-1 in angiogenesis in vitro and in vivo. Vascular endothelial growth factor (VEGF) induced prolonged HO-1 expression and activity in human endothelial cells and HO-1 inhibition abrogated VEGF-driven angiogenesis. Two murine models of angiogenesis were used: (1) angiogenesis initiated by addition of VEGF to Matrigel and (2) a lipopolysaccharide (LPS)-induced model of inflammatory angiogenesis in which angiogenesis is secondary to leukocyte invasion. Pharmacologic inhibition of HO-1 induced marked leukocytic infiltration that enhanced VEGF-induced angiogenesis. However, in the presence of an anti-CD18 monoclonal antibody (mAb) to block leukocyte migration, VEGF-induced angiogenesis was significantly inhibited by HO-1 antagonists. Furthermore, in the LPS-induced model of inflammatory angiogenesis, induction of HO-1 with cobalt protoporphyrin significantly inhibited leukocyte invasion into LPS-conditioned Matrigel and thus prevented the subsequent angiogenesis. We therefore propose that during chronic inflammation HO-1 has 2 roles: first, an anti-inflammatory action inhibiting leukocyte infiltration; and second, promotion of VEGF-driven noninflammatory angiogenesis that facilitates tissue repair.

Weak Polynomial Identities for M1,1(E)

* Partially supported by Universita` di Bari: progetto “Strutture algebriche, geometriche e descrizione degli invarianti ad esse associate”.

Mechanistic studies on the degradation of gasoline oxygenates by advanced oxidation technologies and the reaction of 4-methyl-1,2,4-triazoline-3,5-dione with tetracyclopropylethylene

Gasoline oxygenates (MTBE, methyl tert-butyl ether; DIPE, di-isopropyl ether; ETBE, ethyl tert-butyl ether; TAME, tert-amyl ether) are added to gasoline to boost octane and enhance combustion. The combination of large scale use, high water solubility and only minor biodegradability has now resulted in a significant gasoline oxygenate contamination occurring in surface, ground, and drinking water systems. Combination of hydroxyl radical formation and the pyrolytic environment generated by ultrasonic irradiation (665 kHz) leads to the rapid degradation of MTBE and other gasoline oxygenates in aqueous media. ^ The presence of oxygen promotes the degradation processes by rapid reaction with carbon centered radicals indicating radical processes involving O 2 are significant pathways. A number of the oxidation products were identified. The formation of products (alcohols, ketones, aldehydes, esters, peroxides, etc) could be rationalized by mechanisms which involve hydrogen abstraction by OH radical and/or pyrolysis to form carboncentered radicals which react with oxygen and follow standard oxidation chain processes. ^ The reactions of N-substituted R-triazolinediones (RTAD; R = CH 3 or phenyl) have attracted considerable interest because they exhibit a number of unusual mechanistic characteristics that are analogous to the reactions of singlet oxygen (1O2) and offer an easy way to provide C-N bond(s) formation. The reactions of triazolinedione with olefins have been widely studied and aziridinium imides are generally accepted to be the reactive intermediates. ^ We observed the rapid formation of an unusual intermediate upon mixing tetracyclopropylethylene with 4-methyl-1,2,4-triazoline-3,5-dione in CDCl 3. Detailed characterization by NMR (proton, 13C, 2-D NMRs) indicates the intermediate is 5,5,6,6-tetracyclopropyl-3-methyl-5,6-dihydro-oxazolo[3,2- b][1,2,4]-triazolium-2-olate. Such products are extremely rare and have not been studied. Upon warming the intermediate is converted to 2 + 2 diazetidine (major) and ene product (minor). ^ To further explore the kinetics and dynamics of the reaction activation energies were obtained using Arrhenius plots. Activation energies for the formation of the intermediate from reactants, and 2+2 adduct from the intermediate were determined as 7.48 kcal moll and 19.8 kcal mol−1 with their pre-exponential values of 2.24 × 105 dm 3 mol−1 sec−1 and 2.75 × 108 sec−1, respectively, meaning net slow reactions because of low pre-exponential values caused by steric hindrance. ^

Synthesis and Properties of a Series of 1,1,n,n-Tetramethyl[n](2,11)teropyrenophanes

The work described in this thesis revolves around the 1,1,n,ntetramethyl[n](2,11)teropyrenophanes, which are a series of [n]cyclophanes with a severely bent, board-shaped polynuclear aromatic hydrocarbons (PAH). The thesis is divided into seven Chapters. The first Chapter conatins an overview of the seminal work on [n]cyclophanes of the first two members of the “capped rylene” series of PAHs: benzene and pyrene. Three different general strategies for the synthesis of [n]cyclophanes are discussed and this leads in to a discussion of some slected syntheses of [n]paracyclopahnes and [n](2,7)pyrenophanes. The chemical, structural, spectroscopic and photophysical properties of these benzene and pyrene-derived cyclophanes are discussed with emphasis on the changes that occur with changes in the structure of the aromatic system. Chapter 1 concludes with a brief introduction to [n]cyclophanes of the fourth member of the capped rylene series of PAHs: teropyrene. The focus of the work described in Chapter 2 is the synthesis of of 1,1,n,ntetramethyl[n](2,11)teropyrenophane (n = 6 and 7) using a double-McMurry strategy. While the synthesis 1,1,7,7-tetramethyl[7](2,11)teropyrenophane was successful, the synthesis of the lower homologue 1,1,6,6-tetramethyl[6](2,11)teropyrenophane was not. The conformational behaviour of [n.2]pyrenophanes was also studied by 1H NMR spectroscopy and this provided a conformation-based rationale for the failure of the synthesis of 1,1,6,6-tetramethyl[6](2,11)teropyrenophane. Chapter 3 contains details of the synthesis of 1,1,n,n-tetramethyl[n](2,11)teropyrenophanes (n = 7-9) using a Wurtz / McMurry strategy, which proved to be more general than the double McMurry strategy. The three teropyrenophanes were obtained in ca. 10 milligram quantities. Trends in the spectroscopic properties that accompany changes in the structure of the teropyrene system are discussed. A violation of Kasha’s rule was observed when the teropyrenophanes were irradiated at 260 nm. The work described in the fourth Chapter concentrates on the development of gram-scale syntheses of 1,1,n,n-tetramethyl[n](2,11)teropyrenophanes (n = 7–10) using the Wurtz / McMurry strategy. Several major modifications to the orginal synthetic pathway had to be made to enable the first several steps to be performed comfortably on tens of grams of material. Solubility problems severely limited the amount of material that could be produced at a late stage of the synthetic pathways leading to the evennumbered members of the series (n = 8, 10). Ultimately, only 1,1,9,9- tetramethyl[9](2,11)teropyrenophane was synthesized on a multi-gram scale. In the final step in the synthesis, a valence isomerization / dehydrogenation (VID) reaction, the teropyrenophane was observed to become unstable under the conditions of its formation at n = 8. The synthesis of 1,1,10,10-tetramethyl[10](2,11)teropyrenophane was achieved for the first time, but only on a few hundred milligram scale. In Chapter 5, the results of an investigation of the electrophilic aromatic bromination of the 1,1,n,n-tetramethyl[n](2,11)teropyrenophanes (n = 7–10) are presented. Being the most abundant cyclophane, most of the work was performed on 1,1,9,9-tetramethyl[9](2,11)teropyrenophane. Reaction of this compound with varying amounts of of bromine revealed that bromination occurs most rapidly at the symmetryrelated 4, 9, 13 and 18 positions (teropyrene numbering) and that the 4,9,13,18- tetrabromide could be formed exclusively. Subsequent bromination occurs selectively on the symmetry-related 6, 7, 15 and 16 positions (teropyrene numbering), but considerably more slowly. Only mixtures of penta-, hexa-, hepta and octabromides could be formed. Bromination reactions of the higher and lower homologues (n = 7, 8 and 10) revealed that the reactivity of the teropyrene system increased with the degree of bend. Crystal structures of some tetra-, hexa-, hepta- and octa-brominated products were obtained. The goal of the work described in Chapter 6 is to use 1,1,9,9- tetramethyl[9](2,11)teropyrenophane as a starting material for the synthesis of warped nanographenophanes. A bromination, Suzuki-Miyaura, cyclodehydrogenation sequence was unsuccessful, as was a C–H arylation / cyclodehydrogenation approach. Itami’s recently-developed K-region-selective annulative -extension (APEX) reaction proved to be successful, affording a giant [n]cyclophane with a C84 PAH. Attempted bay-region Diels-Alder reactions and some cursory host-guest chemistry of teropyrenophanes are also discussed. In Chapter 7 a synthetic approach toward a planar model compound, 2,11-di-tbutylteropyrene, is described. The synthesis could not be completed owing to solubility problems at the end of the synthetic pathway.

Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome.

The mechanisms responsible for increased cardiovascular risk associated with HIV-1 infection are incompletely defined. Using flow cytometry, in the present study, we examined activation phenotypes of monocyte subpopulations in patients with HIV-1 infection or acute coronary syndrome to find common cellular profiles. Nonclassic (CD14(+)CD16(++)) and intermediate (CD14(++)CD16(+)) monocytes are proportionally increased and express high levels of tissue factor and CD62P in HIV-1 infection. These proportions are related to viremia, T-cell activation, and plasma levels of IL-6. In vitro exposure of whole blood samples from uninfected control donors to lipopolysaccharide increased surface tissue factor expression on all monocyte subsets, but exposure to HIV-1 resulted in activation only of nonclassic monocytes. Remarkably, the profile of monocyte activation in uncontrolled HIV-1 disease mirrors that of acute coronary syndrome in uninfected persons. Therefore, drivers of immune activation and inflammation in HIV-1 disease may alter monocyte subpopulations and activation phenotype, contributing to a pro-atherothrombotic state that may drive cardiovascular risk in HIV-1 infection.

Geochemistry of sediment core HE337/001-1, North Sea

Reactive iron (oxyhydr)oxide minerals preferentially undergo early diagenetic redox cycling which can result in the production of dissolved Fe(II), adsorption of Fe(II) onto particle surfaces, and the formation of authigenic Fe minerals. The partitioning of iron in sediments has traditionally been studied by applying sequential extractions that target operationally-defined iron phases. Here, we complement an existing sequential leaching method by developing a sample processing protocol for d56Fe analysis, which we subsequently use to study Fe phase-specific fractionation related to dissimilatory iron reduction in a modern marine sediment. Carbonate-Fe was extracted by acetate, easily reducible oxides (e.g. ferrihydrite and lepidocrocite) by hydroxylamine-HCl, reducible oxides (e.g. goethite and hematite) by dithionite-citrate, and magnetite by ammonium oxalate. Subsequently, the samples were repeatedly oxidized, heated and purified via Fe precipitation and column chromatography. The method was applied to surface sediments collected from the North Sea, south of the Island of Helgoland. The acetate-soluble fraction (targeting siderite and ankerite) showed a pronounced downcore d56Fe trend. This iron pool was most depleted in 56Fe close to the sediment-water interface, similar to trends observed for pore-water Fe(II). We interpret this pool as surface-reduced Fe(II), rather than siderite or ankerite, that was open to electron and atom exchange with the oxide surface. Common extractions using 0.5 M HCl or Na-dithionite alone may not resolve such trends, as they dissolve iron from isotopically distinct pools leading to a mixed signal. Na-dithionite leaching alone, for example, targets the sum of reducible Fe oxides that potentially differ in their isotopic fingerprint. Hence, the development of a sequential extraction Fe isotope protocol provides a new opportunity for detailed study of the behavior of iron in a wide-range of environmental settings.