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Structure-activity and mechanistic investigations into the cytotoxicity of flavonols in cancer cells
Thesis (MSc)--Stellenbosch University, 2022.
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| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2022
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| _version_ | 1867613745274945536 |
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| access_status_str | Open Access |
| author | Van Rooyen, Jaco |
| author2 | Kaschula, Catherine H. |
| author_browse | Kaschula, Catherine H. Van Rooyen, Jaco |
| author_facet | Kaschula, Catherine H. Van Rooyen, Jaco |
| author_sort | Van Rooyen, Jaco |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2022. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/124996 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:41:01.634Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/124996 Structure-activity and mechanistic investigations into the cytotoxicity of flavonols in cancer cells Van Rooyen, Jaco Kaschula, Catherine H. Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Confocal UCTD Organic chemistry Flavonols Cytotoxicity, Cell-mediated Cancer cells Thesis (MSc)--Stellenbosch University, 2022. ENGLISH ABSTRACT: Flavonols belong to a group of polyphenolic compounds that are found in medicinal and edible plants. They have a broad range of medicinal properties including anti-cancer properties, being able to inhibit cell proliferation and induce apoptosis in cancer cells in the low micromolar range. Previous studies from our lab have found that the flavonol fisetin is cytotoxic to lung cancer cells. The primary aim of this study was to synthesize a library of flavonols, with varying substituents at the 4’- position, and establishing the structure activity relationship (SAR) of the synthesized flavonols. A total of twelve flavonols were synthesized via the Algar -Flyn-Oyamada (AFO) reaction and a thirteenth via the oxidation of the methyl thiol derivative. The cytotoxicity IC50’s of these compounds were determined in MDA-MB-231 and A549 cancer cell lines by making use of a MTT cytotoxicity assay. The flavonols had an overall higher activity towards the A549 cells over MDA-MB-231 cells. The most potent derivatives were 3,7-dihydroxy-2-(4'-trifluoromethylphenyl)-chromen-4-one (34) and 3,7-dihydroxy- 2-(4'-methylsulfonephenyl)-chromen-4-one (36), 8.2 ± 1.8 and 2.9 ± 1.6 μM against A549 cells, respectively. The 4’-substituents had a significant effect on the cytotoxicity of the flavonols and a linear correlation was drawn between the para-Hammett constant of the 4’-substituents and the cytotoxicity. For the flavonols under investigation, the larger the para-Hammett (σp) constant (more electron withdrawing) of the 4’-substituent, the more cytotoxic the flavonols were in A549 cancer cells. Live cell fluorescent imaging was used to determine the subcellular localization of three natural flavonols. A fluorescent tag (dansyl chloride) was incorporated on to a natural flavonol to allow for fluorescent tracking in MDA-MB-231 breast cancer cells. The addition of the dansyl tag to 3,7- dihydroxy-2-phenyl-chromen-4-one (27) was successful and yielded 1-[5- (dimethylamine)naphthalenyl-1-sulfonyl]azetidine-N-{3-[(2-(phenyl)-3-hydroxy-4-oxo-4H-chromen- 7-yl)oxy]propyl (51). Absorption and emission spectra revealed that the flavonols had intrinsic fluorescence and three natural flavonols were used to determine the localization of the flavonols in the MDA-MB-231 cells. Confocal studies revealed that the three natural flavonols had high affinity towards the ER and cell membrane, with less obvious affinity towards the mitochondria. Flavonol 27 was a perfect control to determine the influence of the dansyl tag on 51, the subcellular localization of the dansyl tagged (51) and free (27) flavonol different significantly. Compound 51 had high affinity towards the ER and no other subcellular localization was observed for 51. Dansyl derivatives, lacking pharmacophores, were used as controls and low affinity towards the ER was observed, dansyl chloride did not accumulate in the cells. Two compounds, 7-deazahypoxanthine and a cis-platin derivatives, with known subcellular localization were chosen to be synthesized to be used as positive controls for a fluorescent tag (Dansyl chloride). The synthesis of the precursor 6-[4-(Benzyloxy)benzoyl]-5-phenyl-1H-pyrrolo-[2,3- d]pyrimidine-2,4(3H,7H)-dione (42) was achieved, but unfortunately the synthesis of the 7- deazahypoxanthine derivative remained unsuccessful. The synthesis of the cis-platin (52) derivative, dichloro(ethylenediamine)platinum(II), was successful however the incorporation of the dansyl tag (fluorophore) was not. AFRIKAANSE OPSOMMING: Een van die hoof doelwitte van die studie was om ‘n reeks van flavonole te sintetiseer wat net verskil op die 4’ – posisie. Die reeks was gebruik om die struktuur se invloed op die reaktiwiteit te bepaal deur gebruik te maak van die MTT toetse. Die kragtigste molekules was 3,7-dihydroxy-2-(4'- trifluoromethylphenyl)-chromen-4-one (34) en 3,7-dihydroxy-2-(4'-methylsulfonephenyl)-chromen- 4-one (36), 8.2 ± 1.8 en 2.9 ± 1.6 μM, in die A549 kankersellyn. Die 4’- substituente het ʼn groot inpak op die toksisiteit van die flavonole gehad en ʼn lineêre korrelasie was gevind tussen die para-Hammet konstante en die toksisiteit. Hoe meer elektron onttrekkend die 4’-substituente was, hoe meer aktief was die molekuul. Twee molekules was gekies om gesintetiseer te word omdat hulle bekende sellulêre organel teikens het wat dit toelaat om die molekules te gebruik as ʼn positiewe toets vir die fluorofoor, dansyl kloried. Die molekules was 7-deazahypoxanthine en ʼn cis-platin afleisel. Die sintese van die 7- deazahypoxanthine afleisel was onsuksesvol en die byvoeging van die fluorofoor aan die cis-platin afleisel was onsuksesvol. Die byvoeging van die flurofoor, dansyl kloried, aan 3,7-dihydroxy-2-phenyl- chromen-4-one (27) was suksesvol en die produk, 1-[5-(dimethylamine)naphthalenyl-1- sulfonyl]azetidine-N-{3-[(2-(phenyl)-3-hydroxy-4-oxo-4H-chromen-7-yl)oxy]propyl (51) was gebruik om die invloed van die fluorofoor op die sellulêre opeenhoping van flavonole te bepaal. Absorpsie en emissie spektra het bewys dat die flavonole ʼn natuurlike fluoressensie het en drie is gekies om die sellulêre opeenhoping van die flavonole te bepaal in MDA-MB-231 kankerselle. Soortgelyke studies het getoon dat die flavonole hoë affiniteit het tot sellulêre organe wat groot hoeveelheid membrane besit. Hulle het die grootste affiniteit gehad tot die endoplasmiese retikulum, selmembraan en die mitochondria. Flavonol 27 het in al drie die bogenoemde organe saamgesmelt waar 51 net in die endoplasmiese retikulum saamgesmelt het. Masters 2022-03-11T15:55:03Z 2022-04-29T09:45:34Z 2022-03-11T15:55:03Z 2022-04-29T09:45:34Z 2022-04 Thesis http://hdl.handle.net/10019.1/124996 en_ZA Stellenbosch University 232 pages application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Confocal UCTD Organic chemistry Flavonols Cytotoxicity, Cell-mediated Cancer cells Van Rooyen, Jaco Structure-activity and mechanistic investigations into the cytotoxicity of flavonols in cancer cells |
| title | Structure-activity and mechanistic investigations into the cytotoxicity of flavonols in cancer cells |
| title_full | Structure-activity and mechanistic investigations into the cytotoxicity of flavonols in cancer cells |
| title_fullStr | Structure-activity and mechanistic investigations into the cytotoxicity of flavonols in cancer cells |
| title_full_unstemmed | Structure-activity and mechanistic investigations into the cytotoxicity of flavonols in cancer cells |
| title_short | Structure-activity and mechanistic investigations into the cytotoxicity of flavonols in cancer cells |
| title_sort | structure activity and mechanistic investigations into the cytotoxicity of flavonols in cancer cells |
| topic | Confocal UCTD Organic chemistry Flavonols Cytotoxicity, Cell-mediated Cancer cells |
| url | http://hdl.handle.net/10019.1/124996 |
| work_keys_str_mv | AT vanrooyenjaco structureactivityandmechanisticinvestigationsintothecytotoxicityofflavonolsincancercells |