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Synthesis of side-chain-modified mycothiol analogues incorporating carbazole quinones, and evaluation as inhibitors of enzymes in the Mycobacteria
Mycothiol is found only in Actinobacteria including M. tuberculosis, and appears to play an important role in the bacterium's defence against xenobiotics and oxidative stress. The biosynthetic pathway to this pseudo-disaccharide has been elucidated and a range of mycothiol-dependent enzymes have bee...
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| Format: | Thesis |
| Language: | English |
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Department of Chemistry
2016
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| _version_ | 1867613222253625344 |
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| access_status_str | Open Access |
| author | Ngumbu Muhunga, Denis |
| author2 | Gammon, David W |
| author_browse | Gammon, David W Ngumbu Muhunga, Denis |
| author_facet | Gammon, David W Ngumbu Muhunga, Denis |
| author_sort | Ngumbu Muhunga, Denis |
| collection | Thesis |
| description | Mycothiol is found only in Actinobacteria including M. tuberculosis, and appears to play an important role in the bacterium's defence against xenobiotics and oxidative stress. The biosynthetic pathway to this pseudo-disaccharide has been elucidated and a range of mycothiol-dependent enzymes have been identified. Compounds A.3, which have naphthoquinonyl units tethered to the pseudodisaccharide core, have significant inhibitory activity against mshB and mca in the biosynthetic pathway. These findings, together with the independent discovery of anti-TB activity associated with carbazole quinones such as B, led to the design and synthesis of a new class of hybrid molecules C which have the carbazole quinone motif tethered to the pseudodisaccharide core. The synthesis of these hybrid molecules involved initial preparation of phenylthio- or methyl-glucosides having either an amine or a suitably-functionalized carbon side-chain at C-2. Carbazole-quinones 37 and 39, bearing carboxyalkyl substituents, were prepared using Knölker methodology, and coupled to phenylthio-2-amino-glucoside 36 to generate, after deprotection, the desired hybrid structures 38 and 40. The preferred strategy for preparing 2-C-alkylglucosides was via initial preparation of a 2-C-carboxymethyl glucoside 44 from D-glucal, and conversion of this to the Weinreb amide 45 for intended coupling with Grignard and other organometallic reagents to form ketones. The Weinreb amide was shown to only react with simple metal-aryl reagents, and but not with those derived from the required tri-substituted benzenes. In the exploration of alternative strategies, the side-chain in 44 was successfully converted to either a 2-C-vinyl or the corresponding (E)-vinyl bromide side-chain, but both proved unreactive in attempts at Pd-mediated cross-coupling reactions to further develop the side-chain. Compound 44 could also be readily converted to either a 2-C-haloethyl or 2-C-aminoethyl derivative: the former resisted conversion to Wittig reagents, while the latter was unreactive in attempted Buchwald-Hartwig amination but successfully underwent reductive amination with a substituted benzaldehyde to give an advanced Abstract precursor of the target hybrid molecules. Compounds 38 and 40 together with similar analogues prepared in parallel with this study showed significant inhibitory activity against mshB, allowing for a preliminary SAR conclusion that the inhibitory activity is dependent on the covalent association of the glycoside and the carbazole-quinone, the point of attachment of the sugar unit to the carbazole quinone, and the length of the tether. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/20002 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:32:42.829Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2016 |
| publishDateRange | 2016 |
| publishDateSort | 2016 |
| publisher | Department of Chemistry |
| publisherStr | Department of Chemistry |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/20002 Synthesis of side-chain-modified mycothiol analogues incorporating carbazole quinones, and evaluation as inhibitors of enzymes in the Mycobacteria Ngumbu Muhunga, Denis Gammon, David W Chemistry Mycothiol is found only in Actinobacteria including M. tuberculosis, and appears to play an important role in the bacterium's defence against xenobiotics and oxidative stress. The biosynthetic pathway to this pseudo-disaccharide has been elucidated and a range of mycothiol-dependent enzymes have been identified. Compounds A.3, which have naphthoquinonyl units tethered to the pseudodisaccharide core, have significant inhibitory activity against mshB and mca in the biosynthetic pathway. These findings, together with the independent discovery of anti-TB activity associated with carbazole quinones such as B, led to the design and synthesis of a new class of hybrid molecules C which have the carbazole quinone motif tethered to the pseudodisaccharide core. The synthesis of these hybrid molecules involved initial preparation of phenylthio- or methyl-glucosides having either an amine or a suitably-functionalized carbon side-chain at C-2. Carbazole-quinones 37 and 39, bearing carboxyalkyl substituents, were prepared using Knölker methodology, and coupled to phenylthio-2-amino-glucoside 36 to generate, after deprotection, the desired hybrid structures 38 and 40. The preferred strategy for preparing 2-C-alkylglucosides was via initial preparation of a 2-C-carboxymethyl glucoside 44 from D-glucal, and conversion of this to the Weinreb amide 45 for intended coupling with Grignard and other organometallic reagents to form ketones. The Weinreb amide was shown to only react with simple metal-aryl reagents, and but not with those derived from the required tri-substituted benzenes. In the exploration of alternative strategies, the side-chain in 44 was successfully converted to either a 2-C-vinyl or the corresponding (E)-vinyl bromide side-chain, but both proved unreactive in attempts at Pd-mediated cross-coupling reactions to further develop the side-chain. Compound 44 could also be readily converted to either a 2-C-haloethyl or 2-C-aminoethyl derivative: the former resisted conversion to Wittig reagents, while the latter was unreactive in attempted Buchwald-Hartwig amination but successfully underwent reductive amination with a substituted benzaldehyde to give an advanced Abstract precursor of the target hybrid molecules. Compounds 38 and 40 together with similar analogues prepared in parallel with this study showed significant inhibitory activity against mshB, allowing for a preliminary SAR conclusion that the inhibitory activity is dependent on the covalent association of the glycoside and the carbazole-quinone, the point of attachment of the sugar unit to the carbazole quinone, and the length of the tether. 2016-06-10T07:39:36Z 2016-06-10T07:39:36Z 2015 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/20002 eng application/pdf Department of Chemistry Faculty of Science University of Cape Town |
| spellingShingle | Chemistry Ngumbu Muhunga, Denis Synthesis of side-chain-modified mycothiol analogues incorporating carbazole quinones, and evaluation as inhibitors of enzymes in the Mycobacteria |
| thesis_degree_str | Doctoral |
| title | Synthesis of side-chain-modified mycothiol analogues incorporating carbazole quinones, and evaluation as inhibitors of enzymes in the Mycobacteria |
| title_full | Synthesis of side-chain-modified mycothiol analogues incorporating carbazole quinones, and evaluation as inhibitors of enzymes in the Mycobacteria |
| title_fullStr | Synthesis of side-chain-modified mycothiol analogues incorporating carbazole quinones, and evaluation as inhibitors of enzymes in the Mycobacteria |
| title_full_unstemmed | Synthesis of side-chain-modified mycothiol analogues incorporating carbazole quinones, and evaluation as inhibitors of enzymes in the Mycobacteria |
| title_short | Synthesis of side-chain-modified mycothiol analogues incorporating carbazole quinones, and evaluation as inhibitors of enzymes in the Mycobacteria |
| title_sort | synthesis of side chain modified mycothiol analogues incorporating carbazole quinones and evaluation as inhibitors of enzymes in the mycobacteria |
| topic | Chemistry |
| url | http://hdl.handle.net/11427/20002 |
| work_keys_str_mv | AT ngumbumuhungadenis synthesisofsidechainmodifiedmycothiolanaloguesincorporatingcarbazolequinonesandevaluationasinhibitorsofenzymesinthemycobacteria |