Ftalocianina de alumínio-cloro (AlClPc) é um fotossensibilizador de segunda geração em terapia fotodinâmica (TFD) caracterizado por seu caráter anfifílico e tendência de auto-agregação em meio aquoso, o que prejudica seu potencial de aplicação. O aCHC é um substrato de transportadores de monocarboxilato (MCT) superexpresso em células de MCF-7. Objetivando a solubilização da AlClPc e aumento de internalização em tecidos neoplásicos nos propomos aqui o uso de DSPC e DOPC em diferentes proporções para formar vesículas lipidicas mistas (LV) na presença de aCHC como sistemas veiculadores de fármaco. Lv foi preparado pelo método de injeção etanólica e formou vesículas de dimensões nanométricas (aproximadamente 100 nm) com bom índice de polidispersão, valores negativos de potencial zeta e estáveis em meio aquoso por mais de 50 dias. AlClPc se complexou com o fosfato das LV o que conferiu uma localização interfacial às moléculas de AlClPc como demonstrado pelos resultados de supressão de fluorescência. Medidas de anisotropia, fluorescência estática e resolvida no tempo corroboram com estes resultados e demonstram que a auto-agregação da AlClPc ocorre mesmo em lipossomas. Entretanto, a veiculação da AlClPc por LV em carcinoma de células escamosas oral (OSCC) levou a um processo de desagregação demonstrado por (FLIM). Este incrível comportamento é novo e aumenta o conhecimento científico sobre o mecanismo intracelular de ação de fotossensibilizadores em TFD. Em TFD, ambos os sistemas LVIII+AlClPc e LVIII+AlClPc+aCHC não apresentaram toxicidade no escuro no período de incubação de 3 h com as concentrações de lipídios, AlClPc e aCHC iguais a 0,15 mmol/L, 0,5 umol/L e 10,0 umol/L, respectivamente. De maneira inesperada, o sistema LVIII+AlClPc foi mais eficiente em TFD que o sistema LVIII+AlClPc+aCHC, devido ao caráter antioxidante do aCHC. Estes resultados abrem uma nova perspectiva do potencial uso de LV-AlClPc para o tratamento fotodinâmico. / Aluminum phthalocyanine chloride (AlClPc) is a second-generation photodynamic therapy (PDT) photosensitizer characterized for its high hydrophobicity and self-aggregation tendency in aqueous media, which hampers its potential application. The aCHC is a monocarboxylate transporter substrate (MCT) overexpressed in MCF-7 line cell. Aiming at AlClPc solubilization and uptake increase we proposed here the use of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) at different proportions to form mixed lipid vesicles (LV) in presence of aCHC as a drug delivery system. LV were prepared by ethanol injection method and formed nano-sized vesicles (about 100 nm) with suitable polydispersity index, negative zeta potential, and stable in aqueous medium for at least 50 days. AlClPc strongly interacts with LV (high binding constant values), especially due to aluminum-phosphate specific interactions, which gives a surface localization to AlClPc molecules as demonstrated by fluorescence quenching data. Anisotropy, static and time-resolved fluorescence measurements corroborated with these results and demonstrated that AlClPc self-aggregation occurred even in the liposomes. However, formulation uptake by oral squamous cell carcinoma (OSCC) the AlClPc suffered a disaggregation process demonstrated by fluorescence life-time imaging microscopy. This amazing behavior is new and increases the scientific knowledge about the intracellular mechanism of action of PDT photosensitizers. In PDT, both systems LVIII+AlClPc e LVIII+AlClPc+aCHC did not show toxicity in the dark at 3 h incubation period with lipid, AlClPc, and aCHC concentrations equal at 0,15 mmol/L, 0,5 umol/L, and 10,0 umol/L, respectively. Unexpectedly, the system LVIII+AlClPc was more effective in PDT that the LVIII+AlClPc+aCHC, devido ao caráter antioxidante do aCHC due to the antioxidant character of aCHC. These results open a new perspective to the potential use of ALClPc-LV formulations for photodynamic treatment.

Neste trabalho investigamos a influência de alquiltio grupos sobre a basicidade e frequência de estiramento do ciano grupo de nitrilas alifáticas. Com esta finalidade foi estudada uma grande série de nitrilas alquiltio-substituidas em posição α, β γ, e δ, além de nitrilas não substituídas, incluídas para efeito de comparação. A série completa compõe-se dos seguintes compostos: acetonitrila, propionitrila, butironitrila, valeronitrila, hexanonitrila, heptanonitrila, octanonitrila, isobutironitrila, 2-metilvaleronitrila, pivalonitrila, 2,2\'-dimetilvaleronitrila, metiltioacetonitrila, α-metiltiopropionitrila, etiltioacetonitrila, α-etiltiopropionitrila, α-etiltioisobutironitrila, α-terc-butiltioacetonitrila, β-etiltiopropionitrila, β-etiltiobutironitrila, γ-etiltiobutironitrila e δ-etiltiovaleronitrila. É apresentada uma revisão bibliográfica na qual são abordados aspectos de estrutura, características espectrais e habilidade de formação de ponte de hidrogênio do ciano grupo de nitrilas, além de serem relatados trabalhos concernentes à auto-associação e momento dipolar de tais compostos. São fornecidos os dados de medidas de deslocamentos da frequência do grupo hidroxila do fenol e p-clorofenol (Δvo(OH)) em complexo 1:1 com as nitrilas estudadas, em tetracloreto de carbono, pelo emprego da espectroscopia no infravermelho. São apresentadas as frequências de estiramento do ciano grupo (vo (CN)) das mesmas nitrilas, em tetracloreto de carbono. São descritas as sínteses de algumas das nitrilas da série estudada, a saber: hexanonitrila, heptanonitrila, 2-metilvaleronitrila, 2,2\'-dimetilvaleronitrila, etiltioacetonitrila, α-etiltioisobutironitrila e γ-etiltiobutironitrila. Feita uma análise dos resultados das medidas realizadas, conclue-se que: 1) as nitrilas α-alquiltio-substituídas apresentam uma diminuição da basicidade e uma diminuição da frequência de estiramento do ciano grupo, com relação aos compostos análogos não substituídos; 2) as nitrilas &#946-etiltio-substituídas apresentam uma ligeira diminuição de basicidade em comparação com os compostos não substituídos correspondentes; 3) a introdução de um etiltio grupo nas posições γ e δ não produz qualquer alteração na basicidade do ciano grupo. Urna discussão é apresentada, focalizando-se a validade dos resultados de basicidade obtidos, assim como a sua atribuição. É eliminada a possibilidade da competição do átomo de enxofre na medida de basicidade do ciano grupo. São excluídas, também, as hipóteses de o impedimento estérico e o efeito indutivo do enxofre serem os únicos efeitos responsáveis pela diminuição de basicidade do ciano grupo, observada em β-alquiltio-nitrilas. Os resultados relatados para as α-, β-, γ-e δ-alquiltio-nitrilas, investigadas pelo emprego de sistema ternário, são comparados com os anteriormente obtidos por B.Wladislaw e col, em sistema ternário. Observa-se concordância no caso de nitrilas α-alquiltio-substituídas, mas não no de nitrilas com enxofre em posições mais afastadas, para as quais, em sistema binário, foi relatado um aumento de basicidade. Discutem-se as divergências observadas, sugerindo-se a possibilidade da ocorrência, no caso de sistema binário, de uma associação intra ou intermolecular envolvendo o enxofre e o ciano-grupo. Finalmente, é sugerida a interação entre enxofre e ciano grupo como provável causa da diminuição de basicidade em α-alquiltio-nitrilas. É aventada a hipótese de que a ligeira diminuição de basicidade em β-etiltio-nitrilas, observada em sistema ternário, seja proveniente do efeito indutivo do enxofre. / This thesis investigates the influence of alkylthio-groups on the basicities and stretching frequencies of the cyano-group of aliphatic nitriles. A large series of alkylthio- and unsubstituted nitriles was studied, including the following compounds: acetonitrile, propionitrile, butyronitrile, valeronitrile, capronitrile, heptanenitrile, octanenitrile, isobutyronitrile, 2-methylvaleronitrile, trimethylacetonitrile, 2,2\'-dimethylvaleronitrile, methylthioacetonitrile, α-methylthiopropionitrile, ethylthioacetonitrile, α-ethyl-thiopropionitrile, α-ethylthioisobutyronitrile, α-tert-butylthioacetonitrile, β.ethylthiopropionitrile, β-ethylthiobutyronitrile, γ-ethylthiobutyronitrile and &#948-ethylthiovaleronitrile. The thesis contains: A literature review on the structure, polarity and hydrogen bonding ability of the cyano-group of aliphatic nitriles, as well as self-association and dipolar moments of the same compounds. The data of relative basicities (Δvo(OH)) of the cyano-group as measured by i.r. shifts of OH stretching vibration of phenol and p-chlorophenol associated to the above mentioned nitriles (1:1), in carbon tetrachloride. The stretching frequencies (vo (CN)) of the cyano-group for the same nitriles, in carbon tetrachloride. The syntheses of the following compounds: capronitrile, heptanenitrile, 2-methylvaleronitrile, 2,2\'-dimethylvaleronitrile, ethylthioacetonitrile, α-ethlthioisobutyronitrile and γ-ethylthiobutyronitrile. The Δvo(OH) measurements show that: 1) the α-alkylthio-nitriles are less basic than the corresponding unsubstituted nitriles; 2) there is a slight decrease of the cyano-group basicity when the β-methylene-group is replaced by a sulphur atom; 3) the nitriles, in which sulphur atom and cyano-group are apart by three or four methylene-groups, do not undergo any change in the basicity. Several aspects are discussed in the light of the obtained data. Thus, evidences are provided that the decrease of basicity observed is a measure of the cyano-group basicity, without any competition of the sulphur atom. The hypotheses of steric hindrance and inductive effect as responsible for the decrease of the cyano-group basicity in the α-alkylthio-nitriles are excluded. The basicity data obtained for α-, β-, γ- and δ-alkylthio-nitriles, in ternary system, are compared with those reported, previously, by B.Wladislaw et al., for binary system. While our results for the &#945-derivatives are in accord with the previous ones, those for the nitriles with sulphur further removed from the cyano-group are contrasting. The increase of basicity for the latter compounds, observed previously, is tentatively explained by intra- or intermolecular association involving the cyano-group and sulphur atom. Finally, an interaction between cyano-group and sulphur is suggested as responsible for the decrease of basicity in the α-alkylthio-nitriles. The slight decrease of basicity, observed for the β-derivatives, is suggested to be best explained as due to the inductive effect of sulphur atom.

No description available.

No description available.

The kinetic and mechanistic features of a new series ofplatinum-thallium cyano compounds containing a direct andunsupported by ligands metal-metal bond have been studied insolution, using standard mix–and–measurespectrophotometric technique and stopped–flow method.These reactions are interpreted as oxidative addition of the cspecies to the square planar Pt(CN)42-complex. Each of these processes was found to befirst-order in Pt(CN)42-, the corresponding TIIIIcomplex and a cyanide ion donating species whichacts as a catalyst. Both di- and trinuclear complexes werestudied, and the kinetically significant thallium complexes intheir formation and the catalytically active cyanide sourcesare as follows: [(CN)5PtTl(CN)3]3-: Tl(CN)4–(alkaline region), Tl(CN)3(slightly acidic region) and CN–; [(CN)5Pt–Tl(CN)]–: Tl(CN)2+and Tl(CN)2+; [(CN)5Pt–Tl–Pt(CN)5]3-: [(CN)5Pt–Tl(CN)]–and HCN. Appropriatemechanisms were postulated for the overall reactions in allcases, which include i) metal–metal bond formation stepand ii) coordination of an axial cyanide ion to the platinumcenter. Two experimentally indistinguishable kinetic modelswere proposed for the formation of the dinuclear complexeswhich are different in the sequence of the two steps. In thecase of the trinuclear complex, experimental evidence isavailable to exclude one of the alternative reaction paths, andit was proven that the metal–metal bond formation precedesthe axial cyanide coordination. The cyanide ligands coordinated to TIIIIin the Pt–Tl complexes could be replacedsuccessfully with aminopolycarboxylates e.g.: mimda2-, nta3-, edta4-. The [(CN)5Pt–Tl(edta)]4-complex, with a direct metal–metal bond hasbeen prepared in solution by two different reactions: a)dissolution of [(CN)5Pt–Tl](s) in an aqueous solution of edta, b)directly from Pt(CN)42-and Tl(edta)(CN)2-. The decomposition reaction is greatlyaccelerated by cyanide and significantly inhibited by edta. Itproceeds through the [(CN)5Pt–Tl(CN)3]3-intermediate. The formation of [(CN)5Pt–Tl(edta)]4-can proceed via two different pathways dependingon the ratio of the cyanide to the edta ligand concentrations.The’direct path’at excess of edta means theformation of intermediate[(CN)4Pt···Tl(CN)(edta)]4-, followed by a release of the cyanide from theTl–centre followed by coordination of a cyanide from thebulk to the Pt–centre of the intermediate. The’indirect path’dominates in the absence of extraedta and the formation of the Pt–Tl bond occours betweenPt(CN)42-and Tl(CN)4–. Homoligand MTl(CN)4(M = TlI, K, Na) and, for the first time, Tl(CN)3species have been synthesized in the solid stateand their structures solved by single crystal X–raydiffraction method. Interesting redox processes have been foundbetween TIIIIand CN–in non–aqueous solution and in Tl2O3-CN–aqueous suspension. In the crystal structureof Tl(CN)3·H2O, the thallium(III) ion has a trigonal bypiramidalcoordination geometry with three cyanides in the trigonalplane, while an oxygen atom of the water molecule and anitrogen atom from a cyanide ligand attached to a neighboringthallium complex, form a linear O–Tl–N fragment.Cyanide ligand bridges thallium units forming an infinitezigzag chain structure. Among the thallium(III) tetracyanocompounds, the isostructural M[Tl(CN)4](M = Tl and K) and Na[Tl(CN)4]·3H2O crystallize in different crystal systems, but thethallium(III) ion has in all cases the same tetrahedralgeometry in the [Tl(CN)4]–unit. Three adducts of mercury(II) (isoelectronic with TIIII) (K2PtHg(CN)6·2H2O, Na2PdHg(CN)6·2H2O and K2NiHg(CN)6·2H2O) have been prepared from Hg(CN)2and square planar transition metal cyanides MII(CN)42-and their structure have been studied by singlecrystal X–ray diffraction, XPS and Raman spectroscopy inthe solid state. The structure of (K2PtHg(CN)6·2H2O consists of strictly linear one dimensional wireswith PtIIand HgIIcenters located alternately, dHg–Pt= 3.460 Å. The structure of Na2PdHg(CN)6·2H2O and K2NiHg(CN)6·2H2O can be considered as double salts, the lack ofhetero–metallophilic interaction between both the HgIIand PdIIatoms, dHg–Pd= 4.92 Å, and HgIIand NiIIatoms, dNi–Pd= 4.60 Å, seems obvious. Electronbinding energy values of the metallic centers measured by XPSshow that there is no electron transfer between the metal ionsin all three adducts. In solution, experimental findingsclearly indicate the lack of metal–metal bond formation inall studied HgII–CN-–MII(CN)42-systems (M = Pt, Pd and Ni). It is in contrary tothe platinum–thallium bonded cyanides. KEYWORDS:metal–metal bond, platinum, thallium,kinetics, mechanism, stopped flow, oxidative addition, cyanocomplexes, edta, redox reaction, metal cyanides, X–raydiffraction, Raman, NMR, mercury, palladium, nickel, onedimensional wire

The structure and dynamics of the smectic-A liquid crystal 8CB (4 cyano-4 octylbiphenyl) when sheared and confined to mesoscale gaps (with crossed cylindrical geometry and mica confining surfaces) were studied using a Surface Forces Apparatus (SFA). Triangular shear patterns with frequencies of 0.01, 0.1, 1.0 and 10 Hz, and amplitudes of 62.5 nm, 625 nm and 6.25 m were applied to samples at gap sizes of 0.5 and 5.0 m. The study was performed at room temperature (20.5C) and at two higher temperatures (22C and 27C). In order to minimize the thermal fluctuations within the test chamber and hence to allow for the rapid re-initialization of test runs, the SFA was modified to allow for quick, precise and remote control of the confining surfaces. The procedure maximized the number of tests that could be undertaken with a single pair of surfaces so that a single gap geometry could be maintained for the duration of the test run. In order to run the SFA remotely, scripts written with a commercial software package, LabVIEW, were used to control of the SFA components, its FECO-monitoring camera and all its peripheral electronic equipment as well. Samples were agitated to disrupt any shear-induced liquid crystal domain alignment from previous testing following each shear test, and methodologies were developed to ascertain the extent of confinement quickly and remotely following agitation. Separate methods were developed for gap sizes at each extreme of the mesoscale regime, where the transition from bulklike structure and dynamics to nano-confinement occurs (between 1 and 10 microns for smectic-A 8CB). The results revealed that the greater amplitude-gap aspect ratio and surface-to-domain contact associated with smaller gaps facilitated reorientation of the domains in the shear direction. Evidence was also presented of domains at the higher end or outside of the mesoscale regime that, while straining and accreting, were unable to reorient and thereby led to an overall increase of viscoelastic response. The effective viscosity was found to obey a simple power law with respect to shear rate, , and the flow behaviour indices, n, slightly in excess of unity indicate shear thickening occurs with large enough shear amplitude, and that the viscosity reached a plateau near unity over shear rates of 0.005 to 500 s-1 within the mesoscale regime. Different K and n values were observed depending on the shear amplitude used. Unlike bulk smectic 8CB, whose domains do not align well in the shear direction with large shear-strain amplitude, at mesoscale levels of confinement large amplitude shearing (up to 12.5 shear strain amplitude) was found to be very effective at aligning domains. In general domain reorientation is found to be much more rapid within the mesoscale regime than has been reported in bulk. Aggressive shearing was found to result in a complete drop in viscoelastic response within seconds, while gentler shearing is found to produce a very gradual increase that persists for more than six hours, with individual shear periods exhibiting frequent and significant deviations from the expected smooth shear path that may be a product of discrete domain reorientations. From these findings, certain traits of the smectic 8CB domain structures under mesoscale confinement were deduced, including how they respond to shear depending on the level of confinement, and how their reorientation due to shear varies not only with shear rate but also independently with shear amplitude. An equation describing the viscosity change as a function of both shear rate and shear amplitude is proposed. The shear amplitude dependence introduces the notion of shearing beyond the proposed smectic 8CB “viscoelastic limit”, which was shown to exhibit behaviour in accordance with Large Amplitude Oscillatory Shear (LAOS) techniques developed for Fourier Transform rheology. The findings provided an understanding of the behavioural changes that occur as one reduces the level of confinement of smectic materials from bulk to nanoconfinement.

<p>The kinetic and mechanistic features of a new series ofplatinum-thallium cyano compounds containing a direct andunsupported by ligands metal-metal bond have been studied insolution, using standard mix–and–measurespectrophotometric technique and stopped–flow method.These reactions are interpreted as oxidative addition of the cspecies to the square planar Pt(CN)₄^2-complex. Each of these processes was found to befirst-order in Pt(CN)₄^2-, the corresponding TI^IIIcomplex and a cyanide ion donating species whichacts as a catalyst. Both di- and trinuclear complexes werestudied, and the kinetically significant thallium complexes intheir formation and the catalytically active cyanide sourcesare as follows: [(CN)₅PtTl(CN)₃]^3-: Tl(CN)₄^–(alkaline region), Tl(CN)₃(slightly acidic region) and CN^–; [(CN)₅Pt–Tl(CN)]–: Tl(CN)₂⁺and Tl(CN)₂⁺; [(CN)₅Pt–Tl–Pt(CN)₅]^3-: [(CN)₅Pt–Tl(CN)]–and HCN. Appropriatemechanisms were postulated for the overall reactions in allcases, which include i) metal–metal bond formation stepand ii) coordination of an axial cyanide ion to the platinumcenter. Two experimentally indistinguishable kinetic modelswere proposed for the formation of the dinuclear complexeswhich are different in the sequence of the two steps. In thecase of the trinuclear complex, experimental evidence isavailable to exclude one of the alternative reaction paths, andit was proven that the metal–metal bond formation precedesthe axial cyanide coordination.</p><p>The cyanide ligands coordinated to TI^IIIin the Pt–Tl complexes could be replacedsuccessfully with aminopolycarboxylates e.g.: mimda^2-, nta^3-, edta^4-. The [(CN)₅Pt–Tl(edta)]^4-complex, with a direct metal–metal bond hasbeen prepared in solution by two different reactions: a)dissolution of [(CN)₅Pt–Tl](s) in an aqueous solution of edta, b)directly from Pt(CN)₄^2-and Tl(edta)(CN)^2-. The decomposition reaction is greatlyaccelerated by cyanide and significantly inhibited by edta. Itproceeds through the [(CN)₅Pt–Tl(CN)₃]^3-intermediate. The formation of [(CN)₅Pt–Tl(edta)]^4-can proceed via two different pathways dependingon the ratio of the cyanide to the edta ligand concentrations.The’direct path’at excess of edta means theformation of intermediate[(CN)4Pt···Tl(CN)(edta)]^4-, followed by a release of the cyanide from theTl–centre followed by coordination of a cyanide from thebulk to the Pt–centre of the intermediate. The’indirect path’dominates in the absence of extraedta and the formation of the Pt–Tl bond occours betweenPt(CN)₄^2-and Tl(CN)4^–.</p><p>Homoligand MTl(CN)₄(M = Tl^I, K, Na) and, for the first time, Tl(CN)₃species have been synthesized in the solid stateand their structures solved by single crystal X–raydiffraction method. Interesting redox processes have been foundbetween TI^IIIand CN^–in non–aqueous solution and in Tl₂O₃-CN^–aqueous suspension. In the crystal structureof Tl(CN)₃·H₂O, the thallium(III) ion has a trigonal bypiramidalcoordination geometry with three cyanides in the trigonalplane, while an oxygen atom of the water molecule and anitrogen atom from a cyanide ligand attached to a neighboringthallium complex, form a linear O–Tl–N fragment.Cyanide ligand bridges thallium units forming an infinitezigzag chain structure. Among the thallium(III) tetracyanocompounds, the isostructural M[Tl(CN)₄](M = Tl and K) and Na[Tl(CN)₄]·3H₂O crystallize in different crystal systems, but thethallium(III) ion has in all cases the same tetrahedralgeometry in the [Tl(CN)₄]^–unit.</p><p>Three adducts of mercury(II) (isoelectronic with TI^III) (K₂PtHg(CN)₆·2H₂O, Na₂PdHg(CN)₆·2H₂O and K₂NiHg(CN)₆·2H₂O) have been prepared from Hg(CN)₂and square planar transition metal cyanides M^II(CN)₄^2-and their structure have been studied by singlecrystal X–ray diffraction, XPS and Raman spectroscopy inthe solid state. The structure of (K₂PtHg(CN)₆·2H₂O consists of strictly linear one dimensional wireswith Pt^IIand Hg^IIcenters located alternately, d_Hg–Pt= 3.460 Å. The structure of Na₂PdHg(CN)₆·2H₂O and K₂NiHg(CN)₆·2H₂O can be considered as double salts, the lack ofhetero–metallophilic interaction between both the Hg^IIand Pd^IIatoms, d_Hg–Pd= 4.92 Å, and Hg^IIand Ni^IIatoms, d_Ni–Pd= 4.60 Å, seems obvious. Electronbinding energy values of the metallic centers measured by XPSshow that there is no electron transfer between the metal ionsin all three adducts. In solution, experimental findingsclearly indicate the lack of metal–metal bond formation inall studied Hg^II–CN^-–M^II(CN)4^2-systems (M = Pt, Pd and Ni). It is in contrary tothe platinum–thallium bonded cyanides.</p><p><b>KEYWORDS:</b>metal–metal bond, platinum, thallium,kinetics, mechanism, stopped flow, oxidative addition, cyanocomplexes, edta, redox reaction, metal cyanides, X–raydiffraction, Raman, NMR, mercury, palladium, nickel, onedimensional wire</p>

The structure and dynamics of the smectic-A liquid crystal 8CB (4 cyano-4 octylbiphenyl) when sheared and confined to mesoscale gaps (with crossed cylindrical geometry and mica confining surfaces) were studied using a Surface Forces Apparatus (SFA). Triangular shear patterns with frequencies of 0.01, 0.1, 1.0 and 10 Hz, and amplitudes of 62.5 nm, 625 nm and 6.25 m were applied to samples at gap sizes of 0.5 and 5.0 m. The study was performed at room temperature (20.5C) and at two higher temperatures (22C and 27C). In order to minimize the thermal fluctuations within the test chamber and hence to allow for the rapid re-initialization of test runs, the SFA was modified to allow for quick, precise and remote control of the confining surfaces. The procedure maximized the number of tests that could be undertaken with a single pair of surfaces so that a single gap geometry could be maintained for the duration of the test run. In order to run the SFA remotely, scripts written with a commercial software package, LabVIEW, were used to control of the SFA components, its FECO-monitoring camera and all its peripheral electronic equipment as well. Samples were agitated to disrupt any shear-induced liquid crystal domain alignment from previous testing following each shear test, and methodologies were developed to ascertain the extent of confinement quickly and remotely following agitation. Separate methods were developed for gap sizes at each extreme of the mesoscale regime, where the transition from bulklike structure and dynamics to nano-confinement occurs (between 1 and 10 microns for smectic-A 8CB). The results revealed that the greater amplitude-gap aspect ratio and surface-to-domain contact associated with smaller gaps facilitated reorientation of the domains in the shear direction. Evidence was also presented of domains at the higher end or outside of the mesoscale regime that, while straining and accreting, were unable to reorient and thereby led to an overall increase of viscoelastic response. The effective viscosity was found to obey a simple power law with respect to shear rate, , and the flow behaviour indices, n, slightly in excess of unity indicate shear thickening occurs with large enough shear amplitude, and that the viscosity reached a plateau near unity over shear rates of 0.005 to 500 s-1 within the mesoscale regime. Different K and n values were observed depending on the shear amplitude used. Unlike bulk smectic 8CB, whose domains do not align well in the shear direction with large shear-strain amplitude, at mesoscale levels of confinement large amplitude shearing (up to 12.5 shear strain amplitude) was found to be very effective at aligning domains. In general domain reorientation is found to be much more rapid within the mesoscale regime than has been reported in bulk. Aggressive shearing was found to result in a complete drop in viscoelastic response within seconds, while gentler shearing is found to produce a very gradual increase that persists for more than six hours, with individual shear periods exhibiting frequent and significant deviations from the expected smooth shear path that may be a product of discrete domain reorientations. From these findings, certain traits of the smectic 8CB domain structures under mesoscale confinement were deduced, including how they respond to shear depending on the level of confinement, and how their reorientation due to shear varies not only with shear rate but also independently with shear amplitude. An equation describing the viscosity change as a function of both shear rate and shear amplitude is proposed. The shear amplitude dependence introduces the notion of shearing beyond the proposed smectic 8CB “viscoelastic limit”, which was shown to exhibit behaviour in accordance with Large Amplitude Oscillatory Shear (LAOS) techniques developed for Fourier Transform rheology. The findings provided an understanding of the behavioural changes that occur as one reduces the level of confinement of smectic materials from bulk to nanoconfinement.

The major part of this thesis describes the asymmetric synthesis of β- and γ-amino alcohols through the combination of ruthenium catalyzed racemization and enzymatic kinetic resolution. The dynamic kinetic resolution, DKR, protocol for chlorohydrins was improved by employing Bäckvall’s catalyst, which is a base activated racemization catalyst, in combination with Burkholderia cepacia lipase. These optimized conditions broadened the substrate scope and improved the yields and ee’s of the obtained chlorohydrin acetates. The utility of the method was demonstrated in the synthesis of (S)-salbutamol. In the second part of the thesis, DKR was utilized in the enantio-determining step of the total synthesis of (R)-duloxetine. Optimized DKR conditions, combining Bäckvall’s catalyst together with Candida antarctica lipase B, afforded a β-cyano acetate in high yield and ee. (R)-Duloxetine was accessible through synthetic alterations of the enantioenriched β-cyano acetate in high overall yield. A dynamic kinetic asymmetric transformation, DYKAT, protocol to obtain enantio- and diastereomerically pure γ-amino alcohols was developed. In a first step N-Boc-aminoketones were obtained in high enantiomeric purity through a proline-catalyzed Mannich reaction. Subsequent in situ reduction coupled with a highly efficient DYKAT yielded γ-amino acetates in high dr and ee. The γ-amino alcohols were available through simple hydrolysis/deprotection with retained stereochemistry. In the final part of the thesis a heterogeneous bifunctional catalytic system is reported, which combines the catalytic properties of transition metal-catalyzed racemization with enzymatic acylation. A novel ruthenium-phosphonate complex was synthesized and then covalently anchored to the active site of solid supported Candida antarctica lipase B. The partially inhibited beads proved to be catalytically active both in racemization as well as enzymatic acylation. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: Epub ahead of print.

Orientador: Maria Palmira Daflon Gremião / Resumo: Glioblastomas (GBM) representam 77% dos tumores malignos do sistema nervoso central (SNC) e ainda hoje, apesar de todos os avanços na terapia, continua com prognóstico limitado. A existência de barreiras fisiológicas como a barreira hematoencefálica (BHE) representa o principal obstáculo que impede que concentrações adequadas do fármaco atinjam o local de ação. Por suas vantagens anatômicas, uma estratégia proposta para a administração de fármacos destinados ao SNC consiste no uso da via nasal. Além disso, o uso de terapias combinadas utilizando fármacos capazes de agir em diferentes alvos moleculares deve ser considerada para o tratamento de doenças complexas como GBM. O candidato a fármaco ácido alfa-ciano-4-hidroxicinâmico (CHC) e o anticorpo monoclonal cetuximab (CTX) já são explorados devido à capacidade de agir em diferentes alvos moleculares nas células tumorais e aplicados em conjunto, como uma nova abordagem combinada, podem melhorar os resultados terapêuticos. De forma complementar, a utilização de sistemas de liberação baseados em nanotecnologia trará inevitavelmente ganhos terapêuticos à combinação proposta, permitindo que atributos específicos sejam agregados ao sistema e possibilite não somente a administração nasal, como também a associação de diferentes fármacos em um único carreador. Assim, o presente estudo propõe o desenvolvimento de diferentes plataformas poliméricas baseadas em poli(ácido láctico-co-glicólico) (PLGA) e quitosana trimetilada (TMC) ou quito... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Glioblastomas (GBM) account for 77% of malignant tumors in the central nervous system (SNC), and today, despite all advances in therapy, remains with a limited prognosis. The existence of physiological barriers as the blood brain barrier (BBB) represents the main obstacle that limits appropriate concentrations of drugs designed to therapy. Due to their anatomical advantages, a strategy proposed for direct delivery to SNC involves the use of the nose-to-brain route. Besides, combination therapy that uses multiple drugs against different molecular targets should be considered for complex diseases such as GBM. Drugs like alpha-cyano-4-hydroxycinnamic acid (CHC) and the monoclonal antibody cetuximab (CTX) are already explored for their capacity to act against different hallmarks of cancer and applied together, as a novel combining approach, might improve therapeutic outcomes. Therefore, advances in nanotechnology-based delivery systems will inevitably bring therapeutic gains to the proposed combination since they enable acquisition of important characteristics desired and also the association of different drugs into a single carrier. Thus, the current study proposes the development of different polymeric platforms based on poly(lactic-co-glycolic acid) (PLGA) and trimethyl chitosan (TMC) /chitosan oligosaccharide (OCS) for CHC encapsulation. Both CHC-loaded developed systems (PLGA/TMC and PLGA/OCS) exhibited nanostructure organization of about 300 to 400 nm, containing chitosan o... (Complete abstract click electronic access below) / Doutor