Browsing by Author "Gammon, David"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Open Access
    Aromatic hydroxylations over titanium-substituted crystalline silicates
    (2001) Wilkenhöner, Uwe; van Steen, Eric; Gammon, David
    This work focuses on aromatic hydroxylations over titanium-substituted zeolites of different pore sizes (TS-1, Al-free Ti-beta and Ti-HMS) using aqueous H2O2 as the oxidant. The aim was to gain a deeper understanding of the key factors controlling activity and selectivity, which implied an investigation of the reaction kinetics and the adsorption and diffusion properties of reactants and products in the various catalysts using different solvents. The role of shape selectivity inside the micropores of the solids and the reaction at their external surface was also examined.
  • Thumbnail Image
    Item
    Open Access
    Chemistry and properties of perhydrobenzo[4.5.6]cholestanes
    (1997) Mohamed, Camielah; Bull, James R; Gammon, David
    The investigations undertaken include an intramolecular Michael-aldol approach and a cycloaddition approach to the synthesis ofperhydrobe,nzo[4.5.6]cholestanes. A reaction sequence has been developed to obtain the 3 P-acetoxy-4cx.,5cx. - dihydrobenzo [ 4.5 .6] cholestan-5' (6'H)-one 85 in an optimised yield from the 3Pacetoacetoxy-i:4-6-ketone 71. The key steps in the transformation involved base-treatment of the 3P-acetoacetoxy enoneto give (2R)-2-(3P-hydroxy-6-oxo-5P-cholestan-4p-yl)-3- oxobutanoic acid 1,3'-lactone 79, which was followed by_lactone cleavage, decarboxylation and intramolecular aldol closure of the derived lactone to give 3P,6-dihydroxy4cx.,4',5P,6P-tetrahydrobenzo[4.5.6]cholestan-5'(6'H)-one 81. Treatment of 3P-acetoxy-6- hydroxy-4cx.,4',5P,6P-tetrahydrobenzo [4.5.6] cholestan-5'(6'H)-one 82 with HMPA and phosphoryl chloride gave the 3p-acetoxy-4cx.,4', sp,6-tetrahydrobenzo [ 4.5.6] cholest-6-en5'(6'H)-one 83 and the 4cx.,5cx. -i:4 '-isomer 85. The formation of 3p-hydroxy-4cx.,5cx. - dihydrobenzo [4.5.6] cholestan-5'(6'H)-one 80 when treating the lactone 79 with potassium hydroxide indicated an alternative reaction pathway to the 4cx.,5cx. -isomer. However, conditions were not established for the isolation of the 4cx.,5cx. -i: 4 '-isomer 80 in an appreciable yield. Access to the 4cx.,5P-isomer was achieved by treating the 3P-acetoxy-6p-hydroxy derivative 82 with BF3.OEt2 which gave the 4cx.,5p-i:6 -isomer 83 and 3P-acetoxy-4cx.,4',5P, 6-dihydrobenzo [4.5.6] cholestan-5'(6'H)-one 86. Thionyl choride-pyridine treatment of the 3 P-acetoxy-6p-hydroxy derivative 82 gave an inconclusive result including the formation of the expected 4cx.,5(3-i:6 -isomer 83. The expected thermodynamic relationship between the 4cx.,5cx. -isomer 85 and the 4P,5cx. -isomer was confirmed by base equilibration of the 4cx.,5cx. -isomer into the 4p,5cx. -isomer. Detailed 400 MHz 1 H and 13C NMR data of key pentacyclic cholestanes enabled interpretations about their structural ~d conformational properties and related thermodynamic stabilities. 2 The Diels-Alder cycloaddition of 6-methylenecholest-4-en-3p-ol 96 with acrolein and methyl vinyl ketone gave 6' a-acetyl-4P,4' ,5' p,6' -tetrahydrobenzo[ 4.5 .6]cholestan-3 Pyl acetate 97 and 3P,6'-epoxymethano-4P,4' ,5' ,6'-tetrahydrobenzo[4.5.6]cholestan-6' 1 P-yl acetate 98 respectively. The structures of these cycloaddition products were determined with 400 MHz 1H and 13C NMR data which included NOE spectra. The 6' -H orientation in the cycloadduct 98 could however not be established unambiguously.
  • Thumbnail Image
    Item
    Open Access
    Exploring the molecular diversity and biomedicinal potential of marine invertebrates and South African actinomycetes for tuberculosis drug discovery
    (2021) Acquah, Kojo Sekyi; Gammon, David; Beukes, Denzil; Meyers, Paul; Warner, Digby
    Tuberculosis (TB) which is caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death from a single infectious disease and remains a global health threat. Although there is medicine for treating TB, it still kills millions each year. This is due to a lengthy and demanding TB treatment regimen with associated problems of adverse drug-drug interactions and toxicities. Several resistant strains of Mtb, which are difficult and more expensive to treat, have also emerged. Therefore, there is a need to discover new potent and safe TB drugs to effectively treat Mtb with its resistant strains. Less explored and biodiversity-rich ecosystems such as the marine environment and South Africa (SA)'s fauna and flora have been a source of new bioactive natural products (NPs). A range of marine invertebrates and SA actinomycetes were therefore studied for the discovery of new antimycobacterial NPs. Several organic and aqueous marine invertebrate extracts were screened for their in vitro inhibitory activity against the Mtb strain H37Rv. The chemical components of two out of 54 active extracts were dereplicated using 1H NMR, HR-LCMS with GNPS molecular networking. The extracts were subsequently subjected to an activity-guided isolation process to yield heteronemin from Hyrtios reticulatus extract, and bengamides P and Q from Jaspis splendens extract. A new bengamide derivative was putatively identified in the molecular network of Jaspis splendens extract, and its structure predicted based on the similarity of its MS/MS fragmentation pattern to that of other bengamides. The isolated bioactive metabolites and semi-pure fractions exhibited antimycobacterial activity with MIC90 in the range of < 0.24 to 62.50 µg/mL. This is first report of antitubercular activity of bengamides P and Q. In studies on actinomycetes, the organic extract of a liquid culture of the South African Streptomyces strain Muiz4Y exhibited antimycobacterial activity against Mycobacterium aurum strain A+ and Mtb strain H37Rv. HR-LCMS analysis of the crude extract for dereplication suggested the presence of new compounds. A bioactivity, spectroscopy and spectrometry guided isolation procedure led to the isolation of three new natural products, a β-carboline alkaloid (1- (1,2-dihydroxyethyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid), a peptide (N-(2- phenylacetyl)-serine), and a glycosylated lactone (4-O-(β-glucopyranosyl)-5-(hydroxymethyl)-3- (4-methylpentyl)-5,6-dihydro-2H-pyran-2-one), together with known compounds 3,6- bis(phenylmethyl)-2,5-piperazinedione and 2,4,6-triphenylhex-1-ene. The structures of the isolated compounds were elucidated based on spectroscopic methods including 1D and 2D NMR, MS, as well as by comparison with the relevant literature. Only 2,4,6-triphenylhex-1-ene exhibited antimycobacterial activity against Mtb strain H37Rv with an MIC90 of 5.8 µg/mL. The novel rare South African Actinomycete Kribbella speibonae strain SK5 exhibited antimycobacterial activity against Mycobacterium aurum A+. Dereplicating the crude extract of a large-scale culture of strain SK5 using 1H NMR, genome mining and HR-LCMS with GNPS molecular networking showed that it is a prolific producer of hydroxamate siderophores including new congeners. Two new analogues, dehydroxylated desferrioxamines, speibonoxamine and desoxy-desferrioxamine D1, were isolated, together with four known hydroxamates, desferrioxamine D1, desferrioxamine B, desoxy-nocardamine and nocardamine, and a diketopiperazine (DKP). The isolated compounds were characterized by the analysis of HRESIMS and 1D and 2D NMR data, as well as by comparison with the relevant literature. Three new dehydroxy desferrioxamine derivatives were tentatively identified in the molecular network of K. speibonae strain SK5 extracts, and structures were proposed based on their MS/MS fragmentation patterns. A plausible spb biosynthetic pathway was proposed. To the best of our knowledge, this is the first report of the isolation of desferrioxamines from the actinobacterial genus Kribbella. The isolated compounds were inactive against Mtb strain H37Rv and Mycobacterium aurum A+. This study confirmed the marine environment as a source of new antimycobacterial NPs and established South African actinomycete as a source of new bioactive NPs.