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Towards the synthesis of makaluvamine-analogues
Thesis (MSc)--Stellenbosch University, 2015.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2015
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| _version_ | 1867613826822701056 |
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| access_status_str | Open Access |
| author | Botes, Marthinus Gerhardus |
| author2 | Van Otterlo, Willem A. L. |
| author_browse | Botes, Marthinus Gerhardus Van Otterlo, Willem A. L. |
| author_facet | Van Otterlo, Willem A. L. Botes, Marthinus Gerhardus |
| author_sort | Botes, Marthinus Gerhardus |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2015. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/96959 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:42:19.474Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2015 |
| publishDateRange | 2015 |
| publishDateSort | 2015 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/96959 Towards the synthesis of makaluvamine-analogues Botes, Marthinus Gerhardus Van Otterlo, Willem A. L. Pelly, Stephen C. Blackie, Margaret A. L. Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Makaluvamines -- Synthesis Anticancer compounds Natural products UCTD Thesis (MSc)--Stellenbosch University, 2015. ENGLISH ABSTRACT: Cancer is one of the leading causes of death in developed countries and rising fast as a cause of death in developing countries. The increase of cancer prevalence in developing countries can be attributed to westernisation trends, with lifestyle cancers such as colorectal and lung cancer being amongst the most commonly reported malignant neoplasms. This means that the development of novel methods of treatment is essential in combatting this disease in the developing world. Combinational chemotherapy is one of the best candidates for treatment, but it is reliant on effective compounds targeting different modes of action. It also means that these compounds should be easily and cheaply available. Makaluvamines have been identified as a class of compounds that may have a novel mode of action on top of being known as topoisomerase II inhibitors. This study attempted to devise a short and concise synthetic strategy, based on reported procedures, to construct makaluvamine C analogues. This involved the introduction of a methyl group to an indole intermediate (7,8-dimethoxy-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline), before oxidation to a quarternized pyrroloiminoquinone (7-methoxy-5-methyl-8-oxo-1,3,4,8- tetrahydropyrrolo[4,3,2-de]quinolin-5-ium chloride). The introduction of this methyl group proved problematic, as the indole substrate proved to be difficult to handle and tended to degrade under reaction conditions. The lack of initial success prompted the deviation from the initial route by quarternizing a quinoline intermediate to form a quinolinium iodide salt (4- (dimethoxymethyl)-6,7-dimethoxy-1-methyl-5-nitroquinolin-1-ium iodide). Upon reduction to give 4-(dimethoxymethyl)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-amine, it was discovered that the subsequent ring-closing reaction to produce 7,8-dimethoxy-5-methyl- 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline was still problematic. The synthesis of the target compounds has not yet been successfully completed, but will still be pursued so these compounds can be evaluated for their anticancer activity and have their mode of action tested. AFRIKAANSE OPSOMMING: Kanker lewer van die grootste bydrae tot mortaliteit in ontwikkelde lande en is vining aan die toeneem in ontwikkelende lande. Die toename van kanker voorvalle in ontwikkelende lande kan toegedra word aan die verwesteringstendens, met kankers soos kolo-rektale- en long kanker onder die mees algemene kwaadaardige neoplasmsas wat aangemeld word – kankers wat gekoppel word aan leefstyl keuses. Dit beteken dat daar ‘n dringende nood is aan nuwe metodes van behandeling van die siekte in ontwikkelende lande. Kombinasie chemoterapie is een van die beste kandidate vir behandel, sienende dat dit gebruik maak van middels was verskillende aspekte van die siekte uitbuit. Om effektief te wees, moet die antikanker middels goedkoop en maklik beskikbaar te wees. Makaluvamines is geïdentifiseer as ‘n klas van antikanker middele wat moontlik ‘n nuwe metode van inhibisie het, tesame met hul topoïsomerase II inhibisie. Hierdie study het daarom gepoog om ‘n korter en meer bondige sintetiese roete saam te stel, wat gebaseer is op literatuur prosedures, om analoeë van makaluvamine C te produseer. Dit het die aanhegging van ‘n metiel group aan ‘n indool tussenproduk (7,8-dimetoksie-1,3,4,5- tetrahidropirolo[4,3,2-de]kinolien) behels, gevolg deur die oksidasie tot die kwaternêre piroloiminokwinoon (7-metoksie-5-metiel-8-oxo-1,3,4,8-tetrahidropirolo[4,3,2-de]kinolin-5-ium chloried). Om hierdie metiel groep aan te voeg was, nietemin, problematies, aangesien die indool produk moeilik was om te hanteer sienende dat dit onder reaksie toestande gedegradeer het. Die aanvanklike onsuksesvolle pogings het daartoe gelei dat die sintetiese roete herdink was en is aangepas om eerder gebruik te maak van ‘n kinolinium jodied sout (4-(dimetoksiemetiel)-6,7-dimetoksie-1-metiel-5-nitrokinolin-1-ium jodied). Die reduksie van hierdie sout en agtereenvolgende annulasie reaksie om 7,8-dimetoksie-5-metiel-1,3,4,5- tetrahidropirolo[4,3,2-de]kinolien te vorm was egter steeds problematies. Die sintese van die beoogde produkte was tot dusver nog nie suksesvol nie, maar sal egter steeds aangedurf word om hulle ten einde suksesvol te sintetiseer en dan te stuur om hulle biologiese eienskappe te toets. Dit sluit hulle antikanker aktiwiteit in asook hul metode van inhibisie. 2015-05-20T09:28:44Z 2015-05-20T09:28:44Z 2015-04 Thesis http://hdl.handle.net/10019.1/96959 en_ZA Stellenbosch University xi, 85 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Makaluvamines -- Synthesis Anticancer compounds Natural products UCTD Botes, Marthinus Gerhardus Towards the synthesis of makaluvamine-analogues |
| title | Towards the synthesis of makaluvamine-analogues |
| title_full | Towards the synthesis of makaluvamine-analogues |
| title_fullStr | Towards the synthesis of makaluvamine-analogues |
| title_full_unstemmed | Towards the synthesis of makaluvamine-analogues |
| title_short | Towards the synthesis of makaluvamine-analogues |
| title_sort | towards the synthesis of makaluvamine analogues |
| topic | Makaluvamines -- Synthesis Anticancer compounds Natural products UCTD |
| url | http://hdl.handle.net/10019.1/96959 |
| work_keys_str_mv | AT botesmarthinusgerhardus towardsthesynthesisofmakaluvamineanalogues |