Dissertations / Theses on the topic 'Dicarboxy'

The one electron oxidant Mn(OAc)3 has been used for years for the oxidative addition of 1,3-dicarbonyls to alkenes to give dihydrofuranes. Since cycloheptatriene is in equilibrium with its valance isomer norcaradiene, it will be interesting to study the reaction of CHT derivatives with Mn(OAc)3 in the presence of 1,3-dicarbonyls. In our research, we have observed that unsubstituted cycloheptatriene gave CHT based products. However, when electron withdrawing -CN group was attached to C-7 position of CHT we obtained norcaradiene based products. We have also observed that there exist an equilibrium between [3+2] addition products through 1,5-hydride shift. In addition, we obtained dihydrofurane derivatives in the presence of Mn(OAc)3 from compounds which have already formed C-C bond between 1,3- dicarbonyl and alkene. Formation of dihydrofurane derivatives from these compounds brought up two questions<br>whether cyclization is going over oxygen atom or not and whether reaction involves a cyclopropane intermediate or not. Despite all efforts, we could not manage to synthesize the required material for the investigation of these questions.

El objetivo principal de esta tesis es contrastar el papel de dichos compuestos 1,3-dicarbonilicos como agentes que dañan el ADN con respecto a su potencial fotoprotector. Primero, 5,6-dihidropirimidinas han sido derivatizadas utilizando el grupo fotolábil t-Bu cetona con el fin de estudiar la generación de radicales en C5 en un medio no acuoso. Después, el estudio por fotólisis de destello láser en ACN de los derivados 1,3-dicarbonilicos diseñados da lugar a la detección de los supuestos radicales 5,6-dihidropirimidin-5-ilo. Su caracterización muestra especies transitorias de vida larga y están centrados a 400-420 nm o 350-400 nm para los derivados 5,6-dihidrouridina o 5,6-dihidrotimidina, respectivamente. Además, la generación de radicales también se ha evidenciado mediante experimentos de fluorescencia en estado estacionario mediante el uso de una sonda profluorescente (AAA-TEMPO) que atrapa el radical. Por lo tanto, la irradiación de los derivados fotolábiles del ácido nucleico en presencia de AAA-TEMPO produce un aumento de la emisión, de acuerdo con la captura del radical C5 por la sonda paramagnética. La formación del aducto se ha confirmado mediante UPLC-HRMS. Los datos experimentales se han corroborado con cálculos teóricos ab initio CASPT2 // CASSCF. Segundo, otro derivado 1,3-dicarbonílico de la pirimidina se ha investigado. De hecho, el daño 5-formiluracilo (ForU) presenta características interesantes como potencial agente fotosensibilizador intrínseco del ADN. Por lo tanto, los estudios espectroscópicos revelan que ForU tiene una absorción en el rango UVA/UVB y también presenta un estado triplete excitado (3ForU *) con un tiempo de vida algunos micros y con una ET suficientemente alta como para fotosensibilizar la formación de los conocidos dímeros de pirimidina de tipo ciclobutano (CPDs) a través de una transferencia de energía triplete-triplete. Este proceso ha sido confirmado por medio de la síntesis de díadas modelo Thy-Thy y Cyt-Cyt, ya que su irradiación en presencia de ForU ha demostrado que producen CPDs. Asimismo, el estudio en ADN plasmídico permitió establecer la capacidad de ForU para inducir roturas de cadena simple y CPDs. A continuación, se ha desarrollo una nueva estrategia para la fotoprotección de moléculas bioactivas aprovechando la reactividad fotoquímica del tautómero 1,3-dicetona de la avobenzona (AB), un filtro del UVA. Los compuestos seleccionados son dos fármacos antiinflamatorios no esteroideos de uso tópico con propiedades fotosensibilizantes, (S)-ketoprofeno (KP) y diclofenaco (DF). El tautómero dicetona de la AB contiene dos restos fenacilo, que es un grupo protector fotolábil muy establecido. Por lo tanto, un diseño juicioso de una díada profármaco/profiltro permite la fotoliberación del fármaco y de su protector, la AB. La viabilidad de esta liberación controlada de los ingredientes se verificó en diferentes disolventes con carácter dador de H y viscosidad para simular la formulación tópica. Además, los estudios de fotólisis de destello láser en EtOH permiten la caracterización de una especie transitoria a 400-420 nm, la cual ha sido asignada al estado excitado triplete de AB-KP. Finalmente, se ha evaluado la fotoseguridad de la díada fotoactivable AB-KP. Los espectros de absorción transitoria de la díada AB-KP en ciclohexano muestra que la especie observada es el estado excitado triplete del KP y no el de la AB en su forma dicetona. El impacto de la díada sobre la membrana celular se ha abordado mediante irradiación UVA de soluciones de ácido linoleico en presencia de AB-KP y su potencial fototóxico se ha evidenciado mediante espectrofotometría UV-Vis revelando la formación de derivados hidroperóxidos diénicos conjugados del ácido linoleico. Sin embargo, la diada AB-KP no exhibe un potencial fotogenotóxico como lo demuestran los experimentos del ensayo comet, donde a diferencia del KP, la forma redonda no<br>The main objective of this thesis is to contrast the role of these 1,3-dicarbonyl compounds as DNA damaging agents to their photoprotective potential. Firstly, 5,6-dihydropyrimidines have been derivatized using a tert-butyl ketone photolabile group in order to study the generation of C5-centered radicals in non aqueous media. Then, laser flash photolysis study in acetonitrile of the designed 1,3-dicarbonyl derivatives yields the formation of the purported 5,6-dihydropyrimidin-5-yl radicals. Their characterization shows long lived transient species, which do not decay in the µs range and are centered at 400-420 nm or 350-400 nm for the 5,6-dihydrouridine or 5,6-dihydrothymidine derivatives, respectively. Moreover, radical generation has also been evidenced by steady state fluorescence experiments by using a profluorescent radical trap (AAA-TEMPO). Thus, irradiation of the photolabile nucleic acid derivatives in the presence of AAA-TEMPO results in an increased emission, in agreement with the trapping of C5 radical by the paramagnetic probe. Formation of the resulting adduct has been confirmed by UPLC-HRMS. Experimental data have been corroborated with ab initio CASPT2//CASSCF theoretical calculations. In a second chapter, another 1,3-dicarbonyl derivative of pyrimidine has been investigated. Indeed, 5-formyluracil (ForU) presents interesting features as a potential intrinsic DNA photosensitizing agent. Thus, spectroscopic studies reveal that ForU has not only an absorption in the UVA/UVB range, but also a triplet excited state (3ForU*) with a lifetime of some micros and with an energy high enough to photosensitize the well-known cyclobutane pyrimidine dimers (CPDs) through triplet-triplet energy transfer. This process has been confirmed by means of the synthesis of model Thy-Thy and Cyt-Cyt dyads, which after irradiation in the presence of ForU have been demonstrated to produce CPDs. Finally, the study extended to plasmid DNA allows establishing the ability of ForU to produce single strand breaks and CPDs. Next, the attention has been focused on the development of a new strategy for photoprotection of bioactive molecules taking advantage of the photochemical reactivity of the 1,3-diketo tautomer of the UVA filter avobenzone (AB). The selected bioactive compounds are two photosensitive topical non steroidal anti-inflammatory drugs, (S)-ketoprofen (KP) and diclofenac (DF). In this context, the diketo tautomer of avobenzone contains two phenacyl moieties, which are well-known photoremovable protecting groups. Thus, a judicious design of a pro-drug/pro-filter dyad allows the photorelease of the drug and its protecting shield, avobenzone. The viability of this controlled release of the active ingredients was checked in different solvents of different H donating properties and viscosity to simulate topical formulation.Plus, laser flash photolysis studies in ethanol allow characterization of a transient absorption band at 400-420 nm assigned to the triplet excited state of the dyad by comparison with that of the diketo form of AB. Finally, the photosafety of the photoactivatable AB-KP dyad has been assessed. The transient absorption spectra obtained for AB-KP dyad in cyclohexane showed the triplet excited state of KP and not that of the AB in its diketo form. The impact on the cellular membrane has been addressed by UVA irradiation of linoleic acid solutions in the presence of the dyad. Phototoxic potential of the dyad has been evidenced by UV-Vis spectrophotometry through the formation of the conjugated dienic hydroperoxides derived from linoleic acid. However, AB-KP does not exhibit a photogenotoxic potential as demonstrated by comet assay experiments, where by contrast with KP, the non damaged round shape of the cell is still observed after UVA irradiation.<br>L'objectiu principal d'aquesta tesi és contrastar el paper d'aquests compostos 1,3-dicarbonil com a agents que danyen l'ADN respecte al seu potencial fotoprotector. En primer lloc, 5,6-dihidropirimidines han sigut derivatitzades utilitzant el grup fotolàbil t-Bu cetona amb la finalitat d'estudiar la generació de radicals centrats en C5 en un mitjà no aquós. Després, l'estudi de fotòlisi de flaix làser en acetonitril dels derivats 1,3-dicarbonil dissenyats produeix la formació dels suposats radicals 5,6-dihidropirimidin-5-il. La seua caracterització mostra espècies transitòries de vida llarga i estan centrats a 400-420 nm o 350-400 nm per als derivats 5,6-dihidrouridina o 5,6-dihidrotimidina, respectivament. Per tant, la irradiació dels derivats fotolàbils d'àcid nucleic en presència de AAA-TEMPO dóna com resultat un augment de l'emissió, d'acord amb la captura del radical C5 per la sonda paramagnètica. La formació del adducte resultant s'ha confirmat mitjançant UPLC-HRMS. Així mateix, les dades experimentals s'han corroborat amb càlculs teòrics ab initio CASPT2 // CASSCF. En un segon capítol, un altre derivat 1,3-dicarbonil de la pirimidina ha sigut investigat. De fet, el dany 5-formiluracil (ForU), presenta característiques interessants com a potencial fotosensibilitzador intrínsec de l'ADN. Per tant, els estudis espectroscòpics revelen que ForU té una absorció en el rang UVA/UVB i també presenta un estat triplet excitat (3ForU*) amb un temps de vida d'alguns micros i amb una ET prou alta com per a fotosensibilitzar la formació dels coneguts dímers de pirimidina de tipus ciclobutà (CPDs) a través d'una transferència d'energia triplet-triplet. Aquest procés ha sigut confirmat per mitjà de la síntesi de diades model Thy-Thy i Cyt-Cyt, que després de la irradiació en presència de ForU s'ha demostrat que produeixen CPDs. Finalment, l'estudi en ADN plasmídic ha permès establir la capacitat de ForU per a produir trencaments de cadena simple i CPDs. A continuació, s'ha desenvolupat una nova estratègia per a la fotoprotecció de molècules bioactives aprofitant la reactivitat fotoquímica del tautòmer 1,3-dicetona del filtre de l'UVA Avobenzone (AB). Els compostos seleccionats són dos fàrmacs antiinflamatoris no esteroïdals d'ús tòpic amb propietats fotosensibilizants, (S)-ketoprofè (KP) i diclofenac (DF). En aquest context, el tautòmer dicetona de l'AB conté dues fraccions fenacil, que es un grup protector fotolàbil ben conegut. Per tant, un disseny judiciós d'una diada profàrmac / profiltre permet el fotoalliberament del fàrmac i del seu escut protector, l'AB. La viabilitat d'aquest alliberament controlat dels ingredients actius s'ha verificat en diferents dissolvents de diferent caràcter dador d'hidrogen i viscositat per a simular la formulació tòpica. A més, els estudis de fotòlisi de flaix làser en EtOH permeten la caracterització d'una banda d'absorció transitòria a 400-420 nm, la qual ha sigut assignada a l'estat excitat triplet de AB-KP. Finalment, s'ha avaluat la fotoseguretat de la diada fotoactivable AB-KP. Els espectres d'absorció transitòria de la diada AB-KP en ciclohexà mostres que l'espècie observada és l'estat excitat triplet del KP i no el de la AB en la seua forma dicetònica. L'impacte sobre la membrana cel·lular s'ha abordat mitjançant la irradiació UVA de solucions d'àcid linoleic en presència de AB-KP. El potencial fototòxic de la diada s'ha evidenciat mitjançant espectrofotometria UV-Vis revelant la formació de derivats hidroperòxids diènics conjugats de l'àcid linoleic. No obstant açò, la diada AB-KP no exhibeix un potencial fotogenotòxic com ho demostren els experiments de l'assaig comet, on a diferència del KP, la forma redona no danyada de la cèl·lula encara s'observa després de la irradiació UVA.<br>Aparici Espert, MI. (2018). Photochemistry of 1,3-Dicarbonyl Compounds: DNA Photodamage vs. Photoprotection [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/105782<br>TESIS

The physicochemical parameters of fifteen honey samples from a wide range of botanical origins were characterized to identify the influence of composition on the formation of alpha-dicarbonyl compounds during heating. Color, pH, moisture content, water activity, hydroxymethylfurfural (HMF), sugar and amino acid content were determined before and after storage at various time and temperatures. The effects of storage time and temperature on the formation of Maillard reaction product were also investigated. Analysis of the data has indicated that they have a significant impact on the rate of production of Maillard related compounds such as alpha-dicarbonyls and HMF. The content of free amino acids was also decreased 'over time with concomitant increase in color intensity. Furthermore, nine alpha-dicarbonyl compounds were detected in honey samples. The analysis of these compounds after derivatization with o-diaminobenzene resulted in the identification of three previously unreported derivatives in honey such as 3-deoxypentulose, 1,4-dideoxyhexulose and 3,4dideoxyglucosone-3-ene. More importantly, the detection of 5-hydroxycyclohexane-1,2,4-trione was to our knowledge the first cyclic alpha-dicarbonyl compound ever reported in literature. Characterization of this molecule by different mass spectrometric techniques and spiking experiments provided evidence that supported the precursor, the structure and proposed mechanism of formation.

Periodontal ligament inflammation or periodontitis is a common disease characterised by gradual destruction of connective tissue fibres that attach a tooth to the alveolar bone within which it sits. Diabetes and inflammation enhances periodontal bone loss through enhanced resorption and diminished bone formation. Periodontal ligament fibroblast attachment to collagen-I and function was impaired by methylglyoxal (MG) modification in vitro. The glyoxalase system is an anti-glycation defence in all cells that metabolises MG and thereby suppresses MG-mediated protein damage. Overexpression of Glo1 decreased the intracellular levels of MG The aim of this investigation was to improve the understanding of protein damage in PDL in diabetes, focusing on protein damage by MG in human periodontal ligament fibroblasts (hPDLFs) in hyperglycaemia and to evaluate the effects of high and low glucose concentrations on MG metabolism in hPDLFs with or without Glo1 inducers. The effect of high glucose concentration on the formation and metabolism of MG was studied in hPDLFs in vitro. The ability of two small molecule Glo1 inducers, individually and in synergistic combination, to counter dicarbonyl stress in hPDLFs in vitro was studied. Interactions between hPDLFs to the extracellular matrix protein, collagen-I, were investigated and impairments in hPDLFs adhesion to MG-modified collagen-I coated plates were assessed. Protein susceptible to MG modification and inactivation in the cytosol of hPDLFs were identified by high resolution mass spectrometry proteomics. The effect of clinical periodontitis on plasma protein glycation, oxidation and nitration was also investigated in a pilot clinical investigation. When hPDLFs were incubated with high glucose concentration in vitro there was a 45% decrease in Glo1 activity and 42% increase in D-lactate flux – surrogate indication of MG flux of formation, which contributed to increased cellular concentration of MG and increase in MG-H1 residue content of cell protein, compared to low glucose control. This indicated dicarbonyl stress was induced in hPDLFs by high glucose concentration in vitro, a model for hyperglycaemia in vivo. Decrease of Glo1 activity and increase in cellular MG concentration and MG-H1 residue content of cell protein was corrected with the addition of Glo1 inducers. The binding of hPDLFs to collagen-I was decreased by 30% in high glucose concentration and was corrected by addition of Glo1 inducers. Proteomics analysis of cytosolic extracts of hPDLFs indicated that high glucose incubations produced changes in MG-modified proteins and also up-regulated and down-regulated unmodified proteins in hPDLFs. The pilot investigation of clinical periodontitis suggested a systemic effect of this local inflammation which was associated with changes in plasma protein glycation, oxidation and nitration. This study reveals that dicarbonyl stress is a potential contributory pathogenic mechanism in hPDLFs in periodontitis and countering it may provide new treatment options to prevent and treat decline in periodontal health, particularly in diabetes. Small molecule inducers of Glo1 expression may in future contribute to improving periodontal health, particularly in diabetes.

L’épididyme est un organe complexe impliqué dans la maturation des spermatozoïdes et l’acquisition de leur pouvoir fécondant. Il possède plusieurs régions présentant toutes, différents profils d’expression génique. Le gène de la DCXR (Dicarbonyle L-xylulose réductase) retrouvé chez plusieurs espèces est fortement conservé au cours de l’évolution. Il code pour une protéine impliquée dans différents processus biologiques dont la voie métabolique énergétique de dégradation de l’inositol. DCXR est exprimée dans l’épididyme chez certaines espèces étudiées (souris, hamster, singe, humain). Chez l’homme, la protéine présente sur les spermatozoïdes est impliquée dans leur liaison à l’ovocyte et son absence sur les spermatozoïdes a été corrélée avec des cas d’infertilité idiopathique. Nous avons émis l’hypothèse que, d’une part la conservation de la séquence du gène de la DCXR entre les espèces permet un maintien de son rôle dans l’interaction entre les gamètes chez ces différentes espèces. D’autre part, la séquence de la protéine DCXR contient des domaines qui lui confèrent ses différentes fonctions. Nous avons basé nos recherches sur les modèles murin, humain et bovin. La possibilité de quantifier l’infertilité du taureau, en fait un modèle de choix pour l’étude des protéines impliquées dans la fécondation. Nous rapportons ici, l’identification de la DCXR dans l’épididyme de taureau. La protéine bovine est fortement exprimée dans l’épididyme, mais présente des différences d’expression et de localisation par rapport au modèle humain. Nous démontrons, dans l’épididyme, l’expression des gènes des enzymes de la voie de dégradation de l’inositol. L’activité enzymatique xylitol déshydrogénase mesurable en présence de la DCXR recombinante ou du fluide épididymaire, suggère un rôle de la DCXR dans le maintien du bilan énergétique via la voie de dégradation de l’inositol. Par induction de mutations ponctuelles dans la DCXR d’origine humaine nous avons mis en évidence les régions impliquées dans le pouvoir enzymatique de la protéine, mais l’impact sur la propriété de liaison à la zone pellucide de l’ovocyte n’a pas pu être vérifié. De même, l’incidence de la délétion génique de DCXR n’a pu être étudiée. Nos résultats suggèrent une différence dans le rôle de la DCXR en fonction de l’espèce malgré la présence d’une forte homologie de séquence.<br>The epididymis is a complex organ involved in spermatozoa maturation and acquisition of their fertilization abilities. The epididymis is segmented in different regions with specific gene expression patterns. DCXR gene, found in many species, is highly conserved during the evolution. The DCXR protein is involved in different biological processes of which, the inositol degradation energetic pathway. DCXR is highly expressed in the epididymis of studied species (mouse, hamster, monkey, human). In human, DCXR protein is found on the spermatozoa and is important for the binding of spermatozoa to the oocyte. The lack of this protein has been correlated with idiopathic infertility cases. We hypothesized that the high sequence homology of DCXR between species is associated with functionally conserved properties of the protein in mediating sperm-oocyte binding. We further hypothesized that the DCXR protein sequence contains specific functional domains that permit its multiple biological roles. We used the murine, human and bovine models for our studies. Bovine is a model in which the fertility can be quantified, what makes it interesting for the study of protein involved in fertilization. We report here the identification of DCXR in bull epididymis. The protein is highly expressed in the epididymis but shows expression and localization differences with the human counterpart. In the bovine epididymis, we identify the gene expression of enzymes involved in the inositol degradation metabolic pathway. The recombinant DCXR protein and the epididymis fluids xylitol dehydrogenase enzymatic activity, suggest the involvement of the protein in energy production by means of the inositol degradations pathway. By point mutations induction in the human DCXR, we revealed the protein domains involved in its enzymatic properties. Preliminary experiments did not conclusively demonstrate a role for DCXR during sperm-zona pellucida binding and a pilot test to create a DCXR-null animal model was unsatisfactory. Therefore, future research should focus on elucidating the function of this protein on male reproductive function. All together our results suggest a difference in the role of DCXR depending on the species studied.

I) Synthesis of Spiroindenes by Enolate-Directed Ruthenium-Catalyzed Oxidative Annulation of Alkynes with 2-Aryl-1,3-dicarbonyl Compounds The synthesis of carbocycles by the ruthenium-catalyzed oxidative annulation of alkynes with 2-aryl cyclic 1,3-dicarbonyl substrates is described. Proceeding by the functionalization of C(sp3)–H and C(sp2)–H bonds, and the formation of all-carbon quaternary centers, the reactions provide a diverse range of spiroindenes in good yields and high levels of regioselectivity. II) Synthesis of Benzopyrans by Pd(II)- or Ru(II)-Catalyzed C–H Alkenylation of 2-Aryl-3-hydroxy-2-cyclohexenones We have explored the 2-aryl-3-hydroxy-2-cyclohexenones as competent substrates for palladium- and ruthenium-catalyzed C–H alkenylation reactions with terminal alkenes. This process affords benzopyrans, in most cases, with good functional group tolerance. III) Synthesis of Spiroindanes by Palladium-Catalyzed Oxidative Annulations of 1,3-Dienes Involving C–H Functionalization 1,3-Dienes have been an underexplored class of substrates in catalytic oxidative annulation reactions involving C‒H functionalization. The synthesis of spiroindanes by the palladium-catalyzed oxidative annulation of 1,3-dienes with 2-aryl cyclic 1,3-dicarbonyl compounds is described. Several examples of the dearomatizing oxidative annulation of 1,3-dienes with 1-aryl-2-naphthols are also presented. IV) Enantioselective Spiroindene Formation via C‒H Functionalization Using Chiral Cyclopentadienyl Rhodium Catalysts A chiral cyclopentadienyl rhodium ligand with an atropchiral biaryl backbone enables an asymmetric synthesis of spiroindenes from 2-aryl-1,3-dicarbonyl compounds and alkynes. The process affords a range of products with all-carbon quaternary center in high yields and excellent enantiselectivities. The good functional group tolerance and broad substrate generality are the advantages of this reaction.

Les groupes pendants benzile (BZ) du copolymère de styrène sont convertis pratiquement quantitativement en fonctions peroxyde de dibenzoyle (BP) par irradiation à l'état solide des films polymères à lamda > 400 nm. La décomposition par voie thermique ou photochimique des BP est une voie efficace d'obtention d'un réseau tridimentionnel de réticulation. Les réseaux finals obtenus par photo-réticulation et thermoréticulation sont similaires. Les réseaux finals ont été caractérisés par rhéologie (Winter-Chambon, Cole-Cole, modèle théorique), gonflement, thermoporosimétrie et densimétrie. Une corrélation a été établie entre les résultats des différentes techniques et le nombre de groupes BP par chaîne. Les facteurs favorisant une construction du réseau dense sont : des masses molaires élevées et une faible polydispersité du copolymère initial et une concentration élevée du BP. L'efficacité de la réticulation du copolymère portant un groupe camphrequinone est nettement inférieure.

Les groupes pendants benzile (BZ) du copolymère de styrène sont convertis pratiquement quantitativement en fonctions peroxyde de dibenzoyle (BP) par irradiation à l'état solide des films polymères à lamda > 400 nm. La décomposition par voie thermique ou photochimique des BP est une voie efficace d'obtention d'un réseau tridimentionnel de réticulation. Les réseaux finals obtenus par photo-réticulation et thermoréticulation sont similaires. Les réseaux finals ont été caractérisés par rhéologie (Winter-Chambon, Cole-Cole, modèle théorique), gonflement, thermoporosimétrie et densimétrie. Une corrélation a été établie entre les résultats des différentes techniques et le nombre de groupes BP par chaîne. Les facteurs favorisant une construction du réseau dense sont : des masses molaires élevées et une faible polydispersité du copolymère initial et une concentration élevée du BP. L'efficacité de la réticulation du copolymère portant un groupe camphrequinone est nettement inférieure

Additions of carbon-centered radicals to alkenes are useful method for cyclic compounds formation. Manganese(III)-based oxidative free-radical cyclizations, where the radicals are generated and terminated oxidatively, are established as efficient methods for the construction of cyclic molecule. Treatment of a mixture of dimedone, Mn(OAc)3, and Cu(OAc)2 in glacial acetic acid with homobenzonorbornadiene (80) (4h at 50 &amp<br>#61616<br>C) gave furan derivative (107), dihydrofuran adduct (108), in addition to rearranged product (109) as a major product. The reaction run under the same reaction conditions without using Cu(II)acetate for 8h afforded dihydrofuran adduct (108) along with dihydrofuran (110), where no rearranged products could be formed. On the other hand, reflux of alkene 80 with a mixture of acetylacetone, Mn(OAc)3, and Cu(OAc)2 in glacial acetic acid (3h at 50 &amp<br>#61616<br>C) gave oxidative product (131) and rearranged product (132) (major). The reaction run under the same reaction conditions without using Cu(II)acetate for 7h produced, in addition to the oxidative product 131, a dihydrofuran derivative (133). In a second system, we examined the oxidation of benzobarrelene 82 with Mn(OAc)3, and Cu(OAc)2 in glacial acetic acid (1h at 50 &amp<br>#61616<br>C) in presence of dimedone resulted in the formation of five different products rearranged products (148, 149) and a dihydrofuran (109), besides, a mixture containing two major rearranged isomers (150/151). The same reaction was carried out under the same conditions in absence of Cu(II) for 9h and gave the isomeric mixture 150/151 exclusively, and the yield was reduced. The oxidative cyclization of acetylacetone with alkene 82 for 3h at 50 &amp<br>#61616<br>C, afforded in addition to the dihydrofuran (132), two rearranged products (169, 170) and a mixture consisting of two isomers (171/ 172). The isomeric mixture was converted to one product by treatment with methanolic ammonia providing hydroxyl derivative which was oxidized by MnO2 to afford product 174 in a good yield. Additionally, we investigated the behavior of nitrogen bridge in the bicyclic system on the course of the reaction. Oxidation of N-carbethoxy-7-aza-2,3-benzonorbornadiene 83 with dimedone in the presence of Cu(OAc)2 as well as in its absence in glacial acetic acid (2h at 50 &amp<br>#61616<br>C), rearranged product (189) was obtained as the sole product. Regarding the reaction of aza-derivative 83 with acetylacetone in the presence of Cu(OAc)2 (18 h at 50 &amp<br>#61616<br>C), rearranged product 195 was resulted as sole product. The reaction of 83 was also run with out Cu(OAc)2 for 22h and gave the rearranged product 195.

UV radiation can cause harmful effects to human skin, including premature skin ageing and skin cancer. Historically, sunscreens were developed to filter out UVB (290 nm-320 nm), but now the importance of UVA (320 nm-400 nm) sunscreens is realised. The most common UVA sunscreens are based on dibenzoylmethane (1,3-diphenyl propan-l,3-dione, DBM), of which the most common is Parsol 1789 (4'- methoxy 4'-tertiarybutyl DBM). The photochemistry of these materials has, however, been poorly understood. In this work the photophysics and photochemistry of DBM, Parsol 1789, Parsol DAM and ditertiarybutyl DBM have been studied, along with the respective 0-methylated and C-methylated compounds of DBM and Parsol 1789.DBMs exist primarily as an intra-molecularly bonded enol, which absorbs strongly at λ≈340 nm due to a π,π* transition. The absorption spectra of DBMs also exhibit a smaller peak at λ≈250 nm, due to an n,π* transition of the diketone content. At low temperature the main absorption band of DBMs shifts to longer wavelengths and vibrational structure can be observed. The enol form of DBMs fluorescence at low temperature, (v(_0)’→v’’(_0) at λ≈385 nm), and phosphorescence can be observed from both the diketone (λ(_em)≈495 nm,) and enol forms (λ(_em)≈425 nm). Thus the triplet energies of the diketones and enols of the DBMs studied have been measured. 0-methylated DBMs do not possess an intra-molecular H-bond, and the π,π* absorption band falls to lower wavelengths than for chelated DBMs. C-methylated DBMs exist as a diketone structure, and display photophysics typical of an aromatic ketone. It has been suggested that the main process on irradiation of DBM is the formation of a short-lived non-chelated enol, however no direct evidence as to the structure of this species is reported in the literature. Formation of the diketone form of DBM on prolonged irradiation in acetonitrile solution has also been reported, and in this work the quantum yield of this process has been measured; ɸ≈0.01 ± 0.004. In this work, direct (low temperature) IR spectroscopic evidence is presented to prove that the short-lived species produced on irradiation is indeed a non-chelated enol. The infra-red studies also suggest that the non-chelated enol form of DBM form complexes with polar solvents, as has been proposed in the literature. Quantum yields of non-chelated enol formation in cyclohexane at room temperature have been measured to be approximately ɸ=0.5 + 0.07. This work indicates that the rate of transient decay is enhanced by the interaction of the transient molecules with chelated enol molecules or other transient molecules. IR studies of low temperature transient formation confirm the interaction of transient molecules by the observation of inter-molecular hydrogen-bonding. By comparison with the E and Z isomers of 0-methylated DBM it is suggested that at low temperature DBM initially forms a Z-cis non-hydrogen bonded enol, which then converts to an E-trans non-hydrogen bonded enol with further irradiation. The kinetics and the temperature variation of the enol recovery support the theory that there is more than one species formed. The photochemistry of DBM in emulsions has also been studied in this work. It has been shown that the photochemistry occurring on irradiation is similar to that observed in solutions. This indicates that simple solutions are a good model for actual sunscreen formulations. Singlet oxygen is a highly reactive species capable of causing serious biological damage, however this work shows that DBM sunscreens generate singlet oxygen by photosensitisation, with quantum yields ɸ∆≈0.005-0.01. It has also been shown that the lifetime of the excited state of DBM involved in singlet oxygen production is very short, approximately τ <1 µs.

Mes deux themes de recherche ont porte sur l'etude de nouvelles methodes de synthese de composes trifluoromethyles : nous avons dans la premiere partie de cet ouvrage, etudie des cycloadditions 1,3-dipolaires entre un ylure d'azomethine stabilise par un groupe ester et le trifluorocrotonate d'ethyle pour synthetiser des pyrrolidines dicarboxylees substituees par un groupe cf 3. Les pyrrolidines 2,3- et 2,4- dicarboxyles ont ete largement etudiees comme analogues rigides d'aminoacides excitateurs. Nous avons etudie tout d'abord la cycloaddition 1,3-dipolaire entre l'ylure d'n-metallo-azomethine et le trans trifluorocrotonate afin de synthetiser des pyrrolidines trifluoromethylees. En suite nous nous sommes proposes d'etudier la synthese de pyrrolidines 3-cf 3 et 4-cf 3 dicarboxylees, et nous avons tente une approche chirale. Dans la deuxieme partie de cette these, nous avons aborde une etude de methodologie importante en chimie des composes fluores : la substitution de l'hydroxyle d'un alcool trifluoromethyle, par une autre fonctionnalite. Nous avons utilise des clusters bimetalliques (co-co, mo-co) d'alcools acetyleniques pour engendrer et stabiliser des ions carbeniums -trifluoromethyles. Nous montrons que ces carbocations peuvent additionner differents nucleophiles en formant des liaisons c-n et c-c.

Cp$ sb2$Ti(C))$ sb2$, where Cp = $ eta sp5$-cyclopentadienyl, reacted with RSSSR to give the catenated sulfur complexes Cp$ sb2$Ti(SR)(SSR), where R = CMe$ sb3$, CHMe$ sb2$, CH$ sb2$Ph, p-C$ sb6$H$ sb4$Me and CPh$ sb3$. These complexes, except for R = CPh$ sb3$, reacted with PhCH$ sb2$Br to give Cp$ sb2$TiBr$ sb2$, PhCH$ sb2$SR and PhCH$ sb2$SSR as major products. Cp$ sb2$Ti(SR)(SSR) desulfurized slowly in solution and rapidly in the presence of Ph$ sb3$P, giving Cp$ sb2$Ti(SR)$ sb2$ and Ph$ sb3$PS, in addition to other species. Similarly, phth-SSR, where phth = phthalimide, oxidatively added to Cp$ sb2$Ti(CO)$ sb2$ to give Cp$ sb2$Ti(X)(SSR), where X = phth and R = CMe$ sb3$, CHMe$ sb2$, CH$ sb2$Ph and p-C$ sb6$H$ sb4$Me. Solvolysis by MeOH and EtOH gave the species where X = OMe and OEt. In a similar manner Ph$ sb3$CSSCl added to Cp$ sb2$Ti(CO)$ sb2$ to give Cp$ sb2$Ti(Cl)(SSCPh$ sb3$). Treatment of Cp$ sb2$Ti(SR)(SSR) with (norbornadiene)Mo(CO)$ sb4$ gave the bridged dimers, (Cp$ sb2$Ti($ mu$-SR)-($ mu$-S$ sb{ rm x}$R)Mo(CO)$ sb4$), where x = 1 and 2 and R = CMe$ sb3$ and CHMe$ sb2$. The complexes where x = 2 contained the rare iso-$ mu$-$ eta sp1$-SSR ligand. In solution at low temperatures the bridging thiolato and disulfano groups were predominantly transoid. At higher temperatures, a dynamic process that allowed averaging of cyclopentadienyl ring environments took place. $ sp1$H NMR studies permitted evaluation of $ Delta{ rm G sbsp{c}{ ddagger}}$ for the averaging process.

Part I - ESR spectra of pure coals, oils and tars are presented; their g values and linewidths are calculated. Almost all the spectra are single, broad resonances; but one coal, Hucknall Coal, exhibits a two line spectrum, a narrow line superimposed on a broad line. On admission of oxygen the narrow line is reversibly lost. On the addition of various solvents to the samples, in most cases, an irreversible loss in ESR signal intensity was observed. There seems to be no direct correlation between which solvent is added to which coal and the effect on the ESR signal intensity. Infra-red spectra of pure coals are studied, both as pressed discs and thin films, and a method for the preparation of these discs and films is given. Solvent addition experiments were undertaken and the results show the breaking of weak coal/water hydrogen bonds and the formation of stronger coal/solvent hydrogen bonds. Part II - ESR spectra of the radical cations of several mono and dicarbonyl compounds are presented and interpretation of these spectra are given. For most compounds the parent radical cation is seen, with the spin on oxygen. The cyclic dicarbonyls show the σ-bonded structure for the cation with coupling to the protons δ to the spin. Some non-aldehydic dicarbonyls show a rearranged structure with the spin on carbon. The aldehydic dicarbonyls all show, in addition to the parent radical cation, lines due to an acetal type species, as yet unidentified. Some compounds containing nitrogen or sulphur in addition to oxygen have the spin localised onto these alternative heteroatoms.

Dicarbonyl glycation - particularly glycation by methylglyoxal (MG) - is an important type of spontaneous damage to the proteome. Proteins that are susceptible to glycation by MG with consequent functional impairment are called collectively the dicarbonyl proteome. Methylglyoxal-derived advanced glycation endproducts (AGEs) are abundant in vascular tissues and are thought to contribute to the development of vascular complications of diabetes. Dicarbonyl stress is the imbalance of reactive dicarbonyls and anti-glycation defences leading to increased AGEs. Previous studies have shown that the concentration of MG is increased in human microvascular endothelial cells in vitro incubated in a model of hyperglycaemia. The glyoxalase system is an anti-glycation defence in all cells that metabolises MG and thereby suppresses MG-mediated protein damage. Overexpression of Glo1 decreased the intracellular levels of MG. Recently it has been reported that primary aortic endothelial cells incubated under high glucose concentration in vitro showed decreased activity of Glo1. The aim of this investigation was to improve the understanding of protein damage in vascular disease in diabetes, -focusing on protein damage by MG in vascular endothelial cells in hyperglycaemia. The effect of high glucose concentrations on formation and metabolism of methylglyoxal was studied in human vascular endothelial cells in vitro. The ability of a Glo1 inducer, resveratrol (RSV), to counter dicarbonyl stress in human endothelial cells in vitro was also assessed. In vivo effects of Glo1 deficiency and over expression on dicarbonyl glycation were also studied in mouse model of diabetic vascular disease. The results show that methylglyoxal concentration is increased by 2 - 3 fold in culture medium and ca. 109% inside human vascular endothelial cells during culture in model hyperglycaemia which is returned to normal by RSV treatment. In addition, the flux of formation of D-lactate, the terminal product of MG metabolism by the glyoxalase system, is increased by 30% in endothelial cell cultured in model hyperglycaemia in vitro is also prevented by RSV. Furthermore, cellular activity of glyoxalase 1 and protein content is decreased by 20 - 30% with high glucose culture due to increased ubiquitination of Glo1 in human vascular endothelial cells in vitro suggesting increased proteolysis of Glo1. RSV also protected the decrease in Glo1 activity in these cells. However the increased formation of AGEs free adducts observed in high glucose conditions were not corrected with RSV but the level of MG-damaged proteins in cells was protected. Disturbance of methylglyoxal metabolism in an experimental model of diabetic vascular disease, Glo1 deficient mice at 20 weeks did not show any increase in dicarbonyl glycation of aortal collagen. However at 35 weeks the major MG and glyoxal derived AGE - MG-H1 and CML - were significantly increased possibly due to deterioration in metabolic resistance to dicarbonyl stress with age or/and decreased turnover in vascular collagen. Overexpression of Glo1 restricted to sites of the proendothelin promoter (endothelial cells and smooth muscle cells) in mice was unable to decrease aortal dicarbonyl glycation and atherosclerosis. This study reveals that the defence against dicarbonyl glycation is decreased in endothelial cells in high glucose in vitro and the flux of formation of methylglyoxal is increased. Induction of Glo1 expression may contribute to health benefits of RSV and Glo1 inducers may protect against the development of vascular complications in diabetes.

Building on previous studies of tape formation by dicarbonyl substituted pyridine derivatives in the solid state, it was proposed that expansion of the hydrogen bonding array from three donor-acceptor pairs to four should increase the strength of the hydrogen-bonded array. Accordingly an investigation into the 1,8-naphthyridine-2,7-dicarbonyl derivatives has now been undertaken. Following the synthesis of 1,8-naphthyridine-2,7-dicarboxylic acid, during which the solid-state structures of three key intermediates were obtained, thirty-five novel 1,8-naphthyridine-2,7-dicarboxylates and fourteen novel 1,8-naphthyridine-2,7-dicarboxamides have been synthesised. Solid-state structures have been obtained for thirty-two of these derivatives confirming that the hydrogen bonding motifs observed for the dicarbonyl-substituted pyridines are also adopted by their naphthyridine analogues. In the diesters the familiar one-dimensional taping motif was observed, with additional secondary interactions, caused by the substitution on the pendent arm, influencing the packing of these structural units. For the corresponding diamides, intramolecular hydrogen bonding was found to organise the molecules into a cleft arrangement. Additionally an initial investigation into the solid-state motifs observed upon co-ordination to a metal centre has been carried out. A number of novel pyridine-2,6-dicarbonyl derivatives have also been synthesised and their solid-state behaviour has been studied. One of these structures is thought to be only the second known non-tape-forming pyridine-2,6-dicarboxylate. Finally the successful synthesis of 4,4’-linked pyridine-2,6-dicarboxamides has been achieved, the latter offering the potential for forming extended networks through co-ordination around metal centres

Les complexes carbonyles de metaux de transition representent des sources potentielles de monoxyde de carbone, principalement dans les reactions de carbonylation. Dans le cas des complexes de la serie cp(co)#2fe (fp), une etude electrochimique menee sur le complexe parent, le dimere fp#2, montre qu'il est possible d'electrogenerer, de maniere controlee, l'anion dicarbonyl cyclopentadienyl ferrate(-1). Nous avons aborde ensuite les mecanismes de formation de la liaison -alkyl-fer lors de l'alkylation de l'anion ferrate cp(co)#2fe#- par divers halogenures d'alkyles et d'acyles dans le contexte de la competition entre substitution nucleophile et transfert d'electrons. Dans un second temps, partant des complexes authentiques stables -alkyl et -acyl-fer de cette serie, nous avons montre que l'activation de ces edifices par transfert d'electron peut induire une reactivite locale autour de l'atome de fer. Une telle reactivite possede non seulement une finalite fondamentale mais egalement synthetique. Ainsi, nous montrons qu'il est possible, moyennant l'activation par transfert d'electrons, de promouvoir l'insertion de co dans une liaison -carbone-fer, etape capitale dans les processus de carbonylation par les metaux carbonyles. Par ailleurs, l'activation des complexes acyl-fer (fpcor) en presence du tributylstanane, declenche un processus electrocatalytique permettant de convertir ces complexes fpcor en aldehydes organiques rcoh correspondants. L'ensemble de ces investigations s'inscrit egalement comme une contribution a la mise en relief de l'interet des especes paramagnetiques a 17 et 19 electrons en catalyse homogene. Dans le cadre de telles etudes, nul ne peut nier que les outils electrochimiques (en l'occurence la voltametrie et la chronoamperometrie), jouissant de la double capacite d'electrogeneration et d'observation d'especes hautement reactives, sont d'une importance inegalable

Glyco-oxidation is linked to the pathophysiology of diabetes and diabetic complications. The process of glyco-oxidation generates reactive dicarbonyls, which form adducts on arginine residues in distributions throughout the proteome that are site-specific depending on the protein microenvironment. Dicarbonyl adducts are thus markers for glyco-oxidative stress. Various approaches using mass spectrometry permits the identification, localization, and quantification of these dicarbonyl adducts. Using MG as a model dicarbonyl, a shotgun proteomics approach identified the sites for modification of major plasma proteins. Thirty five sites on seven abundant plasma proteins were found, and investigation into the microenvironment surrounding the target arginine sites revealed a neighboring charged residue motif where adjacent residues were either negatively or positively charged. One of the sites identified was R257 in HSA, which is located in the important drug binding site I. We validated drug site I as a target for MG modification by the adaptation of two assays to monitor the effect of MG modification. MG significantly decreases the rate of hydrolysis of PGE2 in drug site I, and induces the displacement of prodan from drug site I. Molecular modeling of warfarin docking at drug site I with the MG-modified R257 resulted in significantly decreased binding and change in binding orientation. The oxidation products of susceptible residues methionine, tryptophan, and cysteine were evaluated using MRM of oxidized HSA peptides. Oxidation of methionine gave the M+16 single oxidized product, and M329 in HSA was the most responsive site. Oxidation of the sole W214 tryptophan produced the W+32 double oxidation product, and oxidation of C34 produced the C+48 triple oxidation product. MG, 3DG, and glucosone were evaluated for propensity to modify 12 HSA sites based on MRM of dicarbonyl modified HSA. Dicarbonyl modification was independent of arginine solvent accessibility. In a clinical study using nephropathy as an endpoint, sites of oxidation and modification of HSA by MG, 3DG, and glucosone were quantified by MRM. The most important variable among diabetic subjects was metformin use, and subjects taking metformin had significantly reduced markers for glyco-oxidation. These findings may be useful in the development of new diabetes therapies that aim to ameliorate glyco-oxidative stress.

Foods, from the earliest times, are subjected to man-made modifications to ensure microbiological safety, enzymatic inactivation, destruction of toxic substances, and optimization of storage time. An undisputable role in making the food softer, tasty and preservable over time is exerted by heat treatment. It is during this phase that a series of chain reactions, known like Maillard's reaction, are triggered. During this reaction, products that affect the flavor, color and aroma of foods are formed. Among these, glyoxal, methylglyoxal and 3-deoxyglucosone are of particular importance. These compounds are present in food, have antimicrobial activity, are promoters of advanced glycation end products formationand also have toxic effects in in vitro and in vivo studies. Research activity carried out during Ph.D. study had a common thread: increasing knowledge on 1,2-dicarbonyl compounds. In this field, the overall aims of this thesis work were: assessment of the content of dicarbonyl compounds in Italian food; assessment of their dietary intake; study of formation/degradation of dicarbonyl compounds using food model systems; evaluation of antimicrobial activity of the main dicarbonyl compounds; study of the interaction between the dicarbonyl compounds and the nutrients present in the microbiological culture media, both in the presence and absence of the microorganism. The results obtained by the survey on Italian food show that the concentration is variable and the predominant 1,2-dicarbonyl compounds is 3-deoxyglucosone. The estimation on dietary intake with a Total Diet Study-like investigation, have brought new evidence to assert that the ingestion with foods is high especially for infants (0-2 years) and children (3-9 years). The results obtained with the model systems show that time, temperature and ingredients have a strong influence on the formation of the compounds and that it is possible to reduce the level of 1,2-dicarbonyl compounds. The results of antimicrobial assays lead us to conclude that dicarbonyl compounds, especially GO and MGO, could have a role in the microbial stability of foods, although food composition may strongly influence their availability to act as antimicrobials. The results obtained by the study of the interaction between the dicarbonyl compounds and the nutrients present in the culture media allow us to assert that the 1,2-dicarbonyl compounds are degraded very quickly when they come into contact with bacteria. The results obtained outline a framework of knowledge that is a prelude to subsequent important developments.

Formation of advanced glycation endproducts (AGEs) on proteins has been linked to the pathogenesis of diabetic complications. Importantly, elevated levels of methylglyoxal (MG) occur in type 2 diabetes mellitus (T2DM), and the resulting site-specific formation of stable adducts on arginine residues can cause protein damage. Using MG, site-specific modifications on the plasma protein plasminogen (Pg) were determined following protein digestion into peptides and liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis, and 30 arginine sites were identified on the protein. Investigation into three of the most highly modified sites, R504, R530, and R561, using molecular modeling, identified likely functional changes to the Pg cleavage and the lysine binding pocket as a result of adduct formation at these sites. Overall functional changes to Pg were examined using silver staining and kinetic assays to examine normal protein cleavage by activator enzymes streptokinase (STK), tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). MG-modified Pg exhibited decreased activation into plasmin (Pn), which is the active enzyme that forms via normal Pg cleavage, by all three activator enzymes. Activation into Pn by STK was significantly delayed by MG modification on plasminogen. Similar effects were observed with tPA and uPA. Efforts to identify the primary sites of MG adduction on Pg by two dimensional gel electrophoresis (2DGE) identified six sites, including R504 and R530, as the earliest modified sites. In order to probe MG site specific modification effects on lysine binding, MG-modified protein was run through a lysine-sepharose binding column and fractions were collected. The results indicated that MG-modified Pg bound more weakly to the column and eluted easier than unmodified Pg and LC-MS/MS using a LTQ Orbitrap Velos of the fraction indicated that R504 and R530 were the primary sites of MG adduction within the eluate. To assess MG-modification of Pg in humans, 12 plasma samples were immunodepleted of the top 14 abundant proteins and samples were analyzed by LC-MS/MS using a LTQ Orbitrap Velos. Nine of the 12 patient samples indicated the presence of MG-modified peptides. The antihyperglycemic drug metformin, a drug that scavenges MG and lowers formation of AGEs, was studied in order to better elucidate this scavenging mechanism. A novel reaction imidazolinone product, IMZ, was determined to be the primary product formed in the reaction between metformin and MG, confirmed unequivocally through x-ray diffraction analysis. In order to determine levels of IMZ in human patients on metformin therapy, multiple reaction monitoring (MRM) was employed to quantify the compound. Human urine samples from 92 patients on metformin treatment were analyzed. 66 of the 68 patients to exhibit high concentrations of metformin also indicated the presence of IMZ in their urine. The remaining samples either exhibited no metformin, or levels of metformin too low to detect the presence of IMZ. Importantly, IMZ was never identified in patients without a metformin signal, indicating the validity and quality of the assay. This dissertation builds upon the current knowledge of site-specific MG modifications, both in vitro, identifying for the first time Pg as a sensitive site-specific target of glycation, with functional effects, and importantly in humans, as this is the first identification of MG-modified Pg in vivo. The functional effects associated with this modification may provide a link between elevated MG in T2DM, and resulting cardiovascular complications. Additionally, the identification of the novel reaction product IMZ is important, as it helps to fully elucidate the role metformin plays in treating T2DM patients. The detection of IMZ in the urine of human patients on metformin therapy indicates that metformin plays a role in the reducing MG levels through scavenging in vivo, and the developed MRM method allows for future rapid, sensitive study of cohorts to better understand this mechanism and the role it plays in reducing AGEs and diabetic complications.

The reactions of diagonal and lateral Cp'Re(CO)2Br2 (where Cp' = n5-C5H5, n5-C5Me5) and (n5-CgH7)Re(CO)3 with reducing agents have been examined. Hydride reduction at -78 °C is observed to occur at the Cp ring in both CpRe(CO)2Br2 isomers, affording a thermally unstable [(n4 -C5Hg)Re(CO)2Br2]- complex. The product of hydride ring attack has been characterized by low-temperature IR and 1H NMR measurements in addition to 13C NOE and heteronuclear 2D NMR measurements. Reaction of lateral CpRe(CO)2Br2 with either MeLi or PhLi affords both Cp-ring attack and metalhalogen exchange, [CpRe(CO)2Br]- (1) while t-BuLi reacts exclusively via metal-halogen exchange. diag-CpRe(CO)2Br2 reacts with the above lithium reagents to yield the same metal-halogen exchange anion. Analogous reactions using diag- and lat-Cp*Re(CO)2Br2 (where Cp* = n5-CgMe5) afford only the corresponding rhenium metal-halogen exchange anion, [Cp*Re(CO)2Br] (2). The molecular structures of 1-[Li/15-Crown-5] and 2-PPP were established by X-ray crystallography. 1-[Li/15-Crown-5] crystallizes in the monoclinic space group P21 with a = 10.860(4) A, b = 13.116(5) A, c = 7.417(3) A, B = 105.26(3)0, V = 1018.7(3) A3 , and Z = 2. 2-PPP crystallizes in the orthorhombic space group Pbca with a = 20.646(5) A, b = 17.690(5) A, c = 17.553(3) A, and z = 8. Solution FT-IR studies of 2 in THF reveal the presence of only solvent-separated ion pairs when the gegencation is Li+, K+, or PPP+ from -70 °C to room temperature. 2-Na at room temperature displays a 39:61 mixture of carbonyl oxygen-sodium and solvent-separated ion pairs, respectively. These ion pairs reveals a reversible temperature-dependent equilibrium. The equilibrium constant has been determined by IR band shape analysis over the temperature range -70 °C to room temperature and values of AH and AS are reported. The reaction of the ring-attacked complex, diag-[(n4-C5H6)Re(CO)2Br2]- with PPh3, P(OPh)3, or Me3CNC leads to the formation of the CpRe(CO)2L. Treatment of [Cp'Re(CO)2Br]- with methyltriflate, TFA, and magic ethyl yields the corresponding diag-Cp'Re(CO)2Br(R) (R = CH3, H, C2H5) complexes based on in situ IR analysis. All of these functionalized complexes decomposed in solution over a period of days to give Cp'Re(CO)3 as the only isolable product (20-30 %). The reaction of the [Cp,Re(C0)2Br]- with Bu3SnH at 60 °C leads to the formation of diag-Cp'Re(CO)2(SnBu3)2, which was also synthesized independently by the deprotonation of diag-Cp'Re(CO)2H2 with Et3N in the presence of Bu3SnBr at room temperature. The reaction of Cp'Re(CO)2Br2 with Bu3SnH at room temperature was discovered to afford the dihydride in excellent yield and, thus represents an improved synthetic route for the synthesis of diag-Cp'Re(CO)2H2. The hydride reduction of (n5-CgH7)Re(CO)3 at room temperature leads to the immediate formation of [(n5-CgH7)Re(CO)2H]- complex, which has been characterized by IR analysis and 1H and 13C NMR spectroscopy.

Resumo: A terapia ADEPT (antibody-directed enzyme prodrug therapy) tem sido caracterizada, em vários estudos experimentais focalizados na destruição de células tumorais, como uma alternativa à fármacos citotóxicos sistêmicos (anti-proliferativos). Nesta técnica, o pró-fármaco é ativado por enzimas exógenas que são levadas à célula tumoral por meio de anticorpos monoclonais (Mab). Neste contexto, horseradish peroxidase (HRP) e ácido 3-indolacético (IAA) constituem um dos sistemas mais citados de enzima e pró-fármaco aplicados à destruição de células tumorais com conjugados HRP-Mab. Peroxidases são enzimas inespecíficas e várias moléculas podem ser oxidadas pela suas formas ativas HRP-l e HRP-ll no ciclo clássico da peroxidase, que é dependente de peróxido de hidrogênio ou hidroperóxidos orgânicos. Por outro lado, somente NADH, dihidroxifumarato e a auxina de planta IAA, têm sido descritos como substratos para HRP em reação independente de peróxido de hidrogênio. O objetivo deste trabalho foi estudar o mecanismo pelo qual compostos β-dicarbonílicos são oxidados por HRP e explorar suas aplicações. Foi demonstrado que os compostos dicarbonílicos 2,4-pentanodiona (PD) e 3-metil-2,4-pentanodiona (MePD) são eficientemente oxidados pela HRP, na ausência de peróxido, em tampão fosfato pH 7,4, consumindo oxigênio presente em solução, o que não ocorreu com outros compostos β-dicarbonílicos testados (dimedona e acetoacetato). Observou-se também, via espectrofotometria, durante a reação com PD e MePD, que a enzima nativa passou à sua forma HRP-lll, além disso, a reação produziu espécies reativas de oxigênio (ERO), detectadas por quimiluminescência dependente de luminol e fluorescência dependente de diclorofluoresceína. Também foram realizadas reações de consumo de oxigênio com outros compostos que possuem grupamento... (Resumo completo, clicar acesso eletrônico abaixo)<br>Abstract: Antibody-directed enzyme prodrug therapy (ADEPT) has featured in several experimental studies focused on the destruction of tumor cells, as an alternative to systemic cytotoxic (antiproliferative) drugs. In this technique, the prodrug is activated by exogenous enzymes delivered to tumor cells via monoclonal antibodies (MAb). In this context, horseradish peroxidase (HRP) and indole-3-acetic acid (IAA) constitute one of the most often cited systems of enzyme and prodrug applied to destroy tumor cells with HRP - MAb conjugates. Peroxidases are unspecific enzymes and several molecules can be oxidized by the active forms HRP-I and HRP-II in the classic peroxidase cycle, which depends on hydrogen peroxide or organic hydroperoxides. On the other hand, only NADH, dihydroxyfumarate and the plant auxin IAA have been described as substrates for HRP in a reaction independent of hydrogen peroxide. The objective of this work was to study the mechanism by which β-dicarbonyl compounds are oxidized by HRP and explore possible applications. We demonstrated by measuring oxygen uptake, that the dicarbonyls PD (2,4-pentanedione) and 3-MePD (3-methyl-2,4-pentanedione) can also be oxidized by HRP in the absence of peroxide, in phosphate buffer pH 7.4, consuming the oxygen present in solution, what didn't occur with other β-dicarbonyl compounds (dimedon and acetoacetate), under the same conditions. It was also observed, in the absorption spectrum during the reaction course with PD and 3-MePD, that the native enzyme was transformed to HRP-III; moreover, the reaction produced reactive oxidant species (ROS), detected by luminol-dependent chemiluminescence and dichlorofluorescein-fluorescence dependent. Reactions of oxygen uptake with other heme-compounds (cytochrome C, hemin, myoglobin and myeloperoxidase) had been carried to detect the especificity of the HRP in the oxidation reaction... (Complete abstract click electronic access below)<br>Orientador: Iguatemy Lourenço Brunetti<br>Coorientador: Valdecir Farias Ximenes<br>Banca: Olga Maria mascarenhas de Faria Oliveira<br>Banca: Chung Man Chin<br>Banca: Antonio Cardozo dos Santos<br>Banca: Mariza Pires de Melo<br>Doutor

1. C–H Functionalisation of 2 Aryl Cyclic 1,3-Dicarbonyl Compounds Two enolate-directed C–H functionalisation protocols have been developed using 2-aryl cyclic 1,3-dicarbonyl compounds as substrates. Reactions with activated alkenes, under ruthenium or palladium catalysis produced benzopyrans in most cases, in moderate to good yield. Alternatively, an oxidative annulation of 2-aryl cyclic 1.3-dicarbonyls with 1,3-enynes was facilitated under rhodium catalysis, forming functionalised spiroindene structures in most cases, in generally good yields and high regioselectivity. During the investigation, the serendipitous formation of spirodialin structures was also observed. 2. Enantioselective Rh(I)-Catalysed Cyclisation of Arylboron Compounds onto Ketones Chiral tertiary alcohols, bearing aza-, oxa- and carbocyclic core structures of varying ring size were successfully formed from arylboron substrates under rhodium catalysis. In general the reactions proceeded with good yield and with moderate to high enantioselectivity. A protocol for the formation of a bicyclic lactam system was also achieved in moderate yield and enantioselectivity.

ABSTRACT SYNTHESIS OF 1,2,3,5-TETRASUBSTITUTED PYRROLE DERIVATIVES VIA 5-EXO-DIG TYPE CYCLIZATION AND STEREOSELECTIVE FUNCTIONALISATION OF FERROCENE DERIVATIVES Metin Kayalar M.S., Department of Chemistry Supervisor: Prof. Dr. Ayhan S. Demir January 2005, 102 pages A convenient and new method for the synthesis of 1,2,3,5-tetrasubstituted pyrrole derivatives starting from 1,3,-dicarbonyl compounds through acid catalyzed cyclization reaction is described. Alkylation of 1,3-dicarbonyl compound with propargyl bromide followed by one step cyclization with the introduction of primary amines in the presence of catalytic amount of triflouroacetic acid (TFA) affords the corresponding pyrrole derivatives in high yields. The investigations on the studies of developing a new method for catalytic and stereoselective functionalisation of ferrocene derivatives were summarized. Functionalisation studies were carried out in three main strategy the first one of which is carboxylation, second one is arylation and the last one is oxidative cross-coupling with &amp<br>#945<br>, &amp<br>#946<br>-unsaturated carbonyl compounds.

Esta tese consiste do estudo de reações de ciclofuncionalização de compostos &#946;-enamino carbonílicos e &#946;-dicarbonílicos, contendo uma cadeia alquenílica nas posições &#945; ou &#947;. Os eletrófilos empregados para este fim foram: iodo, brometo de fenilselenenila e tricloreto de p-metóxifeniltelurio. Os iodo-&#946;-enamino ésteres e cetonas cíclicas, após desidroiodação mediada por base, levaram à formação dos correspondentes pirróis, indóis e aminobenzofuranos. A ciclização dos &#946;-ceto ésteres e &#946;-dicetonas levou a enol éteres e benzofuranos funcionalizados. Estes resultados, juntamente com outros obtidos em nosso grupo de pesquisa, foram utilizados em um estudo comparativo entre reagentes de iodo, selênio e telúrio frente a reações de ciclização eletrofílica de substratos &#946;-dicarbonílicos.<br>This thesis presents a study of the cyclofunctionalization of &#946;-enamino carbonyl and &#946;-dicarbonyl compounds, substituted by an alkenyl group at the &#945; or &#947; positions. Iodine, phenyl-selenenyl bromide and p-methoxyphenyltellurium trichloride were employed as the electrophilic reagent. The cyclic iodo-&#946;-enamino esters and ketones, after base-promoted dehydroiodination, led to the corresponding pyrroles, indoles and aminobenzofurans. The cyclization of the &#946;-keto esters and &#946;-diketones afforded five- and six-membered enol ethers and benzofuranones. These results, together with others previously obtained in our research group, allowed us to compare the behavior of the three above mentioned electrophiles toward the cyclofunctionalization of &#946;-dicarbonyl substrates.

Made available in DSpace on 2014-06-11T19:30:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-11-26Bitstream added on 2014-06-13T19:01:09Z : No. of bitstreams: 1 rodrigues_ap_dr_arafcf.pdf: 8313704 bytes, checksum: 2cd8bf6d9e9c4b85c49edb7b6d038519 (MD5)<br>Universidade Estadual Paulista (UNESP)<br>A terapia ADEPT (antibody-directed enzyme prodrug therapy) tem sido caracterizada, em vários estudos experimentais focalizados na destruição de células tumorais, como uma alternativa à fármacos citotóxicos sistêmicos (anti-proliferativos). Nesta técnica, o pró-fármaco é ativado por enzimas exógenas que são levadas à célula tumoral por meio de anticorpos monoclonais (Mab). Neste contexto, horseradish peroxidase (HRP) e ácido 3-indolacético (IAA) constituem um dos sistemas mais citados de enzima e pró-fármaco aplicados à destruição de células tumorais com conjugados HRP-Mab. Peroxidases são enzimas inespecíficas e várias moléculas podem ser oxidadas pela suas formas ativas HRP-l e HRP-ll no ciclo clássico da peroxidase, que é dependente de peróxido de hidrogênio ou hidroperóxidos orgânicos. Por outro lado, somente NADH, dihidroxifumarato e a auxina de planta IAA, têm sido descritos como substratos para HRP em reação independente de peróxido de hidrogênio. O objetivo deste trabalho foi estudar o mecanismo pelo qual compostos β-dicarbonílicos são oxidados por HRP e explorar suas aplicações. Foi demonstrado que os compostos dicarbonílicos 2,4-pentanodiona (PD) e 3-metil-2,4-pentanodiona (MePD) são eficientemente oxidados pela HRP, na ausência de peróxido, em tampão fosfato pH 7,4, consumindo oxigênio presente em solução, o que não ocorreu com outros compostos β-dicarbonílicos testados (dimedona e acetoacetato). Observou-se também, via espectrofotometria, durante a reação com PD e MePD, que a enzima nativa passou à sua forma HRP-lll, além disso, a reação produziu espécies reativas de oxigênio (ERO), detectadas por quimiluminescência dependente de luminol e fluorescência dependente de diclorofluoresceína. Também foram realizadas reações de consumo de oxigênio com outros compostos que possuem grupamento...<br>Antibody-directed enzyme prodrug therapy (ADEPT) has featured in several experimental studies focused on the destruction of tumor cells, as an alternative to systemic cytotoxic (antiproliferative) drugs. In this technique, the prodrug is activated by exogenous enzymes delivered to tumor cells via monoclonal antibodies (MAb). In this context, horseradish peroxidase (HRP) and indole-3-acetic acid (IAA) constitute one of the most often cited systems of enzyme and prodrug applied to destroy tumor cells with HRP – MAb conjugates. Peroxidases are unspecific enzymes and several molecules can be oxidized by the active forms HRP-I and HRP-II in the classic peroxidase cycle, which depends on hydrogen peroxide or organic hydroperoxides. On the other hand, only NADH, dihydroxyfumarate and the plant auxin IAA have been described as substrates for HRP in a reaction independent of hydrogen peroxide. The objective of this work was to study the mechanism by which β-dicarbonyl compounds are oxidized by HRP and explore possible applications. We demonstrated by measuring oxygen uptake, that the dicarbonyls PD (2,4-pentanedione) and 3-MePD (3-methyl-2,4-pentanedione) can also be oxidized by HRP in the absence of peroxide, in phosphate buffer pH 7.4, consuming the oxygen present in solution, what didn’t occur with other β-dicarbonyl compounds (dimedon and acetoacetate), under the same conditions. It was also observed, in the absorption spectrum during the reaction course with PD and 3-MePD, that the native enzyme was transformed to HRP-III; moreover, the reaction produced reactive oxidant species (ROS), detected by luminol-dependent chemiluminescence and dichlorofluorescein-fluorescence dependent. Reactions of oxygen uptake with other heme-compounds (cytochrome C, hemin, myoglobin and myeloperoxidase) had been carried to detect the especificity of the HRP in the oxidation reaction... (Complete abstract click electronic access below)

Reactions of photoexcited 1,2-dicarbonyl compounds with chirally labelled and unlabelled captodative alkenes have been investigated, with special emphasis on their diastereoselection in cycloadditions. Irradiation of methyl phenylglyoxylate in presence of unlabelled alkenes yields to the corresponding rel-(2R, 3R)-head-to-head-oxetanes. Using the chirally labelled (S)-(methoxymethylpiperidinyl)propenenitrile gives rise to two oxetanes, one of which was isolated and identified as (2R, 3R)-head-to-head-oxetane by X-ray cristallography. Additionally, the photoreduction product meso-dimethyl-2,3-diphenyltartrate of the ester was formed in all reactions. The photoreactions of benziles with chirally labelled c,d-alkenes give rise to oxetanes in low yields, in these cases the products of Norrish type I reactions become competitive.

Chiral Baeyer-Villiger (BV) oxidation of cyclic ketones allows rapid access to asymmetric lactones as valuable intermediates in organic chemistry and frequently encountered precursors in enantioselective synthesis. In the first part, BV oxidation of functionalized ketones, especially cyclic &amp<br>#61537<br>-hydroxy and acetoxy ketones is described which could be a straightforward route to the &amp<br>#61537<br>-hydroxy lactones and &amp<br>#61537<br>-hydroxyalkanoic acid derivatives. The &amp<br>#61537<br>-acetoxylation of indanone, tetralone and chromanone derivatives by using Mn(OAc)3 followed by the enzyme catalyzed kinetic resolution of acetoxy ketones gives both of the enantiomers of &amp<br>#61537<br>-acetoxy ketones in good chemical and optical yields. The Bayer-Villiger oxidation of &amp<br>#61537<br>-acetoxy ketones with m-CPBA, CF3SO3H, and CH2Cl2, at rt gives the corresponding lactones without racemization. The phenyl moiety migrates selectively in order to form lactones. The mild hydrolysis of lactones affords phenolic &amp<br>#61537<br>-hydroxycarboxylic acid derivatives. Because of the high importance of pyrrole derivatives which exist in the structure of many natural products possessing biological activity beside their valuable feature of being versatile building blocks in organic synthesis and important starting materials for various synthetic transformations, a convenient method for the synthesis of 1,2,3,5-tetrasubstituted pyrrole derivatives starting from 1,3,-dicarbonyl compounds throuh acid catalyzed cyclization reaction is presented in the second part of the thesis. Alkylation of 1,3-dicarbonyl compound with propargyl bromide followed by one step cyclization with the introduction of primary amines in the presence of catalytic amount of trifluoroacetic acid (TFA) affords the corresponding pyrrole derivatives in high yields. The third part of the thesis describes the cyano-phosphorylation of various alkyl and aryl phosphonates in the presence of diethyl cyanophosphonate (DEPC) as the phosphorylating agent under the promotion of the KCN catalyst. Reaction of acyl phosphonates with DEPC forms the phosphonocyanohydrin-O-phosphates which are the important starting materials of quaternary &amp<br>#945<br>-hydroxy carboxylic acid and phosphonate containing &amp<br>#946<br>-aminoalcohol derivatives.

1,2-Dicarbonylverbindungen spielen aufgrund ihrer Reaktivität gegenüber Aminosäureseitenketten von Proteinen eine Schlüsselrolle bei der Bildung von Maillard Reaktionsprodukten (MRP) und werden auch im Zusammenhang mit der Entstehung pathophysiologischer Konsequenzen bei metabolischen Erkrankungen diskutiert. Vor diesem Hintergrund stellt sich die Frage nach der physiologischen Relevanz alimentär aufgenommener 1,2 Dicarbonylverbindungen. Das Ziel der vorliegenden Arbeit war zunächst eine Bestandsaufnahme zum Vorkommen von 1,2-Dicarbonylverbindungen in einem Spektrum von Lebensmitteln, gefolgt von Untersuchungen zum metabolischen Transit von 3 Desoxyglucoson (3-DG) und Methylglyoxal (MGO) bzw. spezifischer Metabolite in Abhängigkeit der alimentären Aufnahme und zur Stabilität der Verbindungen während einer simulierten gastrointestinalen Verdauung. 1a Die 1,2-Dicarbonylverbindungen 3-DG, 3 Desoxygalactoson (3-DGal), MGO und Glyoxal (GO) sowie das Zuckerabbauprodukt 5-Hydroxymethylfurfural (HMF) als ein wichtiger Indikator für Erhitzungsprozesse in Lebensmitteln wurden in 173 Lebensmittelproben mittels einer optimierten RP-HPLC-Methode mit UV-Detektion bestimmt. Darunter waren neben alkoholfreien und alkoholischen Getränken auch süße Aufstriche, Brot- und Backwaren. In allen untersuchten Lebensmittelproben war 3 DG die quantitativ bedeutendste 1,2 Dicarbonylverbindung. Hohe 3-DG-Gehalte wurden in Bonbons, Honig und süßen Aufstrichen (Mediane: 165–626 mg/kg) und in Essig (Aceto balsamico bis 2622 mg/L) analysiert. Lebensmittel wie Fruchtsäfte, Bier, Brot- und Backwaren wiesen geringere 3 DG-Gehalte auf (Median: 27–129 mg/L bzw. mg/kg). In allen untersuchten Lebensmitteln lagen die Gehalte des 3-DG höher als die des HMF. 3-DGal konnte erstmals in nahezu allen Lebensmittel detektiert werden, mit einem Maximalwert von 162 mg/L in Aceto balsamico. In dieser Probe wurde auch ein hoher MGO-Gehalt (53 mg/L) gemessen. GO kommt in etwa gleichen Konzentrationsbereichen wie MGO vor. Generell lagen die Gehalte für 3-DGal höher als die für MGO. Eine Ausnahme stellt der untersuchte Manuka-Honig dar (463 mg MGO/kg). 1b Auf Basis der quantitativen Daten wurden Gehalte von 1,2-Dicarbonylverbindungen in verzehrüblichen Portionsgrößen verschiedener Lebensmittel berechnet und eine tägliche alimentäre Aufnahme von 20–160 mg (0,1–1,0 mmol) 3-DG und 5–20 mg (0,1–0,3 mmol) MGO abgeschätzt. 2a Der metabolische Transit von 3-DG und MGO wurde jeweils in einer dreitägigen Ernährungsstudie untersucht. Während der 3 Tage hatten die Probanden eine Dicarbonyl- und MRP-freie Diät (Rohkosternährung) einzuhalten. Am Morgen des zweiten Tages erhielten die Probanden eine definierte Menge 3-DG bzw. MGO (je 500 µmol), enthalten in Waldhonig bzw. Manuka-Honig. In den 24 h Urinproben der 3-DG-Interventionsstudie wurde 3-DG und dessen Metabolit 3-Desoxyfructose (3-DF) analysiert, außerdem Pyrralin und 3 DG-Hydroimidazolon (3-DG-H) als 3-DG-spezifisches MRP. In den 24 h Urinproben der MGO-Interventionsstudie wurde MGO und dessen Metabolit D-Lactat analysiert, außerdem MGO-Hydroimidazolon 1 (MG-H1) als charakteristisches MRP des MGO. Alle Verbindungen waren in den Urinproben nachweisbar. 2b Am ersten Tag der 3-DG-Interventionsstudie betrug der Median der renalen 3-DG- und 3 DF-Exkretion aller 9 Probanden 4,6 bzw. 77 µmol/d. Am Tag der definierten 3-DG-Aufnahme (Tag 2) stieg der Median der renalen 3-DG- und 3-DF-Exkretion signifikant auf 7,5 bzw. 147 µmol/d an. An Tag 3 unterschieden sich die täglichen renalen Ausscheidungen von 3-DG und 3-DF nicht signifikant von denen an Tag 1 (P > 0,05). Der Median der renalen Wiederfindung des an Tag 2 alimentär aufgenommenen 3-DG wurde mit 14 % abgeschätzt (Spannweite: 6–25 %). Der Median der renalen Exkretion von Pyrralin und 3-DG-H sank im Verlauf der dreitägigen Studie von 2,5 bzw. 1,0 auf 1,2 µmol/d bzw. 0,5 µmol/d. Diese Ergebnisse deuten erstmalig darauf hin, dass 3-DG aus der Nahrung resorbiert, resorbiertes 3 DG zu 3-DF metabolisiert und resorbiertes 3-DG hauptsächlich als 3-DF renal eliminiert wird. Die Exkretion der untersuchten MRP erwies sich in dieser Studie als nicht abhängig von der alimentären Aufnahme des 3 DG. 2c Die renale MGO- sowie D-Lactat-Ausscheidung wies keinen Zusammenhang mit der oralen Aufnahme einer hohen MGO-Menge auf. An allen 3 Tagen der MGO-Interventionsstudie lag die renale MGO-Exkretion aller 4 Probanden zwischen 0,11 und 0,30 µmol/d und die D-Lactat-Ausscheidung zwischen 52 und 224 µmol/d. Der Median der renalen MG-H1-Ausscheidung sank im Verlauf der dreitägigen Studie von 3,8 auf 1,2 µmol/d an Tag 3. Diese Ergebnisse deuten darauf hin, dass keine Resorption des MGO in die Zirkulation erfolgte. 3a Zur Beurteilung der Stabilität von 3-DG und MGO während der gastrointestinalen Verdauung wurde ein zweistufiges System von Hellwig et al. (2013b) adaptiert, bestehend aus einer zweistündigen „Magenstufe“ (Pepsin, pH = 2) und einer sechsstündigen „Darmstufe“ (Pankreatin/Trypsin, pH = 7,5). Für die Verdauungssimulation wurden jeweils wässrige 3 DG- und MGO-Standardlösungen mit Konzentrationen im lebensmittelrelevanten Bereich eingesetzt. Weiterhin wurde die simulierte Verdauung in Anwesenheit von Casein als Modellprotein, durchgeführt. 3b Nach achtstündiger simulierter Verdauung war im Verdauungsansatz noch 70 ± 10 % der initialen 3-DG-Menge bestimmbar. Die Anwesenheit des Caseins zeigte keinen Effekt auf die 3-DG-Konzentration. Damit dürfte nach gastrointestinaler Verdauung ein Großteil des alimentär aufgenommenen 3-DG zur Resorption zur Verfügung stehen. 3c Im Gegensatz zum 3-DG sank die MGO-Konzentration im Verlauf der achtstündigen simulierten Verdauung auf 15 ± 4 % der Ausgangskonzentration. In Anwesenheit von Casein verstärkte sich die Abnahme der MGO-Konzentration auf 9 ± 1 %. Es konnte gezeigt werden, dass die Abnahme der MGO-Konzentration auf Reaktionen mit den in den Verdauungsansätzen enthaltenen Enzymen und Proteinen zurückzuführen ist. MGO wird damit nach gastrointestinaler Verdauung nur noch in begrenztem Maße zur Resorption zur Verfügung. Die in der vorliegenden Arbeit gewonnenen Resultate lassen den Schluss zu, dass die biologische Verfügbarkeit alimentärer 1,2-Dicarbonylverbindungen gering (3-DG) bis vernachlässigbar (MGO) ist und selbst stark erhitzte Lebensmittel damit keinen maßgeblichen Beitrag zum „Gesamtpool“ an Dicarbonylverbindungen in vivo und den damit möglicherweise einhergehenden physiologischen Konsequenzen leisten.

La sénescence est une réponse cellulaire associée à des marqueurs spécifiques comme un arrêt irréversible du cycle cellulaire ainsi que la sécrétion d’un ensemble de facteurs comme les cytokines, chimiokines et protéases, constituant le SASP, pour Senescence-Associated Secretory Phenotype. Le SASP peut avoir des rôles autocrine et paracrine qui contribuent au renforcement et à la propagation du phénotype sénescent. La composition du SASP et par conséquent son rôle, dépendent notamment du type cellulaire et de la nature du stress inducteur de sénescence. Du fait de sa fonction de barrière avec l’environnement externe, la peau est particulièrement soumise à différents types de stress induisant la sénescence des cellules et un vieillissement prématuré. Le glyoxal, composé dicarbonylé formé au cours des réactions de glycation, d’auto-oxydation du glucose ou de la peroxydation lipidique, est un précurseur des produits avancés de glycation impliqués dans le vieillissement normal et pathologique. Mes travaux de thèse ont permis de montrer que le glyoxal induit la sénescence de kératinocytes humains normaux ainsi qu’une accumulation d’espèces réactives de l’oxygène et de produits avancés de glycation intracellulaires traduisant un état de stress oxydant. L’initiation de cette sénescence est due à l’activation de la voie d’arrêt du cycle cellulaire AKT/FOXO3a/p27KIP1 suivie d’une phase tardive caractérisée par l’activation de la voie p16INK4A/pRb. La caractérisation du phénotype sécrétoire associé à la phase précoce de cette sénescence, a été réalisée par spectrométrie de masse afin d’identifier des facteurs pouvant être ciblés par des ingrédients sénomorphiques<br>Senescence is a well-characterized cellular state associated with specific markers such as permanent cell proliferation arrest, and the secretion of messenger molecules by cells expressing the Senescence-Associated Secretory Phenotype (SASP). The SASP can display autocrine and paracrine effects which contribute to the senescent phenotype reinforcement and propagation. The SASP composition depends on many factors such as the cell type or the nature of the stress that induces senescence. Since the skin constitutes a barrier with the external environment, it is particularly subjected to different types of stresses, and consequently prone to premature cellular aging. Glyoxal, a dicarbonyl compound produced during glucose metabolism and lipid peroxidation, is a precursor of Advanced Glycation End-products (AGEs), whose presence marks normal and pathological aging. My thesis work showed that glyoxal treatment provokes oxidative stress by increasing reactive oxygen species and AGEs levels and induce senescence in human keratinocytes. Furthermore, glyoxal-induced senescence bears a unique molecular progression profile: an “early-stage” when AKT-FOXO3a-p27KIP1 pathway mediates cell-cycle arrest, and a “late-stage” senescence maintained by the p16INK4/pRb pathway. Moreover, we characterized the resulting secretory phenotype during early senescence by mass spectrometry in order to find new targets for senomorphic ingredients. Our study provides evidence that glyoxal can affect keratinocyte functions and act as a driver of human skin aging

碩士<br>大同大學<br>化學工程研究所碩士在職專班<br>91<br>ABSTRACT A novel bis(ether anhydride) monomer, 2’,5’-bis(3,4-dicarboxyphenoxy)-p-terphenyl dianhydride, was synthesized from the nitro displacement of 4-nitrophthalonitrile by the phenoxide ion of 2’,5’-dihydroxy-p-terphenyl, followed by alkaline hydrolysis of the intermediate bis(ether dinitrile) and cyclodehydration of the resulting bis(ether diacid). A series of new poly(ether imide)s bearing laterally attached p-terphenyl groups were prepared from the bis(ether anhydride) with various aromatic diamines via a conventional two-stage process that included ring-opening polyaddition to form the poly(amic acid)s followed by thermal or chemical imidization to the poly(ether imide)s. The inherent viscosities of the poly(amic acid) precursors were in the range of 0.62-1.26 dL/g. Most of the poly(ether imide)s obtained from both routes were soluble in polar organic solvents, such as N,N-dimethylacetamide. All the poly(ether imide)s could afford transparent, flexible, and strong films with high tensile strengths. The glass-transition temperatures of these poly(ether imide)s were recorded between 214 and 276 oC by DSC. The softening temperatures of all the poly(ether imide) films stayed in the 207-265 oC range by TMA. All polymers did not show significant decomposition before 500 oC in nitrogen or air atmosphere.

Aspartase has been purified from E. coli B cells using high performance liquid ion exchange chromatography. This procedure allows rapid purification of the enzyme with >80% recovery of total activity. The kinetic mechanism of aspartase, determined from initial velocity experiments, is best described by the equilibrium ordered addition of a divalent metal cation to free enzyme followed by binding of aspartate. Following interconversion of the central complex, NH(,4)('+) and fumarate are randomly released. Michaelis constants for each substrate are: 85 mM for NH(,4)('+), 0.17 mM for fumarate, 0.6-1.0 mM for aspartate and 9.0 (mu)M for Mg('2+). From the results of inhibition studies using structural analogues of aspartate, it was determined that aspartase recognizes the (beta)-carboxylate group of aspartate. The (alpha)-amino group contributes very little to the binding of aspartate to the enzyme. Compounds having an -OH group in addition to the (beta)-carboxylate had no effect on the rate of deamination of aspartate, suggesting a restricted geometry at the active site. S-2,3-Dicarboxy aziridine was found to be a potent competitive inhibitor of aspartase (K(,i) = 0.1 (mu)M) and fumarase (K(,i) = 0.08 (mu)M). The aziridine did not inactivate either enzyme nor did it exhibit any observable substrate activity. It is likely that it functions as a transition state analogue mimicking the carbanion intermediate found in the normal catalytic reaction. The aziridine inhibited fumarate utilization in ruptured but not intact mitochondria.

碩士<br>國立交通大學<br>應用化學系<br>91<br>As we know, the skeleton of α,β-unsaturated 1,4-dicarbonyl derivatives exist in many useful natural and medicinal compound. It is an interesting topic to study the syntheses of α,β-unsaturated 1,4-dicarbonyl derivatives. We try to create a new system to synthesize α,β-unsaturated 1,4-dicarbonyl derivatives, and it’s unrestricted by the method of furan ring opening. We use benzensulfinic acid sodium salt 1 as starting material, and get target compound 17-19, 36-37 that cut of sulfinyl group. We further discuss whether keto-amide endione can get oxa-cage compound.

博士<br>國立中正大學<br>化學暨生物化學研究所<br>99<br>In traditional manner the organic reaction means linear and stepwise processes in which isolation and purification of key intermediates, these processes usually leads in the reduction of yields which implies the efficiency of the process. On the other hand the domino process could form several bonds in single sequence without isolating the intermediates, changing the reaction conditions, or adding reagents, thus the efficient manner with respect to the stepwise reactions. Also it allows access to a number of complex molecular structures with high stereocontrol in an efficient, atom-economical fashion. Recently, domino reactions have been catalyzed by chiral organic molecules, “organocatalysts”, to provide a variety of complex structures in an efficient and splendid manner. Amine catalysts activate carbonyls by an iminium ion or an enamine formation method, iminium ion formation increases the electrophilicity of the carbonyl carbons, and access to electrophilic conjugate addition reactions, while enamine formation increases the nucleophilicity, and facilitates nucleophilic addition and substitutions reactions. This thesis represents the domino reactions; “Application of dicarbonyl compounds in stereoselective organocatalytic annulations reactions” by enamine-iminium or iminium-enamine activation methods. We further demonstrated their applications towards the synthesis of biologically active intermediates. The second chapter deals with the organocatalytic double Michael reactions of 7-oxohept-2-enoate to nitrostyrene. The first conjugate addition and subsequent intramolecular cyclization afforded the highly functionalized cyclohexane carboester with four stereogenic centers with high diastereoselectivity and high enantioselectivity (>99% ee). Some adducts were transformed into the intermediates of the synthesis of (-)-α- and (-)-β-lycorane. The third chapter deals with the domino double Michael reactions of ethyl (E)-7-oxohept-2-enoate and α, β-unsaturated aldehydes which provides highly functionalized cyclohexane derivatives with excellent diastereoselectivities (>20:1 dr) and enantioselectivities (>99% ee). And some of the adducts were transformed into the important skeletons. The fourth chapter deals with organocatalytic Michael reaction of glutaraldehyde or 5-oxohexanal and α, β-unsaturated aldehydes followed by the subsequent intramolecular aldol condensation provided 2-arylcyclohex-3-ene-1,3-dicarbaldehydes in high diastereoselectivity and high enantioselectivity (>99% ee).

No<br>A transition-metal-free efficient method for the preparation of 1,2,3-trisubstituted benzenes from bispropargyl alcohols and 1,3-dicarbonyl compounds has been developed. The reaction of bispropargyl alcohol with 1,3-dicarbonyl compound proceeds through [3,3]-rearrangement, 6π-electrocyclization, and unexpected Csp3−Csp2 regioselective σ-bond cleavage processes.