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Curcumin is one of the major curcuminoids produced by the ginger family Zingiberaceae. These curcuminoids possess pharmacological properties that include anticancer activities. We have evaluated some synthetic curcumin analogues that have shown potential as anticancer drugs. These antineoplastic agents bearing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore are electrophiles which are designed to preferentially react with sulfhydryl groups present in proteins as opposed to amino and hydroxyl groups present in DNA. In previous pilot studies, three derivatives examined in this thesis showed inhibition towards human cancer cell lines such as Molt 4/C8 and CEM T-lymphocytes. In this thesis work, I determined the cytotoxicity of these derivatives and curcumin towards human colon cancer (HCT-116) cells and also normal colon epithelial (CRL-1790) cells, and examined the possible mechanism(s) involved. I hypothesized that they act via induction of reactive oxygen species (ROS) which elicit a transient surge of mitochondrial ROS generation and a phenomenon known as ROS-induced ROS release (RIRR), along with the mitochondrial permeability transition (MPT) and mitochondrion –dependent apoptosis. I asked whether these agents react with some of the key protein thiols in the mitochondria whose oxidation/alkylation results in mitochondrion - dependent apoptosis. NC-2109 and NC-2346 were found to be potent cytotoxic agents based on their GI50 values of 0.87 ± 0.38 μM and 0.90 ± 0.22 μM, respectively, and were more potent than the anticancer drug 5-fluorouracil (GI50 = 5.47 ± 0.55 μM) and curcumin (GI50 = 3.50 ± 0.36 μM). However NC-2109 was found to have a better selectivity towards cancer cells over normal cells (a selectivity index of 18.81 versus 5-FU, curcumin and NC-2346 which had selectivity indices of 1.87, 16.75 and 4.61, respectively). In the investigations of the mechanisms involved, both curcumin and curcumin analogues were able to induce mitochondrial ROS production. Moreover, curcumin and its synthetic counterparts showed a biphasic ROS profile which is most characteristic of RIRR. Treatment with these agents also led to the disruption of the mitochondrial membrane potential, suggesting oxidation of protein thiols and the opening of the mitochondrial permeability transition pore which is an important step to initiate mitochondria-directed apoptosis. This possibility was confirmed based on GSSG/GSH ratios, since curcumin, NC-2346 and NC-2109 all produced a higher GSSG/GSH ratio than the controls. In addition to their ability to depolarize the mitochondrial membrane in HCT-116 cells, that these molecules acted via the mitochondrial pathway were further authenticated based on their ability to induce mitochondrial swelling in rat liver mitochondria. In another part of this thesis I evaluated the involvement of the critical thiol protein adenine nucleotide translocase (ANT), a bifunctional protein that plays a central role in mitochondrial apoptosis. ANT has four different isoforms; ANT1 and ANT3 are proapoptotic, while ANT2 and ANT4 are antiapoptotic and are overexpressed in cancer states. A combination approach using ANT2 siRNA however did not conclusively show whether these agents acted synergistically with ANT2 knockdown to potentiate mitochondria-mediated cell death. An alternative combination approach was the use of carboxyatractyloside (CAT) which binds to and retains ANT in its ‘c’ conformation, exposing thiols and potentially driving a cell towards programmed cell death. The presence of CAT enhanced the ability of curcumin and its synthetic analogs to collapse the mitochondrial membrane potential, an important step in mitochondrial-mediated apoptosis. In conclusion, curcumin and the curcumin analogue NC-2109 were found to be cytotoxic in vitro, towards HCT-116 cells and also showed good selectivity. In addition, these two molecules were found to be ROS inducers, and coincidentally oxidized cellular thiols and caused depolarization of the mitochondrial membrane potential. The results support a mechanism of mitochondrial-mediated cell death upon MPT pore formation (mitochondrial swelling), perhaps involving ANT2. This conclusion was further supported by the potentiation of cell death in the presence of the ANT2 inhibitor, CAT.

This thesis deals with different optimization problems encountered in organic synthesis. The use of response surface, sequential simplex and PLS techniques, for simultanious optimization of yield and suppression of side reactions is investigated. This is illustrated by an example of enamine synthesis, were a side reaction was a serious problem. The problem of efficient screening to find suitable catalysts and solvents in new reactions is also investigated. Here, the use of principal properties as selection criterion, is demonstrated with a new process for the silylation of a,ß-unsaturated ketones. The extension of the new method to bis silylation of 1,2- and 1,3-diketones is demonstrated. The total synthesis of (±)-geosmin is investigated by an approach aimed to reduce the number of necessary steps involved. The suggested strategy, is to find compatible solvents through several transformations in the sequence to accomplish one-pot multistep reactions. In this context an improved method for the preparation of 1,10-dimethyl-l(9)-octalone-2 was established. Comparison with previously reported total syntheses of (±)-geosmin was done. / digitalisering@umu

The aim of the work was to develop an understanding of the phenomenon of rate enhancement observed when a heterogeneous catalytic reaction system is irradiated by ultrasound. The system under investigation was the catalytic hydrogenation of an a, B - unsaturated ketone, using zinc dust and aqueous nickel chloride as a source of hydrogen. When a slurry of zinc particles and aqueous nickel chloride is stirred or sonicated, nickel deposits in the form of patches on the surface of the zinc particles and simultaneously, zinc dissolves into the solution in the form of zinc ions, a process called pitting corrosion. Hydrogen atoms are formed when hydrogen ions diffuse from the bulk, adsorb onto the nickel surface and take up electrons generated by the dissolution of zinc. Once the atoms are formed on the surface, the atoms combine to form hydrogen molecules, which desorb in the form of hydrogen gas. When ketone is added to this slurry, the hydrogen atom formed on the surface of nickel is used as the source of hydrogen for the hydrogenation reaction. In these processes, nickel serves as catalyst. The ketone first has to diffuse to the bulk, adsorb onto the surface of nickel and undergo reduction by the hydrogen atoms to form the product. The product then has to desorb from the surface and diffuse into the bulk, in order to create vacant sites on the nickel surface for the adsorption of more ketone. Experiments dealing with measurements of hydrogen evolution rates pointed out that hydrogen is not a limiting reactant, since evolution was sustained for long periods of time. The evolution rates versus time data revealed that the nature of the plots for both, the stirred and sonicated systems were similar. These facts lead us to infer that the basic mechanism of nickel deposition, pitting corrosion, etc. was similar for the two cases. To study the hydrogenation reaction, experiments were first conducted keeping the nickel catalyst surface area constant. The results of these experiments showed that the hydrogenation reaction can be explained by a first order mechanism. Changing the speed of the stirrer did not effect the rate of the reaction; hence it was inferred that the reaction was not external mass transfer controlled. It was also seen that there was an no significant difference in reaction rates between the stirred and sonicated systems. Hence we conclude that sonication does not effect any process involved in the actual process of hydrogenation, i.e., adsorption, desorption, surface reaction, etc., do not get effected. It was concluded that the observed rate enhancements of similar compounds in the same system occur only when nickel catalyst is being continuously formed. This is possible only if irradiation with ultrasound enhances the rate of formation of the surface area of the nickel deposit. To study this phenomena, experiments were conducted with continuous formation of nickel catalyst. These experiments were conducted in three ways - stirring with zinc dust, sonication with zinc dust and stirring with presonicated zinc dust. For the first two kinds of experiments, the rates were low, increased to a maximum value and then decreased, but the nature of the third kind of experiments were different. The initial rates were very high as compared to either of the other two kinds of experiments but the rate rapidly reduces and becomes comparable to the rates obtained by stirring with zinc dust. We conclude that sonication creates many active sites on the surface of the zinc particles in the form of crystal defects, which are perhaps necessary for the deposition of nickel. When presonicated zinc particles are used, there are large numbers of these sites and these get consumed rapidly when stirred with aqueous nickel chloride solution. In this work, we do not deal with this case. In the case of sonication with zinc dust, these active sites are continuously created and are consumed by nickel deposition. For the stirred system, these sites are quite small to start with and new ones are not generated since there is no irradiation by ultrasound. Hence, the rates in the latter case are low for both nickel deposition and the hydrogenation reaction. In the model, it was assumed that the rate of increase of surface area of nickel, characterized by a specific rate term k z, was proportional to the amount of nickel in the bulk and also to the amount of free zinc surface area available. Similarly, nickel which deposits on previously deposited nickel (characterized by another specific rate constant, kn) was proportional to the amount of nickel in the bulk, the nickel area already deposited and also the free zinc surface area available. The model is in excellent agreement with the experimental data obtained. The model predicted higher values of kn and kz for the sonicated system, indicating that the rate of deposition of nickel is much higher in this case than for the stirred system. Moreover, the model also predicts that the deposit in the case of a sonicated system is thinner and flatter, since it was seen that the surface area created for the same amount of nickel deposited was much higher in this case than the stirred system.

Die Umsetzung von alpha,beta-ungesättigten Aldehyden und Ketonen mit Wasserstoff über Pd-Modellkatalysatoren wurde anhand von Molekularstrahlmethoden, kombiniert mit Infrarot-Reflexions-Absorptions-Spektroskopie (IRAS), Quadrupol-Massenspektrometrie (QMS) und Röntgen-Nahkanten-Absorptions-Spektroskopie (NEXAFS), unter wohldefinierten Ultrahochvakuumbedingungen untersucht. Das Ziel dieser Arbeit war es, ein atomistisches Verständnis der strukturellen Faktoren zu gewinnen, die die Aktivität und Selektivität eines Pd(111)-Einkristalls und Eisenoxid-geträgerter Pd-Nanopartikel für die Hydrierung der C=C- und C=O-Bindungen bestimmen. Exemplarisch für diese Art von Kohlenwasserstoffen wurden das Aldehyd Acrolein und das Keton Isophoron gewählt. Die NEXAFS- und IRAS-Studien zeigten, dass Isophoron bei niedrigen Bedeckungen auf Pd(111) in einer flachliegenden Geometrie adsorbiert wird. Die Neigungswinkel der C=C- und C=O-Bindungen in Bezug auf die Pd(111)-Ebene nehmen mit zunehmender Oberflächenbedeckung zu. Auf reinem Pd(111) ist die Neigung der C=C-Bindung stärker ausgeprägt, was auf eine Verzerrung des konjugierten pi-Systems hindeutet. Bei Anwesenheit von Wasserstoff wird eine schwächere Bindung von Isophoron an Pd beobachtet. Die selektive partielle Hydrierung über einer Pd(111)-Oberfläche und geträgerten Pd-Nanopartikeln unterschiedlicher Größen wurde unter Verwendung von Acrolein untersucht. Molekularstrahlmethoden wurden mit IRAS- und QMS-Messungen kombiniert, um gleichzeitig die Bildung von Adsorbaten auf der Oberfläche und die der Produkte in der Gasphase verfolgen zu können. Über einem Pd(111)-Kristall wird Propenol mit nahezu 100% Selektivität durch Hydrierung der C=O-Gruppe gebildet, während über Pd-Partikeln Propanal durch selektive Hydrierung der C=C-Gruppe erzeugt wird. IRAS-Untersuchungen zeigten, dass die Propenol-Bildung eine Modifikation der Pd(111)-Oberfläche mit einer dichten Oxopropyl-Monolage voraussetzt. / The conversion of alpha,beta-unsaturated aldehydes and ketones with hydrogen over model Pd catalysts was investigated using molecular beam techniques combined with infrared reflection-absorption spectroscopy (IRAS), quadrupole mass spectrometry (QMS), and near-edge X-ray absorption fine structure (NEXAFS) studies under well-defined ultra-high vacuum conditions. The aim of this work was to gain atomistic-level understanding of structural factors governing the selectivity and activity of a Pd(111) single crystal and iron-oxide-supported Pd nanoparticles for C=C and C=O bond hydrogenation. The ketone isophorone and the aldehyde acrolein were chosen as prototypical alpha,beta-unsaturated carbonyl compounds. NEXAFS and IRAS studies showed that isophorone is adsorbed on Pd(111) in a flat-lying geometry at low coverages. With increasing coverage, both C=C and C=O bonds tilt with respect to the surface plane. The tilting is more pronounced for the C=C bond on pristine Pd(111), indicating a strong distortion of the conjugated pi system upon interaction with Pd. Co-adsorbed hydrogen leads to a conservation of the in-plane geometry of the conjugated pi system, pointing to a much weaker interaction of isophorone with Pd in the presence of hydrogen. The selective partial hydrogenation over a Pd(111) surface and supported Pd nanoparticles with different particle sizes was investigated using acrolein. Molecular beam techniques were combined with IRAS and QMS measurements in order to simultaneously monitor the evolution of surface species and the formation of the final gas-phase products. Over a Pd(111) single crystal, acrolein is hydrogenated at the C=O bond to form propenol with nearly 100% selectivity, while over supported Pd particles, selective conversion of the C=C bond to propanal occurs. IRAS investigations showed that a distinct modification of the Pd(111) surface with a dense overlayer of an oxopropyl species is required for propenol formation.