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Masters Degrees (Chemistry)

Permanent URI for this collectionhttps://hdl.handle.net/10413/6597

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Browsing Masters Degrees (Chemistry) by Author "Albericio, Fernando."

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    2,4,6-Trichloro-1,3,5-triazine as a triorthogonal chemoselective linker.
    (2019) Rotimi, Sheyi Ebenezer.; Albericio, Fernando.; Garcia de la Torre, Beatriz.
    Abstract available in PDF.
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    Globomycin: an interesting antimicrobial depsipeptide discovering new active analogues.
    (2019) Phungula, Amanda.; Albericio, Fernando.; Garcia de la Torre, Beatriz.
    In South Africa and other African countries infectious diseases are reported to be the main health problem and results into death. This is the reason why the pharmaceutical industry has tried to develop new antibiotics to fight these diseases. Medicinal chemists are now being challenged to fight these diseases as few drugs are available and micro-organisms have become resistant towards the available antibiotics. Gram-negative bacteria are one of those bacteria and it is difficult to inhibit it. Globomycin a “head-to-tail” cyclodepsipetide has grown interest in the pharmaceutical industry since it can specifically inhibit Gram-negative by its mode of action. Other Globomycin analogues synthesised have shown activity also against Gram-positive bacteria. In this regard new active Globomycin analogues are to be synthesised in this project to increase the activity of the antibiotic against Gram-negative and Gram-positive bacteria. Since the lipidic chain of Globomycin is aliphatic and is important for its activity, in this project it is studied what will happen on the activity of the peptide if some changes are made on the aliphatic chain such as introducing a carbonyl or sulfonyl group on the lipidic chain. The analogues were synthesised using Fmoc SPPS strategy on 2-CTC-resin as the solid support, cyclised then purified using the SEMI-PREP HPLC. This was the first synthesis of Globomycin in solid phase where cyclization was achieved by lactamization reaction. In total four analogues were synthesised namely Fmoc-Globomycin, di-Hexyl-Globomycin, Hexanoic-Globomycin and Hexanesulfonyl-Globomycin. Antimicrobial activity studies then followed where both linear and cyclic Globomycin analogues were tested against both Gram-negative and Gram-positive bacteria strains. The results illustrated that only the cyclic di-Hexyl-Globomycin analogue was active against both bacteria strains. This demonstrated that the cyclic state of the compound is very important and also the aliphatic nature. The results also agree with the work done by the Kogen group that the L-allo-Thr and L-allo-Ile units are not very important.
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    Proline n-oxide : manipulation of the 3D conformation of linear peptides.
    (2013) Farahani, Majid Darestani.; Maguire, Glenn Eamonn Mitchel.; Govender, Thavendran.; Kruger, Hendrik Gerhardus.; Arvidsson, Per Ingemar.; Albericio, Fernando.
    During the last the few years, the number of peptide pharmaceutical drugs reaching the market has notably increased. Drug based peptides have many advantages, such as high potency of action and limited off-target side effects that are not present in most small molecules. However, oral bioavailability of peptides is a major obstacle that hinders the development of more therapeutic formulations. Physiochemical properties of peptides, such as short plasma half-life, sensitivity to enzyme degradation and the tendency to undergo aggregation, are some of the main reasons for the lack of bioavailability. Enhancement of bioavailability can be achieved when the flexibility of peptides is reduced to a more defined stereochemical structure. There are some approaches that can reduce the flexibility of peptide backbones to a more defined structure e.g. application of peptidomimetics and cyclic peptides. Here, we have investigated another new tool that can lead us to the same goal. The purpose of this study was to investigate the possibility of modulating the secondary structure of short peptides. This was envisaged via the application of a proline N-oxide moiety and by N-methylation of the peptide backbone. The major objectives for this study were: 1. To synthesise a series of tetrapeptides to investigate the effect of proline N-oxide on their secondary structure. 2. The effect of N-methylation of the amide bond on isomerization of the N-oxide peptide backbone in terms of cis- and trans-isomers and how it directs the potential hydrogen bonding interactions 3. To study the effect of side chain bulkiness on the potential of hydrogen bonding interactions of the selected peptides. 4. Analyses of the formed secondary structures with advanced NMR techniques. 5. To perform a thermal coefficient NMR study on these molecules in order to obtain an improved understanding of the nature of hydrogen bond interactions of these peptides.