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.

Several novel multicomponent assembly processes have been developed for the preparation of a diverse array of complex heterocyclic systems from relatively simple starting materials. These studies resulted in the discovery of a new quinazolone forming reaction, which was applied to the one-step synthesis of the quinazolinocarboline alkaloid rutaecarpine. Biological screening of these complex heterocycles culminated in the identification of a potent sigma-2 receptor ligand. A novel N-acyliminium ion mediated cascade reaction was employed for the concise synthesis of (±)-actinophyllic acid. The completion of the synthesis relied on the development of a reaction sequence that avoided a potentially detrimental fragmentation process. Furthermore, several anti-cancer compounds were identified through a diverted total synthesis approach. / text

In this thesis, synthetic chemistry was used as a tool in the exploration of various aspects of natural products discovered by the natural products research group at the University of Canterbury. Work on the constituent amino acids and connectivity of the pteratides, a potently cytotoxic series of cyclodepsipeptides, had been completed before the beginning of this work (carried out by Miss C. Chen). The elucidation of the stereochemistry of the constituent amino acids was undertaken in this present work. The synthesis of all stereochemical entities of a number of unusual amino acids, which were either not available commercially or were expensive, was carried out, providing reference materials for comparison to the natural products. The synthesis of the diastereoisomers of one of these amino acids, 4-methylproline, was carried out by modification of literature procedures, which led to the development of an improved, concise and stereoselective synthesis. The hydrolysis of the natural products, derivatisation of the resultant hydrolysates, synthetic and commercial reference amino acids and HPLC analysis allowed the full stereochemical assignment of the pteratide series. The total synthesis of spiro-mamakone A, a cytotoxic polyketide isolated by Dr S. van der Sar, was undertaken. The synthesis was not successfully completed due to difficulties in the late-stage formation of a crucial enedione motif. However, very advanced intermediates were successfully synthesised. These synthetic analogues of the natural product were analysed for biological activity, allowing valuable insight into the structure-activity relationship, for example, demonstrating the importance of the enedione moiety to biological activity.

Two new synthetic methods for the construction of the C-D moiety of streptonigrin have been developed. The first is the cyclization of beta, gamma unsaturated ketals to cyanopyridines. These ketals were prepared from akylidenemalononitriles. The second method utilized is the ortho-directed metalation of benzamide or oxazoline derivative to give keto compounds. However, attempts to transform these keto compounds to akylidenemalononitriles by Knoevenagel condensations were unsuccessful. With the ease of the reaction and ready availability of starting materials, the beta, gamma unsaturated ketals offer versatile synthons for pyridine C ring synthesis.

No description available.

No description available.

No description available.

No description available.

No description available.

Cancer is a human tragedy that strikes and kills the lives of our beloved people. With a limited number of effective anticancer drugs from natural resources currently in use, there is a real need for new, safe, cheap and effective anticancer drugs to combat this dreaded and formidable disease. Plants have a long history of use in the treatment of cancer. Several plant-derived anticancer agents including taxol, vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan and etoposide derived from epi- podophyllotoxin are in clinical use all over the world. In this study, two endemic plant species from the Rubiaceae and Asteraceae families, namely Anthospermum hispidulum E.Mey. ex Sond. and Eriocephalus tenuifolius DC. were investigated for their anticancer properties. The organic (methanol/dichloromethane, 1:1 v/v) extracts of both plant species were found to have moderate anticancer activity against a panel of three human cancer cell lines namely, breast MCF7, renal TK10 and melanoma UACC62 at the CSIR anticancer screen. Bioassay-guided fractionation of the organic extracts of Anthospermum hispidulum led to the isolation of an active compound which was characterised as ursolic acid. Another compound, namely scopoletin was also isolated. The compounds isolated here are known compounds, but have not previously been reported as present in the genus Anthospermum. Bioassay-guided fractionation of the organic extracts of Eriocephalus tenuifolius resulted in the isolation of 8-O-isobutanoylcumambrin B as the active constituent. This compound is reported to have been isolated from related plant species; however its biological activity is not known. The compounds pectolinagenin, hispidulin, friedelinol and tetracosanoic acid were also isolated, but did not show any significant anticancer activity. The structures of all compounds isolated in this study were elucidated using nuclear magnetic resonance spectroscopy, mass spectroscopy and also by comparison with data reported in the literature. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2008.