No description available.

The decomposition of three phenyl-substituted 1,2-dithiolium salts, 3,5-diphenyl-, 3-phenyl- and 4-phenyl- in aqueous, ethanol and DMSO solutions have been examined. With bases of the type hydroxide, ethoxide, DMSO, and acetate, the 1,2-dithiolium ion formed adducts reversibly. Orders of adduct stability were determined in ethanol and water. Many of the adducts were unstable and decomposed to monothio-(beta)-dicarbonyls. The monothio-(beta)-dicarbonyls were in turn unstable and decomposed in aqueous media to the corresponding-(beta)-diketone in the case of the monothiodibenzoylmethane. / Reaction of the 1,2-dithiolium ions with sodium sulphide or sodium borohydride led to dithio-(beta)-dicarbonyls. These species were unstable and decomposed to monothio-(beta)-dicarbonyls in the presence of water. It was possible to observe the formation of metal chelates of monothio- and dithio-(beta)-dicarbonyls in DMSO for several systems. Metal ion and ligand stability orders were established. / Chelates of dithio-(beta)-dicarbonyls decomposed to monothio-(beta)-dicarbonyls in the presence of trace amounts of water. Monothio-(beta)-dicarbonyl chelates were also sensitive to water with dibenzoylmethane produced from monothiodibenzoylmethane chelate decomposition. / Mechanisms for 1,2-dithiolium ion decomposition in the presence and absence of metal ions have been proposed.

No description available.

No description available.

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 / 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. / 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. / 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 / TESIS

Esta tese consiste do estudo de reações de ciclofuncionalização de compostos β-enamino carbonílicos e β-dicarbonílicos, contendo uma cadeia alquenílica nas posições α ou γ. Os eletrófilos empregados para este fim foram: iodo, brometo de fenilselenenila e tricloreto de p-metóxifeniltelurio. Os iodo-β-enamino ésteres e cetonas cíclicas, após desidroiodação mediada por base, levaram à formação dos correspondentes pirróis, indóis e aminobenzofuranos. A ciclização dos β-ceto ésteres e β-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 β-dicarbonílicos. / This thesis presents a study of the cyclofunctionalization of β-enamino carbonyl and β-dicarbonyl compounds, substituted by an alkenyl group at the α or γ positions. Iodine, phenyl-selenenyl bromide and p-methoxyphenyltellurium trichloride were employed as the electrophilic reagent. The cyclic iodo-β-enamino esters and ketones, after base-promoted dehydroiodination, led to the corresponding pyrroles, indoles and aminobenzofurans. The cyclization of the β-keto esters and β-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 β-dicarbonyl substrates.

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 / #945 / , &amp / #946 / -unsaturated carbonyl compounds.

Esta tese consiste do estudo de reações de ciclofuncionalização de compostos β-enamino carbonílicos e β-dicarbonílicos, contendo uma cadeia alquenílica nas posições α ou γ. Os eletrófilos empregados para este fim foram: iodo, brometo de fenilselenenila e tricloreto de p-metóxifeniltelurio. Os iodo-β-enamino ésteres e cetonas cíclicas, após desidroiodação mediada por base, levaram à formação dos correspondentes pirróis, indóis e aminobenzofuranos. A ciclização dos β-ceto ésteres e β-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 β-dicarbonílicos. / This thesis presents a study of the cyclofunctionalization of β-enamino carbonyl and β-dicarbonyl compounds, substituted by an alkenyl group at the α or γ positions. Iodine, phenyl-selenenyl bromide and p-methoxyphenyltellurium trichloride were employed as the electrophilic reagent. The cyclic iodo-β-enamino esters and ketones, after base-promoted dehydroiodination, led to the corresponding pyrroles, indoles and aminobenzofurans. The cyclization of the β-keto esters and β-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 β-dicarbonyl substrates.

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) / 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) / Orientador: Iguatemy Lourenço Brunetti / Coorientador: Valdecir Farias Ximenes / Banca: Olga Maria mascarenhas de Faria Oliveira / Banca: Chung Man Chin / Banca: Antonio Cardozo dos Santos / Banca: Mariza Pires de Melo / Doutor

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.