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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/96959 |
| Date | 04 1900 |
| Creators | Botes, Marthinus Gerhardus |
| Contributors | van Otterlo, Willem A. L., Pelly, Stephen C., Blackie, Margaret A. L., Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | Unknown |
| Type | Thesis |
| Format | xi, 85 pages : illustrations |
| Rights | Stellenbosch University |
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