Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Ondřej Kratochvíl Supervisor: prof. RNDr. Milan Pour, Ph.D. Supervisor - specialist: Mgr. Rastislav Antal Title of Thesis: Reduction of electron-deficient dendralenes by hydride reagents This diploma thesis is focused on the preparation of electron-deficient [3]dendralenes containing electron withdrawing groups such as carbonyl and ester functionalities. The synthesis is based on a palladium-catalyzed Migita-Stille coupling between stannylated diene and iodinated alkene (cycloalkene). Subsequent reaction of these substituted [3]dendralenes with hydride anion leads to a 1,2- or 1,4-addition to the α, β-unsaturated carbonyl group, resulting in the formation of an enolate or alcoholate, which are further transformed to various products depending on the type of the [3]dendralene.

Heterotrimeric Gi proteins play a role in lipopolysaccharide (LPS) and Staphylococcus aureus (SA) activated signaling leading to inflammatory mediator production. We hypothesized that genetic deletion of Gi proteins would alter cytokine and chemokine production induced by LPS and SA. LPS- and heat killed SA-induced cytokine and chemokine production in splenocytes from wild type (WT), Gαi2 (-/-) or Gαi1/3 (-/-) mice were investigated. LPS- or SA-induced production of TNFα, IL-6, IFNγ, IL-12, IL-17, GM-CSF, MIP-1α, MCP-1, MIG and IP-10 were significantly increased (1.2 to 33 fold, p < 0.05) in splenocytes harvested from Gαi2(-/-) mice compared with WT mice. The effect of Gαi protein depletion was remarkably isoform specific. In splenocytes from Gαi1/3 (-/-) mice relative to WT mice, SA-induced IL-6, IFNγ, GM-CSF, and IP-10 levels were decreased (59% to 86%, p < 0.05), whereas other LPS- or SA-stimulated cytokines and chemokines were not different relative to WT mice. LPS- and SA-induced production of KC were unchanged in both groups of the genetic deficient mice. Splenocytes from both Gαi2 (-/-) and Gαi1/3 (-/-) mice did not exhibit changes in TLR2 and TLR4 expression. Also analysis of splenic cellular composition by flow cytometry demonstrated an increase in splenic macrophages and reduced CD4 T cells in both Gαi2 (-/-) and Gαi1/3 (-/-) mice relative to WT mice. The disparate response of splenocytes from the Gαi2 (-/-) relative to Gαi1/3 (-/-) mice therefore cannot be attributed to major differences in spleen cellular composition. These data demonstrate that Gi2 and Gi1/3 proteins are both involved and differentially regulate splenocyte inflammatory cytokine and chemokine production in a highly Gi isoform specific manner in response to LPS and Gram-positive microbial stimuli.

Magnesium deficiency in rats is known to precipitate audiogenic seizures. An unknown mineral factor in a diet mixture was found to substantially reduce the seizure occurence in magnesium deficient vii animals. This was corrected when the same mineral mixture was remade. Subsequently the faulty mineral mixture was discarded. This research .. as aimed at determining the mineral factor responsible for the observed changes in seizure occurence, and also aimed at investigating the relationships of serum calcium, magnesium and phosphorus concentrations to seizure susceptibility. Treatments to change the serum concentrations of these minerals included dietary manipulation, subcutaneous injection of calcitonin, of 1 ,25-dihydroxycholecalciferol, of calcium and of phosphorus. Animals fed magnesium deficient, low phosphorus diet and magnesium deficient animals fasted over-night were found to have significantly lower audiogenic seizure susceptibility than all other magnesium deficient animals regardless of treatment. Reduced audiogenic seizure susceptibility was not produced by any of the injections. The reduction in seizure with the magnesium deficient, low phosphorus diet indicates that phosphorus is an important factor in the mechanism of audiogenic seizuring in magnesium deficient rats.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19171号 / 医博第4013号 / 新制||医||1010(附属図書館) / 32163 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 柳田 素子, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

付記する学位プログラム名: 充実した健康長寿社会を築く総合医療開発リーダー育成プログラム / 京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第21696号 / 医科博第100号 / 新制||医科||7(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 齊藤 博英, 教授 清水 章, 教授 Shohab YOUSSEFIAN / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Potato production requires high phosphorus (P) application with potential negative environmental or nutritional consequences for potato as well as for subsequent crops. Impacts of high available P on yield and plant nutrition of species in potato cropping rotations are inadequately understood, and could result in antagonistic interactions with cationic micronutrients such as zinc (Zn) and manganese (Mn). Three hydroponic experiments were conducted with Russet Burbank potato to elucidate P and Zn relationships and associated interactions with other nutrients. In the first experiment, P solution concentration was constant at 256 µM while Zn concentration varied: 0.1, 2, 6, 18, 54, 162 and 456 µM Zn. In the second, Zn solution concentration was constant at 6 µM while P concentration varied: 32, 64, 128, 256, 512, 1024 and 2048 µM P. In the third, three levels of P and Zn varied in all possible combinations: 32, 128 and 1024 µM P and 0.1, 54 and 486 µM Zn. As expected, Zn increased in all plant parts with increasing old shoots while root P increased. This suggests a P-Zn complex formation in roots preventing movement of P to the shoots of plants under high Zn. This was confirmed under variable P and Zn. Contrary to expectations, a direct impact of increased solution P on Zn uptake or distribution in potato was not observed except at 486 µM Zn in the third experiment. Increased solution P at low Zn levels resulted in a steep increase of P in new and old shoot growth and an accumulation of Mn in potato roots—factors that might indirectly impact Zn nutrition in potato. Although high P levels in potato did not directly reduce Zn content or cause Zn deficiency, excessive P accumulation with insufficient Zn may reduce the activity of Zn by interacting with other micronutrients such as Mn.

This work investigates a novel iron Fischer-Tropsch (FT) catalyst preparation and describes the development of a trickle fixed-bed recycle reactor model (TFBRRM) for the FT synthesis applicable to both iron and cobalt catalysts. The iron catalyst preparation was developed using a novel solvent deficient precipitation reaction. Fifteen Fe/Cu/K/SiO2 catalysts were prepared to investigate key preparation variables including timing of promoter addition, washing or not washing after precipitation, and drying temperature. Adding promoters to starting materials before precipitation (1S) gives more uniform promoter distributions which gives higher water-gas shift activity and lower methane selectivity. Unwashed catalysts have smaller average pore and crystallite diameters (3.9-10.8 nm versus 15.3-29.5 nm) and 30% smaller pore volumes, but 65% higher rates of reaction than washed catalysts. Catalysts dried first at 100 °C have up to 50% smaller average pore and crystallite diameters, but 10-20% higher rates of reaction than catalysts dried first at 60 °C. Overall, 1S catalysts, left unwashed, and dried first at 100 °C are best suited in activity, selectivity, and stability for wax production from hydrogen-deficient feed stocks such as coal, biomass, or municipal waste. The activity of the most active catalyst of this study is greater than or equal to the activities of two of three catalysts reported in the literature. This dissertation describes in detail the TFBRRM, reports its validation, and presents results of varying fundamental, theoretically-based parameters (e.g. effective diffusivity, Prandtl number, friction factor, etc.) as well as physical process parameters (i.e. recycle ratio, pressure, flow rate, tube diameter, cooling temperature, and pellet diameter and shape). For example, the model predicts that decreasing effective diffusivity from 7.1E-9 to 2.8E-9 m^2/s results in a lower maximum temperature (from 523 to 518 K) and a longer required bed length to achieve 60% conversion of CO (from 5.7 to 8.5 m). Using the Tallmadge equation to estimate friction losses as recommended by the author results in a pressure drop 40% smaller than using the Ergun equation. Validation of the model was accomplished by matching published full-scale plant data from the SASOL Arge reactors.

No description available.

This thesis focuses on the development of molecules that target proteins in a previously undescribed manner for the treatment of BRCA deficient cancers. ZINC 13403027, a clerodan-based natural product, was shown to target a protein called Rad52. Cancers possessing loss of function mutations in BRCA1 and BRCA2 are dependent on Rad52 for DNA repair and replication while normal, healthy cells possess multiple DNA repair/replication pathways. Thus, inhibitors of Rad52 may serve as selective anti-cancer drugs for BRCA deficient tumors. ZNIC 13403027 was selected for its high activity in disrupting the ssDNA-Rad52 interaction in a gel-shift assay as well as exhibiting the required inactivity at disrupting the ssDNA-Rad51 interaction. Due to its lack of permeability, a synthetic route amenable to modification has been partially developed. It is thought that a prodrug or bioisostere of ZINC 13403027 could cross the membrane so that the cellular activity of this novel tool molecule may be established. Additionally, an allosteric PARP1 inhibitor, 5F02, was explored. Discussed here is the synthetic route to 5F02 and its analogs. Structure activity relationships were develop in an attempt to increase inhibitory activity and drug-like properties. This thesis reports the success to date on these two projects. / Pharmaceutical Sciences