Redox-active cytotoxic diorganotin(IV) cycloalkylhydroxamate complexes with different ring sizes: Reduction behaviour and theoretical interpretation

Two series of new diorganotin(IV) cycloalkylhydroxamate complexes with different ring sizes (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), formulated as the mononuclear [R2Sn(HL)(2)] (1:2) (a, R=Bu-n and Ph) and the polymeric [R2SnL](n) (1:1) (b, R=Bu-n) compounds, were prepared and fully characterized. Single crystal X-ray diffraction for [(Bu2Sn)-Bu-n{C5H9C(O)NHO}(2)] (3a) discloses the cis geometry and strong intermolecular NH center dot center dot center dot O interactions. The in vitro cytotoxic activities of the complexes were evaluated against HL-60, Bel-7402, BGC-823 and KB human tumour cell lines, the greater activity concerning [(Bu2Sn)-Bu-n(HL)(2)] [HL=C3H5C(O)NHO (1a), C6H11C(O)NHO (4a)] towards BGC-823. The complexes undergo, by cyclic voltammetry and controlled-potential electrolysis, one irreversible overall two-electron cathodic process at a reduction potential that does not appear to correlate with the antitumour activity. The electrochemical behaviour of [R2Sn(C5H9C(O)NHO)(2)] [R=Bu-n (3a), Ph (7a)] was also investigated using density functional theory (DFT) methods, showing that the ultimate complex structure and the mechanism of its formation are R dependent: for the aromatic (R = Ph) complex, the initial reduction step is centred on the phenyl ligands and at the metal, being followed by a second reduction with Sn-O and Sn-C ruptures, whereas for the alkyl (R=Bu-n) complex the first reduction step is centred on one of the hydroxamate ligands and is followed by a second reduction with Sn-O bond cleavages and preservation of the alkyl ligands. In both cases, the final complexes are highly coordinative unsaturated Sn-II species with the cis geometry, features that can be of biological significance.

Comparative study of the biological behaviour in hamster of two isolates of leishmania characterized respectively as L. major-like and L. donovani

Hamster inoculated intraperitoneally with 1 x 10(7) parasites of L. donovani and L. major-like of the New World were studied in groups of 15, 30, 60 and 90 days of infection. The parasite load and density showed progressive increase with the evolution of the infection and was higher in the L. donovani groups than in the L. major-like groups. The L. major-like groups showed parasite density higher in the spleen than in the liver and was similar in both organs in L. donovani groups. The histopathology showed a diffuse marked hyperplasia and hypertrophy of the reticuloendothelial system with high parasitism in the L. donovani groups while there was focal involvement of these organs in L. major-like groups, forming nodules of macrophages that were scantly parasitised. The biological behaviour could be useful in the preliminary studies of Leishmania strain in regional laboratories and understanding the histopathology of lesions caused by different leishmania species.

Fucosyltransferase IX: characterization and biological role

α3/4-Fucosyltransferases (α3/4-FUTs) are glycosyltransferases (GTs) that catalyze the transfer of fucose in an α3/4-linkage onto the N-acetylglucosamine residue from acceptors containing the type II or type I (Galβ4/3GlcNAc, respectively) structures, thus synthesizing the fucosylated Lewis (Le) carbohydrate determinants. Fucosyltransferase IX (FUT9), the most recently identified member of the family, presents the higher divergence from the other FUTs and its sequence is the only highly conserved among species. FUT9 synthesizes the Lewisx (Lex) epitope (Galβ4(Fucα3)GlcNAc). Recent evidence has suggested that it is the enzyme responsible for the synthesis of Lex in the mouse brain. Lex expression has been described in glycoproteins, proteoglycans and glycolipids from the central nervous system (CNS) of diverse species, including rodents and humans.

Biological and morphological characteristics of Schistosoma mansoni from Ribeira Valley, State of São Paulo, Brazil: I - susceptibility of Biomphalaria tenagophila snail to sympatric S. mansoni strain

In the São Paulo State, Brazil, where the Biomphalaria tenagophila is the intermediate host, the Ribeira Valley is an important endemic schistosomiasis mansoni area. During last eleven years there has been intense control measures focusing on schistosomiasis. The efforts have been concentrated in the municipalities of Pedro de Toledo and Itariri. We determined the susceptibility of B. tenagophila to sympatric strain of S. mansoni, both recently isolated from Itariri field. In 1988, this strain was isolated and maintained in the experimental model: Swiss mice - sympatric B. tenagophila. The second generation of the worm was evaluated. The snail were divided in the three groups of 60 snails each. One group was exposed to 1 miracidium and other to 10. The third group was the control. The mortality and the shedding of cercariae were checked during 78 days. After that, the positive snails were observed until they ceased to shed cercariae. The exposed molluscs showed mortality rates of 23% and 31% and infection indexes were of 8% and 60% to 1 and 10 miracidia respectively. The mortality was of 22% in the control group. The periods of shedding cercariae in the two groups were 82 and 104 days. We can conclude that B. tenagophila is an effective intermediate host to the sympatric strain of S. mansoni sympatric strain

Silver coordination polymers with tri- and hexacyanoethyl-functionalized macrocyclic ligands

Tri-and hexa-cyanoethyl functionalized 17-(L-1) and 42-membered (L-2) macrocyclic compounds were obtained by [1 + 1] (for L-1) or [2 + 2] (for L-2) cyclocondensation of the corresponding dialdehyde and diethylenetriamine, followed by hydrogenation by KBH4 and subsequent cyano-functionalization with acrylonitrile. They react with silver nitrate, leading to the formation of [AgL1](NO3) (1) and of the metalorganic coordination polymers [Ag-2(NO3)(2)L-1](n) (2) and {[Ag2L2](NO3)(2)}(n) (3). The complexes were characterized by elemental analysis, H-1 NMR, C-13 NMR, IR spectroscopies, and ESI-MS; moreover, L-2, 1, 2 and 3 were also characterized by single crystal X-ray diffraction. The metal cation in 1 is pentacoordinated with a N3O2 coordination environment; in 2, the metal cations display N4O2 octahedral and N2O3 square-pyramid coordination and in 3 they are in square-planar N-4 sites. In 1, the ligand acts as a pentadentate chelator, and in the other two cases, the ligands behave as octadentate chelators in a 1 kappa N-3:kappa O-2,2 kappa N,3 kappa N,4 kappa N (in 2) or 1 kappa N-3,2 kappa N-3,3 kappa N,4 kappa N fashion (in 3). The cyanoethyl strands of the ligands are directly involved in the formation of the 2D frameworks of 2 and 3, which in the former polymer can be viewed as a net composed of hexametallic 36-membered macrocyclic rings and in the latter generates extra hexametallic 58-membered cyclic sets that form zig-zag layers. The thermal analytical and electrochemical properties of these silver complexes were also studied.

Y Trinuclear Cu-II structural isomers coordination, magnetism, electrochemistry and catalytic activity towards the oxidation of alkanes

The reaction of the Schiff base (3,5-di-tert-butyl-2-hydroxybenzylidene)-2-hydroxybenzohydrazide (H3L) with copper(II) nitrate, acetate or metaborate has led to the isomeric complexes [Cu-3(L)(2)(MeOH)(4)] (1), [Cu-3(L)(2)(MeOH)(2)]2MeOH (2) and [Cu-3(L)(2)(MeOH)(4)] (3), respectively, in which the ligand L exhibits dianionic (HL2-, in 1) or trianionic (L3-, in 2 and 3) pentadentate 1O,O,N:2N,O chelation modes. Complexes 1-3 were characterized by elemental analysis, IR spectroscopy, single-crystal X-ray crystallography, electrochemical methods and variable-temperature magnetic susceptibility measurements, which indicated that the intratrimer antiferromagnetic coupling is strong in the three complexes and that there exists very weak ferromagnetic intermolecular interactions in 1 but weak antiferromagnetic intermolecular interactions in both 2 and 3. Electrochemical experiments showed that in complexes 1-3 the Cu-II ions can be reduced, in distinct steps, to Cu-I and Cu-0. All the complexes act as efficient catalyst precursors under mild conditions for the peroxidative oxidation of cyclohexane to cyclohexyl hydroperoxide, cyclohexanol and cyclohexanone, leading to overall yields (based on the alkane) of up to 31% (TON = 1.55x10(3)) after 6 h in the presence of pyrazinecarboxylic acid.

Serological, electrophoretic and biological properties of Fasciola hepatica antigens

Fasciola hepatica somatic antigen, its partially purified fractions and excretion-secretion products were investigated as to serological, electrophoretic and biological properties. In a Sephadex G-100 column (SG-100), Fasciola hepatica total antigen (FhTA) gave 5 fractions, and SDS-PAGE analysis showed they were glycoproteins ranging from 14 to 94 kDa molecular weight (MW). When these fractions were analyzed by enzyme linked immunotransfer blot (EITB) and immunodiffusion in gel (ID) with serum from immunized rats with FhTA, the presence of different antigenic components was revealed. In the SDS-PAGE of excretor-secretor antigen (ESA), it was possible to observe peptides from 12 to 22 kDa, which were also present in FhTA. When the FhTA, its fractions and the ESA were analyzed by EITB with the immune rat serum (IRS), it was observed that only some fractions of the SG-100 shared antigens with the FhTA and ESA. Moreover, DTH and ITH responses were studied in FhTA immunized rats challenged with these different antigen components, revealing that the protein/carbohydrate ratio is important for inducing DTH response. The ESA was the most active component in the DTH and ITH response.

Biological activities and oil properties of Origanum glandulosum Desf: a review

Origanum glandulosum Desf. (Species endemic of North Africa: Tunisia and Algeria) is important medicinally as it has antimicrobial, antifungal, antioxidant, antibacterial, antithrombin, antimutagenic, angiogenic, antiparasetic and antihyperglycaemic activities. Phytochemical investigations of the species of this genus have resulted in the extraction of a number of important bioactive compounds. This emphasizes on the need of extensive study for reporting the additional information on the medicinal importance, the biological activities and properties of oil of other unattended species of Origanum glandulosum. © 2015 Springer-Verlag France.

Arylhydrazones of barbituric acid: synthesis, coordination ability and catalytic activity of their CoII, CoII/IIIand CuIIcomplexes toward peroxidative oxidation of alkanes

New ortho-substituted arylhydrazones of barbituric acid, 5-(2-(2-hydroxyphenyl)hydrazono) pyrimidine-2,4,6(1H,3H,5H)-trione (H4L1) and the sodium salt of 2-(2-(2,4,6-trioxotetra-hydropyrimidin-5(2H)-ylidene)hydrazinyl) benzenesulfonic acid (H4L2), [Na(H3L2)(mu-H2O)(H2O)(2)](2) (1), were used in the synthesis of Cu-II, Co-II and Co-II/III complexes, [Cu(H2L1)(H2O)(im)]center dot 3H(2)O (im = imidazole) (2), [Co(H2O)(6)] [Co(H2L1)(2)](2)center dot 8H(2)O (3), [Co(H2L2)(im)(3)] (4), [Cu(H2L2)(im)(2)]center dot H2O (5) and [Co(H2O)(6)][H3L2](2)center dot 8H(2)O (6). The complexes are water soluble and the mono-or di-deprotonated ligands display different coordination modes, depending on the synthetic conditions. The electrochemical behaviour of all the compounds was investigated by cyclic voltammetry and controlled potential electrolysis, revealing that the ligands are also redox active. All the compounds were evaluated as catalysts for the peroxidative (with H2O2) oxidation of cyclohexane at room temperature. The compounds 2 and 3 are the most active ones (yields up to 21% and TON up to 213 are achieved, in the presence of 3).

Novel coordination polymers with (Pyrazolato)-based tectons: catalytic activity in the peroxidative oxidation of alcohols and cyclohexane

Coupling five rigid or flexible bis(pyrazolato)based tectons with late transition metal ions allowed us to isolate 18 coordination polymers (CPs). As assessed by thermal analysis, all of them possess a remarkable thermal stability, their decomposition temperatures lying in the range of 340-500 degrees C. As demonstrated by N-2 adsorption measurements at 77 K, their Langmuir specific surface areas span the rather vast range of 135-1758 m(2)/g, in agreement with the porous or dense polymeric architectures retrieved by powder X-ray diffraction structure solution methods. Two representative families of CPs, built up with either rigid or flexible spacers, were tested as catalysts in (0 the microwave-assisted solvent-free peroxidative oxidation of alcohols by t-BuOOH, and (ii) the peroxidative oxidation of cydohexane to cydohexanol and cydohexanone by H2O2 in acetonitrile. Those CPs bearing the rigid spacer, concurrently possessing higher specific surface areas, are more active than the corresponding ones with the flexible spacer. Moreover, the two copper(I)-containing CPs investigated exhibit the highest efficiency in both reactions, leading selectively to a maximum product yield of 92% (and TON up to 1.5 x 10(3)) in the oxidation of 1-phenylethanol and of 11% in the oxidation of cydohexane, the latter value being higher than that granted by the current industrial process.

Trypanosoma cruzi strains: behavior after passage into authoctonous or foreign species of triatomine (biological and biochemical patterns)

The behavior of T. cruzi strains from S. Felipe - BA (19 SF, 21 SF and 22 SF) classified as Type II Zymodeme 2, was investigated after passage through the authoctonous (P. megistus) and foreign vectors (T. infestans and R. prolixus). For each strain Swiss mice were infected: I - with blood forms (control); II - with metacyclic forms (MF) from P. megistus; III - with MF from T. infestans; IV - with MF from R. prolixus. Inocula: MF from the three species of triatomine, 60 to 120 days after feeding in infected mice, adjusted to 10 4. Biological behavior in mice (parasitemia, morphology, mortality, virulence and pathogenicity) after passage through triatomine was compared with data from the same strain in control mice. Isoenzymic electrophoresis (ASAT, ALAT, PGM, GPI) were also performed after culture into Warren medium. The three strains maintained the isoenzyme profiles (zymodeme 2), in the control groups and after passages through different species of triatomine. Biological characterization disclosed Type II strains patterns for all groups. An increased virulence was observed with the 22 SF strain isolated from P. megistus and T. infestans and higher levels of parasitemia and predominance of slender forms in mice inoculated with the 19 SF and 21 SF from these same species. Results indicate that the passage through the two species T. infestans and P. megistus had a positive influence on the virulence of the regional strains of S. Felipe, regardless of being autocthonous (P. megistus) or foreign to the area (T. infestans).

Biological activity of well defined hydantoin derivatives on efflux pump systems of bacteria and cancer cells

A multi-resistência a antibióticos e medicamentos usados em quimioterapia é um dos grandes problemas com os quais as instituições de saúde se debatem hoje em dia. A acção provocada por bombas de efluxo é uma das suas causas. Estas bombas têm uma importância fundamental, uma vez que, ao expelirem todo o tipo de tóxicos para o exterior das células, também expelem medicamentos, fazendo com que estes não tenham o efeito desejado dentro delas. As bombas de efluxo são transportadores que se encontram nas membranas de todo o tipo de células. Existem dois grandes tipos de bombas de efluxo: as primárias e as secundárias. As primeiras conferem multi-resistência principalmente em células eucariotas, como as células do cancro em humanos, tendo como função a mediação da repulsa de substâncias tóxicas por intermédio da hidrólise de ATP. A primeira a ser descoberta e mais estudada destas bombas foi a ABCB1 que é o gene que codifica a glicoproteína-P (P de permeabilidade). Enquanto as secundárias, que são a maior fonte de multi-resistência em bactérias, promovem a extrusão de substâncias tóxicas através da força motriz de protões. Neste tipo de bombas são conhecidas quatro famílias principais, das quais uma das mais importantes é a superfamília RND, uma vez que inclui a bomba AcrAB-TolC, que é muito importante no metabolismo xenobiótico de bactérias Gramnegativas, nomeadamente a E.coli. Com o objectivo de reverter a multi-resistência, tanto em células eucariotas como procariotas, têm-se desenvolvido estratégias de combate que envolvem a descoberta de substâncias que inibam as bombas de efluxo. Assim sendo, ao longo dos tempos têm sido descobertas variadas substâncias que cumprem este objectivo. É o caso, por exemplo, dos derivados de fluoroquinolonas usados como inibidores de bombas de efluxo em bactérias ou do Tamoxifen, utilizado na terapia de pacientes com cancro da mama. Um dos grupos de substâncias estudados para o desenvolvimento de possíveis compostos que actuem como reversores de multi-resistência são os compostos derivados de hidantoínas. Estes, são conhecidos por possuírem uma grande variedade de propriedades bioquímicas e farmacológicas, sendo portanto usados para tratarem algumas doenças em humanos, como a epilepsia. Nestes, estão englobados compostos com actividade anti-convulsão que constitui a sua grande mais-valia e, dependente da substituição no anel que os constitui, uma grande variedade de outras propriedades farmacológicas como a anti-fungica, a anti-arritmica, a anti-viral, a anti-diabética ou por exemplo a antagonização de determinados receptores, como os da serotonina. Apesar de pouco usados em estudos experimentais para desenvolver substâncias anti-carcinogénicas, existem alguns estudos com este efeito. Objectivos: O presente projecto envolve o estudo de bombas de efluxo primárias e secundárias, em células eucariotas e procariotas, respectivamente. Em bactérias, foram usados quatro modelos experimentais: Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212, E. coli AG 100 e Salmonella Enteritidis NCTC 13349. Em células de cancro foram usadas, células T de linfoma de rato parentais e células T de linfoma de rato transfectadas com o gene humano MDR-1. O principal objectivo deste estudo foi a pesquisa de novos moduladores de bombas de efluxo presentes em bactérias e células do cancro, tentando assim contribuir para o desenvolvimento de novos agentes farmacológicos que consigam reverter a multi-resistência a medicamentos. Assim sendo foram testados trinta compostos derivados de hidantoínas: SZ-2, SZ-7, LL-9, BS-1, JH-63, MN-3, TD-7k, GG-5k, P3, P7, P10, P11, RW-15b, AD-26, RW-13, AD-29, KF-2, PDPH-3, Mor-1, KK-XV, Thioam-1, JHF-1, JHC-2, JHP-1, Fur-2, GL-1, GL-7, GL-14, GL-16, GL-18. Como forma de atingir estes objectivos, a actividade biológica dos trinta compostos derivados de hidantoínas foi avaliada nas quatro estirpes de bactérias da seguinte forma: foram determinadas as concentrações mínimas inibitórias dos trinta compostos como forma de definir as concentrações em que os compostos seriam utilizados. Os compostos foram posteriormente testadas com um método fluorométrico de acumulação de brometo de etídeo, que é um substrato comum em bombas de efluxo bacterianas, desenvolvido por Viveiros et al. A actividade biológica dos compostos derivados de hidantoínas nas células de cancro foi demonstrada por diferentes métodos. O efeito anti-proliferativo e citotóxico dos trinta compostos foi avaliado nas células T de linfoma de rato transfectadas com o gene humano MDR-1 pelo método de thiazolyl de tetrazólio (MTT). Como o brometo de etídeo também é expelido pelos transportadores ABC, estes compostos foram posteriormente testados com um método fluorométrico de acumulação de brometo de etídeo desenvolvido por Spengler et al nos dois diferentes tipos de células eucariotas. Resultados: A maioria dos compostos derivados de hidantoínas foi eficaz na modulação de bombas de efluxo, nas duas estirpes de bactérias Gram-negativas e nos dois diferentes tipos de células T de linfoma. Em contraste com estes resultados, nas duas estirpes de células Gram-positivas, a maioria dos compostos tiveram pouco efeito na inibição de bombas de efluxo ou até nenhum, em muitos dos casos. De uma maneira geral os melhores compostos nas diferentes estirpes de bactérias foram: Thioam-1, SZ-2, P3, Rw-15b, AD-26, AD-29, GL-18, GL-7, KF-2, SZ-7, MN-3, GL-16 e GL- 14. Foram portanto estes os compostos que provocaram maior acumulação de brometo de etídeo, inibindo assim com maior eficácia as bombas de efluxo. No presente estudo, a maioria dos compostos conseguiu inibir a resistência provocada pela bomba de efluxo ABCB1, tanto nas células parentais bem como nas células que sobre-expressam esta bomba, causando a acumulação de brometo de etídeo dentro das células. As células que sobreexpressam a bomba ABCB1 foram posteriormente testadas com citometria de fluxo que é a técnica padrão para pesquisa de inibidores de bombas de efluxo. Os compostos que foram mais efectivos na inibição da bomba ABCB1, causando assim maior acumulação de brometo de etídeo nas células que sobre-expressam esta bomba foram: PDPH-3, GL-7, KK-XV, AD-29, Thioam-1, SZ-7, KF-2, MN-3, RW-13, LL-9, P3, AD-26, JH-63 e RW- 15b. Este facto não corroborou totalmente os resultados da citometria de fluxo uma vez que os moduladores que provocaram maior inibição da bomba ABCB1 foram o MN-3, JH-63 e o BS-1, sendo que o último não foi seleccionado como um bom composto usando o método fluorométrico de acumulação de brometo de etídeo. Conclusão: Os compostos derivados de hidantoínas testados tiveram maior efeito nas estirpes de bactérias Gram-negativas do que nas Gram-positivas. Relativamente às células eucariotas, as estruturas mais activas apresentam substituintes aromáticos bem como alguns fragmentos aminicos terciários.

Modelling of the kinetics of municipal solid waste composting in full-scale mechanical-biological treatment plants

A thesis submitted in fulfilment of the requirements for the Degree of Doctor of Philosophy in Sanitary Engineering in the Faculty of Sciences and Technology of the New University of Lisbon

Vibroacoustic disease II: The biological and acoustical basis of low frequency noise induced pathology

Proceedings Institute of Acoustics (UK); vol. 25, nº2, p. 72-78.