Browsing by Author "Gould, Khaya TImothy"

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    4-Aza-Podophyllotoxins: synthesis and use as anti-cancer agents
    (Stellenbosch : Stellenbosch University, 2020-03) Gould, Khaya TImothy; Van Otterlo, Willem A. L.; Blackie, Margaret; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Podophyllotoxins, and their derivatives, have shown significant anti-proliferative properties. Etoposide and other semi-synthetic analogues, such as teniposide, have been successfully employed as clinical anti-cancer agents. 4-Aza-podophyllotoxins, which are structurally simplified synthetic analogues of podophyllotoxin, have been successfully synthesised and have shown comparable biological activity to the naturally occurring (-) podophyllotoxin. To further investigate the method of inhibition of this class of compounds, which have been reported to act as either tubulin inhibitors or topoisomerase II poisons, two libraries of 4-aza-podophyllotoxin analogues were synthesised. The biological test results from the first library of analogues was used to inform the synthesis of a second library of compounds. The first library contains a diverse group of twelve 4-aza- podophylltoxin analogues, six with differences in the 4N- position. Half of these compounds were modelled after etoposide, and half modelled after the naturally-occurring (-)-podophyllotoxin. This was achieved through N- functionalization of the starting material, an aniline, prior to its use in a multicomponent reaction with tetronic acid and a functionalized benzaldehyde. The second library of four compounds was generated using an azide alkyne cycloaddition to modify two alkyne-containing compounds from the first library. The first library has shown IC50 values of nano-molar concentrations (125-250 nM) against a WHCO1 oesophageal cell line assay. A small structure activity relationship from these biological results was obtained.