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I detta arbete så har en uppsättning aromatiska ditiol-ligander framställts (3,5-dimerkaptobensoesyra I, methyl-3,5-dimerkaptobensoat II, 3,5-dimerkaptotoluen III, 4,6-dimerkaptoisoftalaldehyde IV). En trestegssyntes innehållande Newman-Kwart omlagring som nyckelsteg användes för framställning av föreningarna I-III medan förening IV togs fram via en annan syntesväg. De fyra föreningarna syntetiserades I relativt bra utbyte (5-80% över 3, 4 eller 6 steg) och karaktäriserades med hjälp av 1H-NMR, 13C-NMR, och högupplösande masspektrometri. I en framtida fortsättning av projektet så kommer föreningarna I-IV användas som organiska ligander i koordinationspolymerer, vilka kommer karaktäriseras i termer av elektriska och termiska egenskaper. / In this work, a family of aromatic dithiol ligands were synthesized in the laboratory (3,5-dimercapto benzoic acid I, methyl 3,5-dimercapto benzoate II, 3,5-dimercapto toluene III, 4,6-dimercaptoisophthalaldehyde IV). A three-step synthesis strategy, involving the Newman-Kwart rearrangement as key step, for the formation of I, II and III was used, whereas compound IV required a different synthetic route. The four compounds were synthesized with relatively good yields (5-80% over 3, 4 or 6 steps) and were fully characterized using 1H-NMR, 13C-NMR, and high-resolution mass spectrometry. In a future extension of this work, compounds I-IV will be used as organic ligands in coordination polymers (CPs), which will be characterized in terms of electric and thermal properties.

<p>  </p> <p>The access of ring junction functionalized 5,6-hydrindanone systems has been elusive in the realm of synthetic methodology, and the functionalization of a pre-built ring system rarely explored. These 5,6-hydridanone systems are prevalent in a variety of terpenoid ring systems, especially that of steroidal molecules. Previous synthetic methods to reach these systems using a Diels-Alder cycloaddition proved to be difficult and lacked labile functional groups that would be useful for substitution after the cycloaddition. The design of the α-nitrile cyclopentenone dienophile allows for both post-cyclization adduct functionalization, as well as lowering the energy barrier of the cycloaddition itself. In this work, it is shown that the Lewis acid promoted Diels-Alder reaction with α-nitrile β-methyl cyclopentenone dienophile can be performed under standard temperatures and pressures unlike previously established methods.1 This reaction can generate four chiral centers in a single synthetic step when the starting materials are prochiral. After the generation of 5,6-hydrindanone systems, radical cleavage of the nitrile functionality also allowed for electrophile trapping at the ring junction. This radical cleavage and electrophile trapping pathway allows for functionalization of a quaternary carbon at the ring junction, a method that should be fruitful in the generation of difficult to synthesize steroidal and other terpenoid molecules.</p> <p>In the work on synthetic cell penetrating peptides, camptothecin whilst a notably effective topoisomerase I inhibitor, has never quite reached it’s potential as a therapeutic due to its poor solubility in living systems. Previously, cationic amphiphilic polyproline helices (CAPH) molecules from the Chmielewski lab have been hydrophobically functionalized through O-alkylation of hydroxyprolines at specific regions within the peptide to generate a hydrophobic face. The combination of the cationic faces and the hydrophobic face have made the CAPH molecules notably cell penetrant and tunable. With camptothecin’s notable insolubility in water, it may serve as valuable surrogate to the hydrophobic groups on CAPH molecules and allowing it to be delivered intracellularly. Using an endogenously cleavable linker, we have worked towards a CPP that acts as a drug delivery vehicle. Acting as a replacement of the hydrophobic residue of a CAPH molecule, camptothecin will be chaperoned into the cell and should be released through the action of intracellular esterases.</p>

<p> 2-Tetrazens are often used as high energy-density materials. Only a few synthetic methods  exist for making them. Further, their structure-property relationships remain largely unexplored.  Asphaltenes are usually a complex mixture found in the heaviest fraction of heavy crude oil. Their structural characterization and understanding have become a pertinent task for petroleum industry  around the world. Mass spectrometry is a powerful analytical tool for the detection and  characterization of unknown compounds even in complex mixtures. It features high sensitivity and  speed and can provide a variety of valuable information for different types of analytes. This thesis  focuses on the development of an effective synthetic method for 2-tetrazenes and the mass  spectrometry study of the ionized 2-tetrazenes. In addition, the mass spectrometric behavior of  ionized asphaltene model compounds are also discussed in this thesis. Chapter 2 describes the instrumentation and fundamental aspects of the mass spectrometers used in the research discussed in this thesis. Chapter3 introduces an effective synthetic method for  2-tetrazens based on iodine-mediated oxidative N-N coupling reaction of hydrazines. Chapter 4  presents the fragmentation behavior of ionized 2-tetrazenes in tandem mass spectrometry experiments. Upon collision-activated dissociation (CAD), ionized alkyl-substituted linear 2- tetrazenes underwent simpler fragmentation reactions than the ionized aromatic 2-tetrazenes or a  cyclic 2-tetrazene. The observations were rationalized by using quantum chemical calculations.  Chapter 5 presents the fragmentation behavior of ionized asphaltene model compounds under  medium-energy collision-activated dissociation (MCAD). The comparison between the different  behaviors of the molecular radical cations of these compounds provided useful information for the  identification of related unknown compound </p>

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Imaging membrane potential is a promising technique in the elucidation of the interactions of large networks of neurons. The membrane potential in a neuron varies as an action potential, the basic electrical signal of neuronal communication, travels along the length of the cell. Voltage sensitive dyes play a key role by providing an optical readout of the electric field generated across a neuron membrane by the action potential. However, none of the dyes reviewed in Chapter 1 generate sufficient signal change with changes in membrane potential; this sensitivity problem limits the ability of the imaging membrane potential technique to allow the high spatial and temporal resolution necessary for neuronal networks to be better understood. This thesis features two avenues of research that are expected to result in the necessary enhancements to voltage sensitive dyes to improve the signal change. The first avenue is based on the effect of an electric field upon the non-linear optical properties of a porphyrin macromolecule. The encouraging field sensitivity of a previous porphyrin monomer voltage sensor inspired an investigation which identified optimisations to enhance the voltage sensitivity (Chapter 2). The design, synthesis and initial characterisation of optimised porphyrin voltage sensors is detailed in Chapter 3. The second avenue is based on the effect of an electric field upon the rate of intermolecular electron transfer. In a suitably designed dye, the competition between electron transfer and fluorescence, following excitation by incoming light, allows the fluorescence intensity to act as an optical indicator of the electron transfer rate. New dyes were rationally designed and synthesised, as this effect had not been applied to voltage sensitive imaging before the research detailed in Chapter 4. The challenging purification of the new amphiphilic dyes synthesised also inspired research into a novel testing method which does not require amphiphilic dyes (Chapter 5).

This thesis describes our examination of the reactivity of allenylpalladium intermediates generated from the reaction of palladium(0) with propargylic electrophiles. Chapter 1 provides a general overview of the literature reported to date concerning the nature and reactivity of allenylpalladium intermediates. The coupling of a variety of propargylic electrophiles with aryl boronic acids to form allenes is examined in Chapter 2. However, when employing diastereomerically pure electrophiles, some erosion of stereochemistry was observed in the allene products. This effect was examined further, and epimerisation of the allene product was found to be the origin of the loss of stereochemistry. Evidence for the species likely responsible for this epimerisation is presented. The serendipitous formation of tetrahydrofurans (THFs) from propargylic 7-membered cyclic carbonates prompted an in-depth examination of this reactivity, as described in Chapter 3. The reaction of these cyclic carbonates was rendered stereoselective and the stereochemical outcome of the reaction elucidated. The methodology was extended to propargylic acyclic carbonates which allowed the formation of tetrahydropyrans (THPs). The effect of ring-size and substituents on the cyclisations was examined, culminating in the formation of two rings in a single step from diol-containing bis-carbonates. Chapter 4 describes the extension of this methodology to the formation of azacyclic products. This built upon foundation work conducted by a Part II student within the group, and further improved the selectivity of the reaction. Two diverse azacyclic skeletons could be formed from the same substrate by the employment of different bidentate phosphine ligands, and a variety of substrates were examined under these conditions. Chapter 5 draws general conclusions and sets out possible future directions for the methodology, and full experimental details are outlined in Chapter 6.

Lysine acetylation is a widespread protein post-translational modification that influences diverse cellular processes. An association between acetylation of histone N-terminal tails and transcriptional activation has been recognised since the 1960s. However, it has only become apparent since 2000 that many of the effects of histone acetylation are mediated by proteins that bind to acetyl-lysine through a specialised acetyl-lysine recognition domain, the bromodomain. Small-molecule inhibitors of bromodomain-histone interactions can greatly assist studies into the functions of bromodomain-containing proteins, and show promise as treatments for several diseases, including cancers. Herein I describe the discovery and development of a novel chemical series of bromodomain-binding ligands containing the 3,5-dimethyisoxazole moiety. This heterocycle acts as an acetyl-lysine bioisostere, mimicking key interactions formed between acetyl-lysine and the bromodomain. Optimised compounds show sub-micromolar affinities for bromodomains of the BET family, a class of transcriptional co-regulators. Crystallographic and structure-activity relationship studies shed light on the structural requirements for potent and selective BET ligands. Furthermore, the compounds show cellular effects consistent with BET bromodomain inhibition: cytotoxicity studies in a range of cell lines, including the NCI-60 human tumour cell line screen, reveal differential activity, with leukaemias showing particular sensitivity. 3,5-Dimethylisoxazole-containing compounds were also shown to downregulate known BET target genes. Further studies investigated the effect of modifying or replacing the methyl groups of 3,5-dimethylisoxazole on BET bromodomain affinity, which indicated that the 3-methyl group is necessary for affinity. Finally, three novel isoxazole-containing amino acids were synthesised and incorporated into histone peptides as potential bromodomain-binding, non-hydrolysable, acetyl-lysine mimics. These amino acids might be useful in uncovering the function of individual acetylated lysine residues. The identification of methyl-isoxazoles as acetyl-lysine-mimetic bromodomain ligands represents a significant advance in our understanding of structure-activity relationships for these important proteins. The confirmed cellular activity of these compounds will enable their use in future biological studies.