No description available.

In an effort to partially mimic the complex interaction between nerve growth factor (NGF) and its membrane-bound tyrosine kinase A receptor (TrkA), several small organic molecules with functionalities similar to the side-chains of the amino acid residues of NGF critical to binding were devised. These molecules were studied computationally using the program Affinity. Each molecule was individually docked onto one of the binding sites on TrkA as determined by mutagenesis studies and the x-ray crystal structure obtained from the Protein Data Bank. One of the strategies to enhance binding of active peptidomimetics to their target proteins is to link them together to form either homodimers or heterodimers. However, these dimers have low solubility in water and mimic only residues that are close together on the protein. Triethylene oxide- and hexaethylene oxide-based linker molecules were designed to circumvent these limitations. The increased polarity will improve the watersolubility and the added lengths, which can be controlled and varied by simple chemical manipulations, will allow for mimicking critical residues that are farther apart on the protein.

The thesis analyses a variety of clause linkers used in the world’s languages as dedicated markers of four circumstantial relations between states of affairs: anteriority (‘after’), causality (‘because’), purpose (‘in order to’) and conditionality (‘if’). Focusing primarily on the function of the linkers rather than on their formal properties the study scrutinizes the origin and functioning of free-word adverbial subordinators, converbal endings as well as other subordinating affixes and polymorphemic structures specialized for clause-linking functions. The database consist of nearly 700 items which come from a geographically and genetically balanced sample of 84 languages. In the first part of the thesis I discuss in detail the scope of the study, theoretical foundations (functional approach to language analysis) and methodology. In the second part I focus on the issues of grammaticalization and semantic scope of the linkers. The analysis of patterns of polysemy of the linkers, as well as the make-up of the polymorphemic items among them provide material for the reconstruction of the most common sources and pathways of grammaticalization. Looking closer at the patterns of semantic polyfunctionality (i.e. other circumstantial meanings that the clause linkers convey in addition to being markers of the four analysed relations) I reveal the architecture of the network of their cognitive affinities. The result of this investigation is a set of findings, which add to our understanding of the origin and functioning of the markers – a topic which has received little attention so far. The third part of the dissertation is dedicated to the analysis of the crosslinguistic variation in the degree of grammaticalization, lexicalization and explicitness of the linkers and discussion on the motivations behind their development. The main body of the analyses is focused on the investigation of the potential influence of a variety of socio-cultural factors on the variations observed. The factors include those most often mentioned in the context of the forces shaping language structure: presence and vitality of written form as well as other media of displaced communication, presence of the language in schooling, population size of the speech community, and type of society. The results obtained show that the degrees of grammaticalization, lexicalization and explicitness are much stronger correlated with socio-cultural factors for anteriority and conditionality than for causality and purpose. In order to account for the differences I evoke the concepts of cognitive salience and communicative pressure arguing that the influence of socio-cultural factors on language structure should always be considered in a broader context which includes also pragmatics and cognitive psychology.

A method for the synthesis of a symmetrical fluorous tagged benzodithiol support has been developed through a seven-step synthetic pathway. The Wittig olefination and catalytic hydrogenation reactions were employed to attach two perfluoroalkyl chains in the o-positions of phthalaldehyde. These fluorous tags were used as soluble supports which facilitated the purification of the crude reaction mixtures using fluorous solid phase extraction (FSPE). A selective and high yielding dibromination reaction was developed to synthesize a fluorous tagged 1,2-dibromo aryl compound. A thorough study was carried out to demonstrate the ease of an aryl-sulfur bond formation with the 1,2-dibromo compound varying palladium catalysts and ligands. A new palladium catalyzed dithiolation reaction is reported to synthesize a surrogated dithiol, which was exploited as a precursor for the synthesis of hitherto inaccessible symmetrical fluorous tagged benzodithiol support. The utility of the benzodithiol was explored by the synthesis of benzodithianes with two aldehydes. The lithiated dithiane generated was further used to form a C-C bond employing the umpolung reaction. The ring-closing metathesis reaction using Grubbs II catalyst was performed to construct 5-membered and 6-membered spiro-ring systems. Several approaches were made to form a C-C bond with lithiated dithianes using various nitrogen containing electrophiles leading to N-heterocycles. / October 2008

A method for the synthesis of a symmetrical fluorous tagged benzodithiol support has been developed through a seven-step synthetic pathway. The Wittig olefination and catalytic hydrogenation reactions were employed to attach two perfluoroalkyl chains in the o-positions of phthalaldehyde. These fluorous tags were used as soluble supports which facilitated the purification of the crude reaction mixtures using fluorous solid phase extraction (FSPE). A selective and high yielding dibromination reaction was developed to synthesize a fluorous tagged 1,2-dibromo aryl compound. A thorough study was carried out to demonstrate the ease of an aryl-sulfur bond formation with the 1,2-dibromo compound varying palladium catalysts and ligands. A new palladium catalyzed dithiolation reaction is reported to synthesize a surrogated dithiol, which was exploited as a precursor for the synthesis of hitherto inaccessible symmetrical fluorous tagged benzodithiol support. The utility of the benzodithiol was explored by the synthesis of benzodithianes with two aldehydes. The lithiated dithiane generated was further used to form a C-C bond employing the umpolung reaction. The ring-closing metathesis reaction using Grubbs II catalyst was performed to construct 5-membered and 6-membered spiro-ring systems. Several approaches were made to form a C-C bond with lithiated dithianes using various nitrogen containing electrophiles leading to N-heterocycles.

A method for the synthesis of a symmetrical fluorous tagged benzodithiol support has been developed through a seven-step synthetic pathway. The Wittig olefination and catalytic hydrogenation reactions were employed to attach two perfluoroalkyl chains in the o-positions of phthalaldehyde. These fluorous tags were used as soluble supports which facilitated the purification of the crude reaction mixtures using fluorous solid phase extraction (FSPE). A selective and high yielding dibromination reaction was developed to synthesize a fluorous tagged 1,2-dibromo aryl compound. A thorough study was carried out to demonstrate the ease of an aryl-sulfur bond formation with the 1,2-dibromo compound varying palladium catalysts and ligands. A new palladium catalyzed dithiolation reaction is reported to synthesize a surrogated dithiol, which was exploited as a precursor for the synthesis of hitherto inaccessible symmetrical fluorous tagged benzodithiol support. The utility of the benzodithiol was explored by the synthesis of benzodithianes with two aldehydes. The lithiated dithiane generated was further used to form a C-C bond employing the umpolung reaction. The ring-closing metathesis reaction using Grubbs II catalyst was performed to construct 5-membered and 6-membered spiro-ring systems. Several approaches were made to form a C-C bond with lithiated dithianes using various nitrogen containing electrophiles leading to N-heterocycles.

No description available.

Metal-organic frameworks (MOFs) are crystalline hybrid materials with interesting chemical and physical properties. This thesis is focused on the synthesis and characterization of different MOFs and their use in heterogeneous catalysis. Zeolitic imidazolate frameworks (ZIFs), including ZIF-4, ZIF -7 and ZIF -62, Ln(btc)(H2O) (Ln: Nd, Sm, Eu, Gd, Tb, Ho, Er and Yb), Ln2(bpydc)3(H2O)3, (Ln: Sm, Gd, Nd, Eu, Tb, Ho and Er), MOF-253-Ru and Zn(Co-salophen) MOFs were synthesized. Various characterization techniques were applied to study the properties of these MOFs. X-ray powder diffraction (XRPD), single crystal X-ray diffraction (XRD), scanning electron microscopy (SEM) and thermogravimetric analysis (TGA) were extensively used. The effect of synthesis parameters, such as batch composition and temperature, on the formation and morphology of ZIF-7 and ZIF-62 was studied. Structural transformation and flexibility of two series of lanthanide-based MOFs, Ln(btc)(H2O) (Ln: Nd, Ho and Er) and Ln2(bpydc)3(H2O)3, (Ln: Sm and Gd) upon drying and heating were characterized. Relations between metal coordination, structure flexibility and thermal stability among the Sm2(bpydc)3(H2O)3, Nd(btc)(H2O) and MOF-253 were investigated. Salophen- and phenanthroline-based organic linkers were designed, synthesized and characterized. Metal complexes were coordinated to these linkers to be used as catalytic sites within the MOFs. Catalytic studies using two MOF materials, Ln(btc) and MOF-253-Ru, as heterogeneous catalysts in organic transformation reactions were performed. The heterogeneous nature and recyclability of these MOFs were investigated and described. / <p>At the time of doctoral defence the following papers were unpublished and had a status as follows: Paper nr 4: Submitted; Paper nr 5: Submitted</p>

The design and synthesis of new finely tunable porous materials has spurred interest in developing novel uses in a variety of systems. Zeolites, inorganic materials with high thermal and mechanical stability, in particular, have been widely examined for use in applications such as catalysis, ion exchange and separation. A relatively new class of inorganic-organic hybrid materials known as metal-organic frameworks (MOFs) has recently surfaced, and many have exhibited their efficiency in potential applications such as ion exchange and drug delivery. A more recent development is the design and synthesis of a subclass of MOFs based on zeolite topologies (i.e. ZMOFs), which often exhibit traits of both zeolites and MOFs. Bio-compatible hydrogels already play an important role in drug delivery systems, but are often limited by stability issues. Thus, the addition of ZMOFs to hydrogel formulations is expected to enhance the hydrogel mechanical properties, and the ZMOF-hydrogel composites should present improved, symbiotic drug storage and release for delivery applications. Herein we present the novel composites of a hydrogel with a zeolite-like metal-organic framework, rho-ZMOF, using 2-hydroxyethyl methacrylate (HEMA), 2,3-dihydroxypropyl methacrylate (DHPMA), N-vinyl-2-pyrolidinone (VP) and ethylene glycol dimethacrylate (EGDMA), and the corresponding drug release. An ultraviolet (UV) polymerization method is employed to synthesize the hydrogels, VP 0, VP 15, VP 30, VP 45 and the ZMOF-VP 30 composite, by varying the VP content (mol%). The rho-ZMOF, VP 30, and ZMOF-VP 30 composite are all tested for the controlled release of procainamide (protonated, PH), an anti-arrhythmic drug, in phosphate buffer solution (PBS) using UV spectroscopy. Blister agents are chemical compounds that induce severe skin, eye, mucosal pain and irritation. The research focuses on sequestering a blister agent analog, thioanisole in hydrogels. HEMA polymers and copolymers of HEMA with 2,3-dihydroxyproyl methacrylate (DHPMA) and vinyl pyrrolidone (VP) were synthesized with crosslinkers of various dimensions. These were: ethylene glycol dimethacrylate (EGDMA), diethylene glycol dimethacrylate (DiEGDMA), triethylene glycol dimethacrylate (TriEGDMA), tetraethylene glycol dimethacrylate (TetEGDMA) and neopentyl glycol dimethacrylate (NPEGDMA). Equilibrium swelling was characterized gravimetrically and pore size was estimated via scanning electron microscopy (SEM). Glass transition temperatures were measured by differential scanning calorimetry (DSC). The absorption of thioanisole in methanol was characterized with via ultra-violet (UV) spectroscopy. Poly(2-hydroxyethyl methacrylate) (PHEMA) composites constructed from a paddle-wheel, a secondary building unit (SBU) for metal organic frameworks, Cu2(p-OH benzoate)4(DMSO)2*2DMSO (CPW) were also investigated for a broad analysis of dielectric spectra. The dielectric spectrum of poly(2-hydroxyethyl methacrylate) and its copolymer with Poly(2,3-dihydroxy propyl methacrylate) (PDHPMA) are already reported in the literature. This study delineates the effects on the dielectric behavior as a result of CPW addition. The dielectric permittivity and the loss factor were measured using a dielectric analyzer in the frequency range of 1 Hz to 100 k Hz and between the temperature range of -140 and 250°C. The electric modulus formalism was used to reveal the viscoelastic and conductivity relaxations present in the polymers. Significant changes were observed as CPW concentration increased from 0.1 to 0.5 wt%. It was determined through DSC that the glass transition temperature increased with the filler concentration. The secondary dielectric relaxations were also affected as it was recorded that the activation energy for the γ, Β, and conductivity relaxation increased with CPW content. AC and DC conductivity are also evaluated. The ionic conductivity data revealed that the CPW impedes the ion mobility when compared to the neat PHEMA. Organic azides have become a very vital class of chemical compounds in synthetic organic chemistry and in many more fields due to their applications. Azido compounds are considered high-energetic compounds and are studied very little due to their explosive nature. There is an urge to evaluate the thermal stability of this wide variety of compounds which have tremendous applications in synthetic as well as organic chemistry. Here in we report the thermal stability of some organic azides such as sulfonyl, phosphoryl and carbonyl azides using differential scanning calorimetry (DSC) as an evaluating tool. Initial temperature of decomposition (Ti) and temperature of maximum decomposition (Tmax) are recorded. The area under exotherm peak during decomposition is used to determine the energy of decomposition (Ed) and is compared to threshold value for hazardous/explosive compounds. The effect of substituent groups at different positions, nature of the substituent groups (electron donating or electron withdrawing) and the steric hindrance on the thermal stability of these azides is studied in detail to verify the explosive nature of these compounds.

Effective detection and treatment of tumor malignancies depends upon identifying targets – molecular markers that differentiate cancer cells from healthy cells. Current cancer therapies involve targeting overexpressed specific gene products. An alternative approach is proposed here: to specifically target combinations of cell-surface receptors using heteromultivalent ligands (htMVLs). There are about 2500 genes encoding for cellsurface proteins in the human genome that can potentially be targeted. Taken as sets, there can be ~ 10⁶ two-receptor combinations and ~ 10⁹ three-receptor combinations available. Our group envisions that using cell-surface protein combinations that are expressed on a cancer cell but not on a normal cell, multivalent constructs displaying complementary ligands of weak affinities can be assembled. These multivalent ligands should bind with high avidity to cancer populations in vivo, and provide a degree of specificity not seen with current approaches. As a proof-of-concept, a series of multivalent ligands were designed and synthesized for a model system consisting of the human Melanocortin subtype 4 receptor (hMC4R) and the Cholecystokinin subtype 2 receptor (CCK-2R). Modeling studies on GPCR dimers predicted that a minimum linker span of 20 - 50 Å would be required to non-covalently crosslink these two receptors. The multivalent ligands were assembled using a modular parallel synthesis approach and using solidphase chemistries. A variety of linkers were explored ranging from highly rigid to highly flexible, and using natural and/or synthetic building blocks. Ligand binding affinities were evaluated using a lanthanide based competitive binding assay in cells that expressed both receptors (bivalent binding) vs those that expressed only one of the receptors (monovalent binding), and were demonstrated to have enhanced binding affinities of up to nearly two orders of magnitude. The promising ligands were further explored by synthesizing fluorescently labeled and/or lanthanide chelate labeled monovalent and heterobivalent ligands designed for in vitro and in vivo studies. More explorative work using these labeled constructs is in progress. To the best of our knowledge, the author believes this is the first such demonstration of a 'synthetic htMVL' directed recruitment and crosslinking of two heterologous cell-surface receptors. This receptor combination approach opens up new possibilities for single cell imaging, cancer detection and therapeutic intervention, and can provide a revolutionary new platform technology with which to direct therapeutics to defined cell populations.