4-Aza-Podophyllotoxins: synthesis and use as anti-cancer agents
| dc.contributor.advisor | Van Otterlo, Willem A. L. | en_ZA |
| dc.contributor.advisor | Blackie, Margaret | en_ZA |
| dc.contributor.author | Gould, Khaya TImothy | en_ZA |
| dc.contributor.other | Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. | en_ZA |
| dc.date.accessioned | 2020-02-25T20:44:32Z | |
| dc.date.accessioned | 2020-04-28T15:15:39Z | |
| dc.date.available | 2020-02-25T20:44:32Z | |
| dc.date.available | 2020-04-28T15:15:39Z | |
| dc.date.issued | 2020-03 | |
| dc.description | Thesis (MSc)--Stellenbosch University, 2020. | en_ZA |
| dc.description.abstract | 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. | en_ZA |
| dc.description.abstract | AFRIKAANSE OPSOMMING: Podofilotoksien, en hul afgeleides, het beduidende anti-proliferatiewe eienskappe. Etoposiede en ander semi-sintetiese analoë, soos teniposiede, is suksesvol as kliniese teenkankermiddels gebruik. 4-Aza- podofilotoksien, wat struktureel vereenvoudigde sintetiese analoë van podofilotoksien is, is suksesvol gesintetiseer en het vergelykbare biologiese aktiwiteit getoon met (-) podophyllotoxin wat natuurlik voorkom in plante. Twee groepe van 4-aza-podofilotoksien analoë is gesintetiseer sodat die metode van inhibering van hierdie klas verbindings verder ondersoek kan word. Die inligting van die biologiese toetsresultate uit die eerste groep met analoë, is gebruik in die sintese van 'n tweede groep van verbindings. Die eerste groep bevat 'n uiteenlopende groep van twaalf 4-aza-podofilotoksien-analoë waarvan ses verskille toon in die 4N-posisie. Die helfte van hierdie verbindings gemodelleer na etoposied en die ander is helfte gemodelleer na (-) podofilotoksien vat in natuur voorkom. Dit is bereik deur N-funksionalisering van die uitgangsmateriaal, 'n anilien, voordat dit in 'n multikomponentreaksie met tetronsuur en 'n gefunksionaliseerde bensaldehied gebruik is. Die tweede groep van vyf verbindings is gegenereer met behulp van 'n aziedalkyne-cycloaddition om twee alkienbevattende verbindings uit die eerste groep te verander. Die eerste biblioteek het IC50-waardes van nano-molêre konsentrasies (125-250 nM) teen 'n WHCO1-slukderm-sellyn-toets getoon. Ons het daarin geslaag om 'n klein struktuuraktiwiteitsverhouding te genereer uit hierdie biologiese resultate. | af_ZA |
| dc.description.version | Masters | en_ZA |
| dc.embargo.terms | 2021-02-26 | |
| dc.format.extent | 192 pages | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/10019.1/108480 | |
| dc.language.iso | en_ZA | en_ZA |
| dc.publisher | Stellenbosch : Stellenbosch University | en_ZA |
| dc.rights.holder | Stellenbosch University | en_ZA |
| dc.subject | Podophyllotoxin | en_ZA |
| dc.subject | Anti-cancer Agents | en_ZA |
| dc.subject | Synthetic drugs | en_ZA |
| dc.subject | Multicomponent reaction | en_ZA |
| dc.title | 4-Aza-Podophyllotoxins: synthesis and use as anti-cancer agents | en_ZA |
| dc.type | Thesis | en_ZA |