The Synthesis of Imidazole Fatty Acid Conjugates as Inhibitors of Apoptosis

Ionizing radiation is known to initiate apoptosis in mammalian cells by causing the transformation of cytochrome c into a peroxidase, which results in the specific peroxidation of the mitochondrial phospholipid cardiolipin. Here we report the design and synthesis of 8 imidazole fatty acid derivatives that bind to the cyt c:CL complex and inhibit the peroxidase activity required for the initiation of apoptosis. We postulate that imidazole acts as a sixth ligand to the haem iron and stops the interaction with H2O2. Two mitochondrially directed analogues (3-hydroxypropyl)triphenylphosphonium esters) of 12-imidazole-stearic acid and 12-imidazole-oleic acid not only were demonstrated to be peroxidase inhibitors in vitro, but were also extraordinarily effective in protecting mice from lethal doses (9 Gy) of ionization radiation. We studied the structure activity relationship to a group of triphenyl phosphonium derivatives containing imidazole at different positions on the fatty acid chain, and observed that the C8-imidazole stearate analogue had marginally better activity than the others. But overall, the structure activity result were remarkable “flat” with all compounds prepared having rather similar inhibitory strength. We also synthesized carnitine mono and di-esters of 12-imidazole fatty acids but full biological data is not yet available for these compounds.

Synthesis, Catalysis and Stoichiometric Reactivity of Mo Imido Complexes

The syntheses, catalytic reactivity and mechanistic investigations of novel Mo(IV) and Mo(VI) imido systems is presented. Attempts at preparing mixed bis(imido) Mo(IV) complexes of the type (RN)(R′N)Mo(PMe3)n (n = 2 or 3) derived from the mono(imido) complexes (RN)Mo(PMe3)3(X)2 (R = tBu (1) or Ar (2); X = Cl2 or HCl, Ar=2,6-iPr2C6H3) are also described. The addition of lithiated silylamides to 1 or 2 results in the unexpected formation of the C-H activated cyclometallated complexes (RN)Mo(PMe3)2(η2-CH2PMe2)(X) (R = Ar, X = H (3); R = tBu, X = Cl (4)). Complexes 3 and 4 were used in the activation of R′E-H bonds (E = Si, B, C, O, P; R′ = alkyl or aryl), which typically give products of addition across the M-C bond of the type (RN)Mo(PMe3)3(ER′)(X) (4). In the case of 2,6-dimethylphenol, subsequent heating of 4 (R = Ar, R′ = 2,6-Me2C6H3, E = O) to 50 °C results in C-H activation to give the cyclometallated complex (ArN)Mo(PMe3)3(κ2-O,C-OPh(Me)CH2) (5). An alternative approach was developed in synthesizing the mixed imido complex (ArN)(tBuN)Mo(PMe3)(η2-C2H4) (6) through EtMgBr reduction of (ArN)(tBuN)MoCl2(DME) in the presence of PMe3. Complex 6 reacts with various hydro- and chlorosilanes to give β-agostic silylamido complexes and in one case, when Me2SiHCl is the silane, leads to the silanimine complex (tBuN)Mo(η2-SiMe2-NAr)(Et)(η2-C2H4) (7). Mechanistic studies on the formation of the Mo(VI) tris(silyl) complex (tBuN)Mo(SiHPh)(H){(μ-NtBu)(SiHPh)}(PMe3)2 (8) were done from the addition of three equivalents of PhSiH3 to (tBuN)Mo(PMe3)(η2-C2H4), resulting in identification of β- and γ-agostic SiH…Mo intermediates. The reactivity of complex 8 towards ethylene and nitriles was studied. In both cases coupling of unsaturated substrates with the Mo-Si bond of the metalacycle was observed. In the case of nitriles, insertion into the 4-membered disilaazamolybdacycle results in complexes of the type (tBuN)Mo{(κ2-Si,C-SiHPh-NtBu-SiHPh-N=C(R)}(PMe3)2. Catalytic hydrosilylation of carbonyls mediated by the β-agostic silylamido complex (ArN)2Mo(η3-NtBu-SiMe2-H)(H) (9) was investigated. Stoichiometric reactions with organic substrates showed that catalysis with 9 does not proceed via the conventional insertion of substrate into the Mo-H bond.

POCN-type Pincer Complexes of NiII and NiIII : synthesis, reactivities, catalytic activities and physical properties

Cette thèse décrit la synthèse, la caractérisation, les réactivités, et les propriétés physiques de complexes divalents et trivalents de Ni formés à partir de nouveaux ligands «pincer» de type POCN. Les ligands POCN de type amine sont préparés d’une façon simple et efficace via l’amination réductrice de 3-hydroxybenzaldéhyde avec NaBH4 et plusieurs amines, suivie par la phosphination de l’amino alcool résultant pour installer la fonction phosphinite (OPR2); le ligand POCN de type imine 1,3-(i-Pr)2PC6H4C(H)=N(CH2Ph) est préparé de façon similaire en faisant usage de PhCH2NH2 en l’absence de NaBH4. La réaction de ces ligands «pincer» de type POCN avec NiBr2(CH3CN)x en présence d’une base résulte en un bon rendement de la cyclométalation du lien C-H situé en ortho aux fonctions amine et phosphinite. Il fut découvert que la base est essentielle pour la propreté et le haut rendement de la formation des complexes «pincer» désirés. Nous avons préparé des complexes «pincer» plan- carrés de type POCN, (POCNRR΄)NiBr, possédant des fonctions amines secondaires et tertiaires qui démontrent des réactivités différentes selon les substituants R et R΄. Par exemple, les complexes possédant des fonctions amines tertiaires ArCH2NR2 (NR2= NMe2, NEt2, and morpholinyl) démontrent des propriétés rédox intéressantes et pourraient être convertis en leurs analogues trivalents (POCNR2)NiBr2 lorsque réagis avec Br2 ou N-bromosuccinimide (NBS). Les complexes trivalents paramagnétiques à 17 électrons adoptent une géométrie de type plan-carré déformée, les atomes de Br occupant les positions axiale et équatoriale. Les analyses «DSC» et «TGA» des ces composés ont démontré qu’ils sont thermiquement stables jusqu’à ~170 °C; tandis que la spectroscopie d’absorption en solution a démontré qu’ils se décomposent thermiquement à beaucoup plus basse température pour regénérer les complexes divalents ne possédant qu’un seul Br; l’encombrement stérique des substitutants amines accélère cette route de décomposition de façon significative. Les analogues NMe2 et N(morpholinyl) de ces espèces de NiIII sont actifs pour catalyser la réaction d’addition de Kharasch, de CX4 à des oléfines telles que le styrène, tandis qu’il fut découvert que l’analogue le moins thermiquement stable (POCNEt2)Ni est complètement inerte pour catalyser cette réaction. Les complexes (POCNRH)NiBr possédant des fonctions amines secondaires permettent l’accès à des fonctions amines substituées de façon non symétrique via leur réaction avec des halogénures d’alkyle. Un autre avantage important de ces complexes réside dans la possibilité de déprotonation pour préparer des complexes POCN de type amide. De telles tentatives pour déprotoner les fonctions NRH nous ont permis de préparer des espèces dimériques possédant des ligands amides pontants. La nature dimérique des ces complexes [P,C,N,N-(2,6-(i-Pr)2PC6H3CH2NR)Ni]2 (R= PhCH2 et Ph) fut établie par des études de diffraction des rayons-X qui ont démontré différentes géométries pour les cœurs Ni2N2 selon le substituant N : l’analogue (PhCH2)N possède une orientation syn des substitutants benzyles et un arrangement ressemblant à celui du cyclobutane du Ni et des atomes d’azote, tandis que l’analogue PhN adopte un arrangement de type diamant quasi-planaire des atomes du Ni et des atomes d’azote et une orientation anti des substituants phényles. Les espèces dimériques ne se dissocient pas en présence d’alcools, mais elles promouvoient l’alcoolyse catalytique de l’acrylonitrile. De façon intéressante, les rendements de ces réactions sont plus élevés avec les alcools possédant des fonctions O-H plus acides, avec un nombre de «turnover» catalytique pouvant atteindre 2000 dans le cas de m-cresol. Nous croyons que ces réactions d’alcoolyse procèdent par activation hétérolytique de l’alcool par l’espèce dimérique via des liaisons hydrogènes avec une ou deux des fonctions amides du dimère. Les espèces dimériques de Ni (II) s’oxydent facilement électrochimiquement et par reaction avec NBS ou Br2. De façon surprenante, l’oxydation chimique mène à l’isolation de nouveaux produits monomériques dans lesquels le centre métallique et le ligand sont oxydés. Le mécanisme d’oxydation fut aussi investigué par RMN, «UV-vis-NIR», «DFT» et spectroélectrochimie.

Synthesis of ring A of (+)-Ambruticin S and bicyclic nucleosides for antisense drug technology

La synthèse énantiosélective de la (+)-ambruticine S, un produit naturel antifongique a été effectuée au sein de notre groupe. Trois approches ont été développées pour la synthèse du fragment lactone (cycle A). Ces trois voies d’accès au cycle A ont pour intermédiaire commun le methyl α-D-glycopyranoside déjà porteur du diol requis et disponible commercialement à bon prix. Une désoxygénation de l’hydroxyle en C-4 et l’homologation d’un carbone de la chaine latérale en C-6 ont permis l’obtention du cycle lactonique A. Le deuxième projet est une collaboration entre le groupe Hanessian et ISIS Pharmaceuticals afin de développer de nouveaux oligonucléosides antisens. Les nucléosides antisens [4.3.0]-bicycliques cis et trans ont été synthétisés avec succès à partir d’un monosaccharide naturel commun, L-arabinose, porteur des stéréocentres requis. Un réaction clé d’allylation de Sakurai a permis d’obtenir les diastéréoisomères cis et trans dans des conditions de contrôle de type Felkin-Ahn et de contrôle par chélation respectivement. Les composés bicycliques finaux cibles ont été obtenus par une réaction d’aldol intramoléculaire catalyzéé par la proline, par métathèse de fermeture de cycle et par l’application de la méthode de Vorbrüggen pour la synthèse de nucléosides.

Introduction of vinyl and hydroxymethyl functionalities at C-4 of glucose-derived substrates: synthesis of spirocyclic, bicyclic, and tricyclic nucleosides

Installing hydroxymethyl and hydroxyethyl substitutions at C-4 through vinylation and hydroboration-oxidation reactions of the C-4 bis-hydroxymethyl derivative of D-glucose based substrate, and inserting heteroatoms thereafter permitted formation of N-, O-, or S-heterocycles leading to [4,5]or [5,5]-spirocycles and a bicyclo[3.3.0]octane product. Some of the spirocycles were converted to spironucleosides under Vorbruggen glycosidation reaction conditions. Similarly, the bicyclic product was elaborated to the corresponding bicyclic nucleoside as well as an unexpected tricyclic nucleoside.

A method of synthesis of silicious inorganic ordered materials (MCM-41-SBA-1) employing polyacrylic acid-C(n)TAB-TEOS nanoassemblies

In this work we describe the synthesis of a variety of MCM-41 type hexagonal and SBA-1 type cubic mesostructures and mesoporous silicious materials employing a novel synthesis concept based on polyacrylic acid (Pac)-C(n)TAB complexes as backbones of the developing structures. The ordered porosity of the solids was established by XRD and TEM techniques. The synthesis concept makes use of Pac-C(n)TAB nanoassemblies as a preformed scaffold, formed by the gradual increase of pH. On this starting matrix the inorganic precursor species SiO2 precipitate via hydrolysis of TEOS under the influence of increasing pH. The molecular weight (MW) of Pac, as well as the length of carbon chain in C,TAB, determine the physical and structural characteristics of the obtained materials. Longer chain surfactants (C(16)TAB) lead to the formation of hexagonal phase, while shorter chain surfactants (C(14)TAB, C(12)TAB) favor the SBA-1 phase. Lower MW of Pac (approximate to2000) leads to better-organized structures compared to higher MW ( 450,000), which leads to worm-like mesostructures. Cell parameters and pore size increase with increasing polyelectrolyte and/or surfactant chain, while at the same time SEM photography reveals that the particle size decreases. Conductivity experiments provide some insight into the proposed self-assembling pathway. (C) 2003 Elsevier Inc. All rights reserved.

The synthesis, structure, reactivity and electrochemical properties of ruthenium complexes featuring cyanoacetylide ligands

The complex [Ru(C&3bond; CC&3bond; N)(dppe)Cp*] (1) is readily obtained (ca. 70%) from the sequential reaction of [Ru(C=CH2)(dppe)Cp*]PF6 with (BuLi)-Bu-n and phenyl cyanate. The complex behaves as a typical transition metal acetylide upon reaction with tetracyanoethene, affording a metallated pentacyanobutadiene. Complex I is a useful metalloligand, and its reactions with [W(thf)(CO)5], [RuCl(PPh3)(2)Cp], [RuCl(dppe)Cp*] or cis-[RuCl2(dppe)(2)] all afforded products featuring the M-C&3bond; CC&3bond; N-M' motif, for which ground state structures indicate a degree of polarisation. Electrochemical and spectroelectrochemical studies reveal moderate interactions between the metal centres in the 35-electron dications [{Cp*(dppe)Ru}(mu-C&3bond; CC&3bond; N){RuL2Cp'}](2+) Ru(PPh3)(2)CP, Ru(dppe)Cp*).

Synthesis of the C7-C24 fragment of (-)-Macrolactin F

An enantioselective and convergent synthesis of the C7-C24 fragment of Macrolactin F was achieved from four main fragments. A hydrotelluration/transmetalation sequence was used to install the E,Z diene present in the molecule, while a hydrozirconation/transmetalation sequence was used to connect two advanced intermediates. (C) 2008 Elsevier Ltd. All rights reserved.

Synthesis, characterization and spectroscopic investigation of new tetrakis(acetylacetonato)thulate(III) complexes containing alkaline metals as countercations

In this work a series of tetrakis complexes C[Tm(acac)(4)] where C(+) = Li(+) Na(+) and K(+) countercations and acac = acetylacetonate ligand were synthesized and characterized for photoluminescence investigation The relevant aspect is that these complexes are water-free in the first coordination sphere The emission spectra of the tetrakis Tm(3+)-complexes present narrow bands characteristic of the (1)G(4)->(3)H(6) (479 nm) (1)G(4)->(3)F(4) (650 nm) and (1)G(4) ->(3)H(5) (779 nm) transitions of the Tm(3+) ion with the blue emission color at 479 nm as the most prominent one The lifetime values (tau) of the emitting (1)G(4) level of the C[Tm(acac)(4)] complexes were 344 360 and 400 ns for the Li(+) Na(+) and K(+) countercations respectively showing an increasing linear behavior versus the ionic radius of the alkaline ion An efficient intramolecular energy transfer process from the triplet state (T) of the ligands to the emitting (1)G(4) state of the Tm(3+) ion is observed This fact together with the absence of water molecules in first coordination sphere allows these tetrakis Tm(3+)-complexes to act as efficient blue light conversion molecular devices (c) 2010 Elsevier B V All rights reserved

Synthesis and physical properties of lipid-based poly(ester-urethane)s, I: Effect of varying polyester segment length

Four aliphatic thermoplastic poly(ester-urethane)s (PEUs) with similar molecular weights but varying polyesters molecular weight (534-1488 g/mol) were prepared from polyester diols, obtained by melt condensation of Azelaic acid and 1,9-Nonanediol, and 1,7-heptamethylene di-isocyanate (HPMDI) all sourced from vegetable oil feedstock. The thermal, and mechanical properties, and crystal structure of PEUs were investigated using DSC, TGA, DMA, tensile analysis and WAXD. For sufficiently long polyester chain, WAXD data indicated no hydrogen bonds polyethylene (PE)-like crystalline packing and for short polyester chains, small crystal domains with significant H-bonded polyamide (PA)-like packing. Crystallinity decreased with decreasing polyester molecular weights. The polymorphism of PEUs and consequently their melting characteristics were found to be largely controlled by polyester segment length. TGA of the PEUs indicated improved thermal stability with decreasing polyester chain length, suggesting a stabilization effect by urethane groups. Mechanical properties investigated by DMA and tensile analysis were found to scale predictably with the overall crystallinity of PEUs. (C) 2012 Elsevier Ltd. All rights reserved.

Use of commercial anion-exchange resins as solid support for peptide synthesis and affinity chromatography

This report demonstrates that due to the presence of residual reactive sites in their matrices, classical diethylaminoethyl-attaching commercial anion-exchanger resins such as DEAE-MacroPrep and DEAE-Sephadex A50 supports can be used for peptide synthesis. Moreover, due to the high stability of the peptide-resin bond in the final cleavage treatments, desired peptidyl-resins free of side-chain protecting groups, which enables them to be further used as solid support for affinity chromatography, can be obtained. To demonstrate this potentiality, a fragment corresponding to the antigenic and immunodominant epitope of sporozoites of the Plasmodium falciparum malaria parasite was synthesized in these traditional resins and antibody molecules generated against the peptide sequence were successfully retained in these peptidyl supports. Due to the maintenance of their original anion-exchange capacities, the present findings open the unique possibility of applying, simultaneously, dual anion-exchange and affinity procedures for purification of a variety of macromolecules. (C) 2003 Elsevier B.V. (USA). All rights reserved.

Synthesis and electrical characterization of tungsten doped Pb(Zr0.53Ti0.47)O-3 ceramics obtained from a hybrid process

Pure and W-doped PZT ceramics (PZT and PZTW) were prepared by a hybrid process consisting in the association of polymeric precursor and partial oxalate methods. The phase formation was investigated by simultaneous thermal analysis (TG/DSC) and X-ray diffraction (XRD). The effect of W doping PZT and their electrical properties was evaluated. Substitution of W by Ti leads to an increase of Curie temperature and broadening of dielectric constant. A typical hysteresis loop was observed at room temperature and the remnant polarization was increased with the content of W. (c) 2007 Elsevier B.V. All rights reserved.

Mechanochemical synthesis of PZT powders

PZT ceramic powders were successfully prepared from the mixture of PbO, ZrO2 and TiO2 by mechanochemical synthesis in a planetary ball mill, under different milling conditions. Phase evolution during synthesis was monitored by X-ray diffraction analysis. Intensive milling resulted in formation of the nanocrystalline, perovskite PZT powders after 1 h of milling. This is a significant improvement in comparison to milling conditions reported by other authors. Depending on milling parameters the presence of some other phases, such as unreacted ZrO2, was also detected in some samples. The changes in powder size and morphology due to intensive milling, were determined by SEM and TEM, while BET analysis was used to determine specific surface area of the powders. Conclusions about processes taking place during mechanochemical synthesis of PZT powders were made based on the results of characterization. (C) 2002 Elsevier B.V. B.V. All rights reserved.

Preparation and characterization of nanosized SrBi2Nb2O9 powder by the combustion synthesis

This work presents the preparation of SrBi2Nb2O9 (SBN) directly by the combustion synthesis. Strontium nitrate, niobium ammonium oxalate (NH4H2[NbO-(C2O4)(3)].3H(2)O) and bismuth oxide were used as oxidant reactants and urea as fuel. The influence of the fuel was evaluated by the addition of different fuel amounts (50%, 100%, 200% and 300%), 100% being the stoichiometric proportion. The XRD patterns showed that the SBN perovskite crystallized as the majority phase. The as-synthesized stoichiometric powder presented a specific surface area of around 13 m(2)/g and a mean grain size of around 16 nm. Dilatometric measurements showed that the maximum sintering rate occurs at 1275degreesC. The determination of the ferroparaelectric transition showed a Curie temperature (T-c) of 429degreesC. (C) 2002 Elsevier B.V. B.V. All rights reserved.

Comparative study of the efficacies of nine assay methods for the dextransucrase synthesis of dextran

A comparative study of nine assay methods for dextransucrase and related enzymes has been made. A relatively widespread method for the reaction of dextransucrase with sucrose is the measurement of the reducing value of D-fructose by alkaline 3,5-dinitrosalicylate (DNS) and thereby the amount of D-glucose incorporated into dextran. Another method is the reaction with C-14-sucrose with the addition of an aliquot to Whatman 3MM paper squares that are washed three times with methanol to remove C-14-D-fructose and unreacted C-14-sucrose, followed by counting of C-14-dextran on the paper by liquid scintillation counting (LSC). It is shown that both methods give erroneous results. The DNS reducing value method gives extremely high values due to over-oxidation of both D-fructose and dextran, and the C-14-paper square method gives significantly low values due to the removal of some of the C-14-dextran from the paper by methanol washes. In the present study, we have examined nine methods and find two that give values that are identical and are an accurate measurement of the dextransucrase reaction. They are (1) a C-14-sucrose/dextransucrase digest in which dextran is precipitated three times with three volumes of ethanol, dissolved in water, and added to paper and counted in a toluene cocktail by LSC: and (2) precipitation of dextran three times with three volumes of ethanol from a sucrose/dextransucrase digest, dried, and weighed. Four reducing value methods were examined to measure the amount of D-fructose. Three of the four (two DNS methods, one with both dextran and D-fructose and the other with only D-fructose, and the ferricyanide/arsenomolybdate method with is-fructose) gave extremely high values due to over-oxidation of D-fructose, D-glucose, leucrose, and dextran. (C) 2011 Elsevier Ltd. All rights reserved.