3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item The development of novel pterin chemistry leading to potential dihydrofolate reductase inhibitors with potential antimalarial activity(2012-01-31) Nxumalo, WinstonThis thesis describes the application pteridine chemistry in various aspects of methodology development and natural product synthesis. The introductory chapter sets the scene by describing naturally occurring pteridines, their applications in biological systems, and recent synthetic strategies. Firstly, Sonogashira coupling reactions employing benzenesulfonyloxy-O-pteridine (27) and terminal alkynes to give various 6-substituted pteridines are described. This methodology allowed for the total synthesis of a natural occurring pteridine, Sepiapterin-C (46). Negishi coupling reactions involving benzenesulfonyloxy-O-pteridine (27) and various Znreagents are also reported. This methodology, representing the first Negishi coupling on a pteridine nucleus, allowed for the introduction of both aryl- and heteroaryl- substituents at the 6- position of the pteridine ring. The use of methanesulfonyloxy-O-pteridine (26) as a coupling partner is also described. Selective deprotection and hydrolysis of the formamidine protecting groups to give either the 6- substituted 2,4-diaminopterine or 2-amino-4-oxo-pteridine (pterin), is described. The synthesized structures are supported by NMR and mass spectral data and melting points where applicable. Novel compounds are verified by NMR spectroscopy, infrared and mass spectrometry.Item Reactions of N-sulfonylpyrroles yielding metal complexes with potential anti-cancer activity(2009-03-05T08:15:45Z) Nxumalo, WinstonThe dissertation describes the synthesis of sulfonylimine ligands from N-sulfonylpyrrole. These ligands form metal complexes with various transition metals and are to be tested for activity against cancer cells. The introductory chapter sets the scene by describing transition metals in existing therapy and current investigations on transition metals in therapy. It also covers current methodology for deprotonation of N-sulfonylpyrrole leading to carbon-carbon bond formation. The second chapter describes the experimental work performed in this project. A synthetic route towards sulfonylimine ligands, 4-methyl-N-[phenyl(1H-pyrrol- 2yl)methylene]benzenesulfonamide 15 and N-[phenyl(1H-pyrrol- 2yl)methylene]benzenesulfonamide 6, is described. The mechanism for the 1,4- migration of the sulfonyl group was investigated in a crossover experiment and was found to occur via an intra molecular shift. The sulfonylimine ligands were complexed with late transition metals from the first row (cobalt(II), nickel(II), copper (I), copper(II) and zinc(II)), second row (palladium(II) and silver(I))and third row (platinum(II)), and were submitted for testing against cancer cells. The first row transition metal complexes did not show activity against HeLa cancer cells, while in the second row, activity was observed for the silver complexes. The third row metal complex also showed anti-cancer activity. Previously reported methodology employing Grignard reagent and catalytic amine base to deprotonate N-sulfonylpyrrole and quenching with electrophiles was extended to indole, imidazole and benzimidazole ring systems. Results obtained were comparable to those reported using lithium bases. Addition of lithium chloride to the Grignard reagent reduces the mole equivalent of the reagent required for deprotonation. A comparison between the arylsulfonyl and dimethylsulfamoyl protecting groups in pyrrole and imidazole showed that arylsulfonyl are better protecting groups for pyrrole, while dimethylsulfamoyl is a better protecting group for imidazole. All synthesized organic structures were characterized by NMR spectral data, mass spectrometry and melting points where applicable. The synthesized metal complexes were characterized by mass spectroscopy, infrared spectroscopy and X-ray crystallography where applicable.