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Chapter 1: Chapter One provides an overview on the Bohlmann-Rahtz pyridine synthesis. New procedures, implementing metal based Lewis acids, Brønsted acids and metal-free Lewis acid catalysts have been used in this process. Also, new one-pot two- and three-component methodologies have been developed for the synthesis of various natural products containing the pyridine motif and these have been compared and contrasted. This chapter also discusses signalling pathways in Werner syndrome cells. The inhibitor SB203580 has been shown to prevent the phosphorylation of the p38α kinase in a ATP competitive manner and this implicates this mechanism in accelerated ageing and gives potential to the prospect of targeting this pathway in a drug discovery programme, if better mechanistic understanding can be garnered. Chapter 2: Chapter Two discusses the Bohlman–Rahtz synthesis of various substituted pyridines. The process has been modified to be simple, involves mild conditions and provides the heterocyclic targets in high yield. We have shown that substituted pyridines could be synthesised efficiently under microwave conditions using a relatively short reaction time. The process was also successful for the production of a range of fused heterocycles containing the pyridine moiety in high yield, including pyrido[2,3-d]pyrimidin-4(3H)-ones and pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones. Chapter 3: Chapter Three describes the efficient synthesis of the p38 MAPK inhibitor UR-13756 using a Hantzsch-type three component cyclocondensation. Microwave irradiation of a mixture of 3-amino-1-methylpyrazole hydrochloride, 1-(4-fluorophenyl)-2-(pyridine-4-yl)ethanone and 4-fluorobenzaldhyde for 4 hours in ethanol under acidic catalytic conditions provided UR-13756 in high yield (71%) after purification by column chromatography. Chapter 4: Chapter Four shows the synthesis of 4-(3-amino-1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzamide in three steps by the use of rigorous experimental procedures under microwave conditions. This technique led to faster heating rates and allowed the rapid optimization of yields. These advantages were observed in all steps and allow formation of products in high yields. Biological study of the inhibitor 4-(3-amino-1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzamide showed, by ELISA analysis, that p38a signalling was inhibited in control dermal cells. Some progress was made towards the synthesis of 3-amino-4-[1-(3-1H-pyrazol-4-yl)]benzamide. Chapter 5: Chapter Five investigates the synthesis of the chemotherapeutic agent RO3201195, a highly selective inhibitor of p38α, in seven steps under microwave conditions. The procedure provides a relatively high overall yield of the desired product and all other intermediates involved in individual steps compared with conventional heating methods. Chapter 6: Chapter Six provides the experimental procedures and various spectroscopic data for the synthesized compounds. |
