Processos de preparação de complexos fosfínicos de rutênio contendo íon picolinato e/ou diiminas e/ou bifosfinas em sua estrutura, complexos fosfínicos de Rutênio obtidos pelos referidos processos e seus usos.

The invention relates to the synthesis and characterisation of ruthenium(II) phosphine complexes containing picolinate and/or diimine and/or biphosphine ions and having an outstanding pharmacological activity for inhibiting the growth of tuberculosis mycobacteria. These complexes can first be used in the chemical industry, and in the medium and long term, in the pharmaceutical industry. The invention also describes how the activity against tuberculosis bacillus was determined, and how the toxicity of the complexes against macrophage cells within which the tuberculosis bacillus grows was assessed.

Avaliação do desenvolvimento do sistema genital e da funçao reprodutiva da prole feminina de ratos Wistar expostos à cisplatina durante a peri-puberdade

Pós-graduação em Biologia Geral e Aplicada - IBB

Luminescent threat: toxicity of light stick attractors used in pelagic fishery

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Structural characterization of an etheno-2 '-deoxyguanosine adduct modified by tetrahydrofuran

The reaction of 2'-deoxyguanosine with the alpha,beta-unsaturated aldehydes trans-2-octenal, trans-2-nonenal, trans-2-decenal, trans,trans-2,4-nonadienal, and trans,trans-2,4-decadienal in THF gives rise to three novel adducts: 3-(2'-deoxy-beta-D-erythro-pentafuranosyl)-7-[3-hydroxy-1-(3(2'-deoxy-beta-D-erythro-pentafuranosyl)-3,5-dihydro-imidazo[1,2-alpha]purin-9-one-7-yl)-propyl] -3,5-dihydro-imidazo[1,2-alpha]purin-9-one (M) and 3-(2'-deoxy-beta-D-erythro-pentafuranosyl)-7-(tetrahydrofuran-2-yl)-3,5-dihydro-imidazo[1,2-alpha]purin-9-one (A8 and A9), which are not observed in the absence of THF. These adducts were isolated from in vitro reactions by reversed-phase HPLC and fully characterized on the basis of spectroscopic measurements. Adduct A7 consists of two 1,N-2-etheno-2'-deoxyguanosine (1,N-2-epsilondGuo) residues linked to a hydroxy-carbon side chain; adducts A8 and A9 are interconvertible 1,N-2-epsilondGuo derivatives bearing a THF moiety. The proposed reaction mechanism involves the electrophilic attack on 1,N-2-epsilondGuo by the carbonyl of 4-hydroxy-butanal, generated via ring opening of alpha-hydroxy-THF (THF-OH), yielding adducts A8 and A9. A further combination of these adducts with another 1,N-2-epsilondGuo produces the double adduct A7. These findings demonstrate that reactions of unsaturated aldehydes in the presence of THF produce novel condensation 1,N-2-epsilondGuo-THF adducts. Further studies would indicate the relevance of these adducts in THF toxicity.

Genes differentially expressed by Mycobacterium tuberculosis after exposure to ruthenium phosphinic compound and isoniazid

Background- The evaluation of the effects of new compounds and nonconventional anti-tuberculous drugs have grown and become increas-ingly more popular in recent years. Studies have shown anti-tuberculous activity for Ruthenium complexes, including organometallic com-pounds containing phosphine ligands such as picolinic acid generating great expectations and hopes. Methods- The Representational Difference Analysis (RDA) was applied in order to gain insight about differences in expression of Mycobacte-rium tuberculosis H37Rv exposed to [Ru(dppb)(pic)(bypy)] PF6 (SCAR1) and isoniazid (INH). Total RNA was extracted from the bacillus not exposed and exposed to SCAR1 and INH separately at concentration of MIC for 12 hours at 35°C. RDA was carried out and differentially expressed products were sequenced. Results- RDA-sequencing identified, for both compounds, orthologs that encode hypothetical and predict proteins. One related cell wall syn-thesis gene, identified by RDA, and genes related to INH target as inhA, katG and ahpC had their expression confirmed and quantified by real-time PCR. The gene encoding the cell wall associated hydrolase was induced 4.627 and 1.189, inhA 0.983 and 1.027, katG 1.111 and 1.345 and ahpC 1.063 and 1.039 fold after exposure to SCAR1 and INH respectively, compared to not exposed growth. Conclusion- The RDA brings, for the first time, directions to study related genes with metabolic pathways of SCAR1. RDA and Real-Time PCR highlight the idea that one of the SCAR1 interaction, in M tuberculosis may be in the cell wall biosynthesis considering the differential expression of a cell wall hydrolase and warrants further investigation.

Síntese de polímeros supramoleculares derivados dos ácidos palmítico e mirístico com meglumina e suas caracterizações em meio aquoso

Pós-graduação em Química - IQ

Investigation of Ground- and Excited-State Photophysical Properties of 5,10,15,20-Tetra(4-pyridyl)-21H,23H-porphyrin with Ruthenium Outlying Complexes

The present work employs a set of complementary techniques to investigate the influence of outlying Ru(II) groups on the ground- and excited-state photophysical properties of free-base tetrapyridyl porphyrin (H(2)TPyP). Single pulse and, pulse train Z-scan techniques used M association with laser flash photolysis, absorbance and fluorescence spectroscopy, and fluorescence decay measurements, allowed us to conclude that the presence of outlying Ru(II) groups causes significant changes on both electronic structure and vibrational properties of porphyrin. Such modifications take place mainly due to the activation of. nonradiative decay channels responsible for the emission, quenching, as well as by favoring some vibrational modes in the light absorption process, It is also observed that, differently from what happens when the Ru(II) is placed at the center of the macrocycle, the peripheral groups cause an increase of the intersystem crossing processes, probably due to the structural distortion of the ring that implies a worse spin orbit coupling, responsible for the intersystem crossing mechanism.

On the Reaction of Lupulones, Hops beta-Acids, with 1-Hydroxyethyl Radical

Lupulones, hops beta-acids, are one of the main constituents of the hops resin and have an important contribution to the overall bacteriostatic activity of hops during beer brewing. The use of lupulones as natural alternatives to antibiotics is increasing in the food industry and also in bioethanol production. However, lupulones are easy oxidizable and have been shown to be very reactive toward 1-hydroxyethyl radical with apparent bimolecular rate constants close to diffusion control k = 2.9 x 10(8) and 2.6 x 10(8) L mol(-1) s(-1) at 25.0 +/- 0.2 degrees C in ethanol water solution (10% of ethanol (v/v)) as probed by EPR and ESI-IT-MS/MS spin-trapping competitive kinetics, respectively. The free energy change for an electron-transfer mechanism is Delta G degrees = 106 kJ/mol as calculated from the oxidation peak potential experimentally determined for lupulones (1.1 V vs NHE) by cyclic voltammetry and the reported reduction potential for 1-hydroxyethyl radical. The major reaction products identified by LC-ESI-IT-MS/MS and ultrahigh-resolution accurate mass spectrometry (orbitrap FT-MS) are hydroxylated lupulone derivatives and 1-hydroxyethyl radical adducts. The lack of pH dependence for the reaction rate constant, the calculated free energy change for electron transfer, and the main reaction products strongly suggest the prenyl side chains at the hops beta-acids as the reaction centers rather than the beta,beta'-triketone moiety.

Both XPA and DNA polymerase eta are necessary for the repair of doxorubicin-induced DNA lesions

Doxorubicin (DOX) is an important tumor chemotherapeutic agent, acting mainly by genotoxic action. This work focus on cell processes that help cell survival, after DOX-induced DNA damage. In fact, cells deficient for XPA or DNA polymerase eta (pol eta, XPV) proteins (involved in distinct DNA repair pathways) are highly DOX-sensitive. Moreover, LY294002, an inhibitor of PIKK kinases, showed a synergistic killing effect in cells deficient in these proteins, with a strong induction of G2/M cell cycle arrest. Taken together, these results indicate that XPA and pol eta proteins participate in cell resistance to DOX-treatment, and kinase inhibitors can selectively enhance its killing effects, probably reducing the cell ability to recover from breaks induced in DNA. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Comparative Studies of the (Anti) Mutagenicity of Baccharis dracunculifolia and Artepillin C by the Bacterial Reverse Mutation Test

Baccharis dracunculifolia is a plant native from Brazil, commonly known as 'Alecrim-do-campo' and 'Vassoura' and used in alternative medicine for the treatment of inflammation, hepatic disorders and stomach ulcers. Previous studies reported that artepillin C (ArtC, 3-{4-hydroxy-3,5-di(3-methyl-2-butenyl)phenyl}-2(E)-propenoic acid), is the main compound of interest in the leaves. This study was undertaken to assess the mutagenic effect of the ethyl acetate extract of B. dracunculifolia leaves (Bd-EAE: 11.4-182.8 mu g/plate) and ArtC (0.69-10.99 mu g/plate) by the Ames test using Salmonella typhimurium strains TA98, TA97a, TA100 and TA102, and to compare the protective effects of Bd-EAE and ArtC against the mutagenicity of a variety of direct and indirect acting mutagens such as 4-nitro-O-phenylenediamine, sodium azide, mitomycin C, benzo[a]pyrene, aflatoxin B1, 2-aminoanthracene and 2-aminofluorene. The mutagenicity test showed that Bd-EAE and ArtC did not induce an increase in the number of revertant colonies indicating absence of mutagenic activity. ArtC showed a similar antimutagenic effect to that of Bd-EAE in some strains of S. typhimurium, demonstrating that the antimutagenic activity of Bd-EAE can be partially attributed to ArtC. The present results showed that the protective effect of whole plant extracts is due to the combined and synergistic effects of a complex mixture of phytochemicals, the total activity of which may result in health benefits.

Exploring the intrinsic polar [4?+?2+] cycloaddition reactivity of gaseous carbosulfonium and carboxonium ions

Gas-phase reactions of model carbosulfonium ions (CH3-S+?=?CH2; CH3CH2-S+?=?CH2 and Ph-S+?=?CH2) and an O-analogue carboxonium ion (CH3-O+?=?CH2) with acyclic (isoprene, 1,3-butadiene, methyl vinyl ketone) and cyclic (1,3-cyclohexadiene, thiophene, furan) conjugated dienes were systematically investigated by pentaquadrupole mass spectrometry. As corroborated by B3LYP/6-311?G(d,p) calculations, the carbosulfonium ions first react at large extents with the dienes forming adducts via simple addition. The nascent adducts, depending on their stability and internal energy, react further via two competitive channels: (1) in reactions with acyclic dienes via cyclization that yields formally [4?+?2+] cycloadducts, or (2) in reactions with the cyclic dienes via dissociation by HSR loss that yields methylenation (net CH+ transfer) products. In great contrast to its S-analogues, CH3-O+?=?CH2 (as well as C2H5-O+?=?CH2 and Ph-O+?=?CH2 in reactions with isoprene) forms little or no adduct and proton transfer is the dominant reaction channel. Isomerization to more acidic protonated aldehydes in the course of reaction seems to be the most plausible cause of the contrasting reactivity of carboxonium ions. The CH2?=?CH-O+?=?CH2 ion forms an abundant [4?+?2+] cycloadduct with isoprene, but similar to the behavior of such alpha,beta-unsaturated carboxonium ions in solution, seems to occur across the C?=?C bond. Copyright (c) 2012 John Wiley & Sons, Ltd.

Organocatalytic asymmetric mannich-type reactions: an easy approach to optically active amine derivatives

The topics I came across during the period I spent as a Ph.D. student are mainly two. The first concerns new organocatalytic protocols for Mannich-type reactions mediated by Cinchona alkaloids derivatives (Scheme I, left); the second topic, instead, regards the study of a new approach towards the enantioselective total synthesis of Aspirochlorine, a potent gliotoxin that recent studies indicate as a highly selective and active agent against fungi (Scheme I, right). At the beginning of 2005 I had the chance to join the group of Prof. Alfredo Ricci at the Department of Organic Chemistry of the University of Bologna, starting my PhD studies. During the first period I started to study a new homogeneous organocatalytic aza-Henry reaction by means of Cinchona alkaloid derivatives as chiral base catalysts with good results. Soon after we introduced a new protocol which allowed the in situ synthesis of N-carbamoyl imines, scarcely stable, moisture sensitive compounds. For this purpose we used α-amido sulfones, bench stable white crystalline solids, as imine precursors (Scheme II). In particular we were able to obtain the aza-Henry adducts, by using chiral phase transfer catalysis, with a broad range of substituents as R-group and excellent results, unprecedented for Mannich-type transformations (Scheme II). With the optimised protocol in hand we have extended the methodology to the other Mannich-type reactions. We applied the new method to the Mannich, Strecker and Pudovik (hydrophosphonylation of imines) reactions with very good results in terms of enantioselections and yields, broadening the usefulness of this novel protocol. The Mannich reaction was certainly the most extensively studied work in this thesis (Scheme III). Initially we developed the reaction with α-amido sulfones as imine precursors and non-commercially available malonates with excellent results in terms of yields and enantioselections.3 In this particular case we recorded 1 mol% of catalyst loading, very low for organocatalytic processes. Then we thought to develop a new Mannich reaction by using simpler malonates, such as dimethyl malonate.4 With new optimised condition the reaction provided slightly lower enantioselections than the previous protocol, but the Mannich adducts were very versatile for the obtainment of β3-amino acids. Furthermore we performed the first addition of cyclic β-ketoester to α-amido sulfones obtaining the corresponding products in good yield with high level of diastereomeric and enantiomeric excess (Scheme III). Further studies were done about the Strecker reaction mediated by Cinchona alkaloid phase-transfer quaternary ammonium salt derivatives, using acetone cyanohydrin, a relatively harmless cyanide source (Scheme IV). The reaction proceeded very well providing the corresponding α-amino nitriles in good yields and enantiomeric excesses. Finally, we developed two new complementary methodologies for the hydrophosphonylation of imines (Scheme V). As a result of the low stability of the products derived from aromatic imines, we performed the reactions in mild homogeneous basic condition by using quinine as a chiral base catalyst giving the α-aryl-α-amido phosphonic acid esters as products (Scheme V, top).6 On the other hand, we performed the addition of dialkyl phosphite to aliphatic imines by using chiral Cinchona alkaloid phase transfer quaternary ammonium salt derivatives using our methodology based on α-amido sulfones (Scheme V, bottom). The results were good for both procedures covering a broad range of α-amino phosphonic acid ester. During the second year Ph.D. studies, I spent six months in the group of Prof. Steven V. Ley, at the Department of Chemistry of the University of Cambridge, in United Kingdom. During this fruitful period I have been involved in a project concerning the enantioselective synthesis of Aspirochlorine. We provided a new route for the synthesis of a key intermediate, reducing the number of steps and increasing the overall yield. Then we introduced a new enantioselective spirocyclisation for the synthesis of a chiral building block for the completion of the synthesis (Scheme VI).

Microwave-Mediated Hetero Diels-Alder reaction: Synthesis of biologically active compounds

Heterocyclic compounds represent almost two-thirds of all the known organic compounds: they are widely distributed in nature and play a key role in a huge number of biologically important molecules including some of the most significant for human beings. A powerful tool for the synthesis of such compounds is the hetero Diels-Alder reaction (HDA), that involve a [4+2] cycloaddition reaction between heterodienes and suitable dienophiles. Among heterodienes to be used in such six-membered heterocyclic construction strategy, 3-trialkylsilyloxy-2-aza-1,3-dienes (Fig 1) has been demonstrated particularly attractive. In this thesis work, HDA reactions between 2-azadienes and carbonylic and/or olefinic dienophiles, are described. Moreover, substitution of conventional heating by the corresponding dielectric heating as been explored in the frame of Microwave-Assisted-Organic-Synthesis (MAOS) which constitutes an up-to-grade research field of great interest both from an academic and industrial point of view. Reaction of the azadiene 1 (Fig 1) will be described using as dienophiles carbonyl compounds as aldehyde and ketones. The six-membered adducts thus obtained (Scheme 1) have been elaborated to biologically active compounds like 1,3-aminols which constitutes the scaffold for a wide range of drugs (Prozac®, Duloxetine, Venlafaxine) with large applications in the treatment of severe diseases of nervous central system (NCS). Scheme 1 The reaction provides the formation of three new stereogenic centres (C-2; C-5; C-6). The diastereoselective outcome of these reactions has been deeply investigated by the use of various combination of achiral and chiral azadienes and aliphatic, aromatic or heteroaromatic aldehydes. The same approach, basically, has been used in the synthesis of piperidin-2-one scaffold substituting the carbonyl dienophile with an electron poor olefin. Scheme 2 As a matter of fact, this scaffold is present in a very large number of natural substances and, more interesting, is a required scaffold for an huge variety of biologically active compounds. Activated olefins bearing one or two sulfone groups, were choose as dienophiles both for the intrinsic characteristic flexibility of the “sulfone group” which may be easily removed or elaborated to more complex decorations of the heterocyclic ring, and for the electron poor property of this dienophiles which makes the resulting HDA reaction of the type “normal electron demand”. Synthesis of natural compounds like racemic (±)-Anabasine (alkaloid of Tobacco’s leaves) and (R)- and (S)-Conhydrine (alkaloid of Conium Maculatum’s seeds and leaves) and its congeners, are described (Fig 2).

Synthese und Charakterisierung neuer funktionalisierter Mono- und Bis-tetrahydropyrrolo[3,4-b]carbazole als potentielle DNA-Liganden

Synthese und Charakterisierung neuer funktionalisierter Mono- und Bis-tetrahydro-pyrrolo[3,4-b]carbazole als potentielle DNA-Liganden In der Carbazol-Chemie sollen neue anellierte Verbindungen mit potentieller DNA-Affinität und damit verbundener Antitumoraktivität entwickelt werden. Auf molekularer Ebene sind DNA-Interkalation oder DNA-Rinnenbindung zu erwarten. Darauf aufbauend wurden in Anlehnung an literaturbekannte Cytostatika Mono- und Bis-tetrahydropyrrolo[3,4-b]carbazole synthetisiert, die zur Entwicklung neuer Leitstrukturen bzw. -substanzen beitragen können.In der vorliegenden Arbeit wurde als synthetische Schlüsselreaktion die in unserem Arbeitkreis etablierte Indol-2,3-chinodimethan-Diels-Alder-Reaktion mit geeigneten cyclischen Mono- und Bismaleinimiden als Dienophilen weiterführend genutzt. Auf Grund des Aufbaus von künftigen Struktur-Wirkungsbeziehungen wurden variable Linker zwischen die beiden zu verbindenden Pyrrolotetrahydrocarbazole eingeführt. Diese waren aliphatischer und diamidischer Natur. Diamidische Strukturelemente wurden im Hinblick auf die Entwicklung neuer Peptidomimetika eingeführt. Deren Synthese gelang zum einen über die gemischte Säureanhydrid-Methode und zum anderen über die Azolid-Methode. Die Struktursicherung der als Cycloaddukte erhaltenen Tetrahydrocarbazole erfolgte mittels Standardverfahren (1D-, 2D-NMR-, IR-Spektroskopie und Massenspektrometrie).Enantiomere bzw. Diastereomere chiraler Wirkstoffe unterscheiden sich stark in ihren pharmakologischen Eigenschaften, deshalb müssen Verfahren entwickelt werden, um diese Substanzen gegebenenfalls auch in enantiomerenreiner Form darstellen zu können. Die Racemate der Monotetrahydrocarbazole und die Racemate sowie die dazu diastereomeren meso-Formen der Bistetrahydrocarbazole, die bei der Reaktion entstehen, konnten erstmals mittels chiraler HPLC analytisch getrennt werden.In einer der Synthese ergänzten theoretischen Studie wurde Computer-Molecular-Modelling zur Problematik der Diels-Alder-Reaktion durchgeführt, außerdem wurden kraftfeld-mechanische Berechnungen zur Konformationsanalyse der 'einfachen' Monotetrahydro-carbazole herangezogen und darauf aufbauend schließlich einfache DNA-Docking-Experimente zur ersten Abschätzung des DNA-Binde-Verhaltens der synthetisierten Verbindungen vorgenommen.

Design and development of new green catalytic methodologies for the synthesis of enantiomerically enriched molecules

The following Ph.D work was mainly focused on catalysis, as a key technology, to achieve the objectives of sustainable (green) chemistry. After introducing the concepts of sustainable (green) chemistry and an assessment of new sustainable chemical technologies, the relationship between catalysis and sustainable (green) chemistry was briefly discussed and illustrated via an analysis of some selected and relevant examples. Afterwards, as a continuation of the ongoing interest in Dr. Marco Bandini’s group on organometallic and organocatalytic processes, I addressed my efforts to the design and development of novel catalytic green methodologies for the synthesis of enantiomerically enriched molecules. In the first two projects the attention was focused on the employment of solid supports to carry out reactions that still remain a prerogative of omogeneous catalysis. Firstly, particular emphasis was addressed to the discovery of catalytic enantioselective variants of nitroaldol condensation (commonly termed Henry reaction), using a complex consisting in a polyethylene supported diamino thiopene (DATx) ligands and copper as active species. In the second project, a new class of electrochemically modified surfaces with DATx palladium complexes was presented. The DATx-graphite system proved to be efficient in promoting the Suzuki reaction. Moreover, in collaboration with Prof. Wolf at the University of British Columbia (Vancouver), cyclic voltammetry studies were reported. This study disclosed new opportunities for carbon–carbon forming processes by using heterogeneous, electrodeposited catalyst films. A straightforward metal-free catalysis allowed the exploration around the world of organocatalysis. In fact, three different and novel methodologies, using Cinchona, Guanidine and Phosphine derivatives, were envisioned in the three following projects. An interesting variant of nitroaldol condensation with simple trifluoromethyl ketones and also their application in a non-conventional activation of indolyl cores by Friedel-Crafts-functionalization, led to two novel synthetic protocols. These approaches allowed the preparation of synthetically useful trifluoromethyl derivatives bearing quaternary stereocenters. Lastly, in the sixth project the first γ-alkylation of allenoates with conjugated carbonyl compounds was envisioned. In the last part of this Ph.D thesis bases on an extra-ordinary collaboration with Prof. Balzani and Prof. Gigli, I was involved in the synthesis and characterization of a new type of heteroleptic cyclometaled-Ir(III) complexes, bearing bis-oxazolines (BOXs) as ancillary ligands. The new heteroleptic complexes were fully characterized and in order to examine the electroluminescent properties of FIrBOX(CH2), an Organic Light Emitting Device was realized.