Synthesis and biological evaluation of salicylaldimine complexes based on an alkylated PTA scaffold

Simple item page
dc.contributor.advisorHutton, Alan Ten_ZA
dc.contributor.advisorPrince, Sharonen_ZA
dc.contributor.advisorStringer, Tamerynen_ZA
dc.contributor.authorCassells, Irwinen_ZA
dc.date.accessioned2017-09-14T12:28:22Z
dc.date.available2017-09-14T12:28:22Z
dc.date.issued2017en_ZA
dc.description.abstractCancer remains one of the largest pandemics in the world, with millions affected by this disease every year. Since the discovery of the anticancer properties of cisplatin and other platinum-based drugs, metal-based chemotherapies have been extensively researched. Due to the elevated levels of toxicity of many platinum-based drugs, a rise in research using other metal-based drugs for the treatment of cancer has been observed. Of these, platinum group metals such as ruthenium, rhodium and iridium have shown great promise over the last several decades. RAPTA-type (ruthenium arene 1,3,5-triaza-7-phosphaadamantane) complexes have shown great promise in vivo for the treatment of certain cancers. Combining RAPTA with other biologically active groups has often resulted in increased potency and selectivity against various cancer cells in vitro. In this study, we investigated the synthesis, characterisation and biological evaluation of salicylaldimine complexes with an alkylated PTA scaffold. All of the metal complexes were screened for their activity against MCF7 breast cancer cells in vitro, in addition, the most active complexes were screened against Chinese Hamster Ovarian (CHO) non-cancerous cells to evaluate their selectivity. A series of salicylaldimine ligands, as well as a benzyl alkylated PTA scaffold were prepared. Complexes of these ligands were synthesised by a reaction with [RuCl(µ-Cl)(p-cymene)]₂, [RhCl(µ-Cl)(Cp*)]₂ or [IrCl(µ-Cl)(Cp*)]₂. In addition to this, new PTA containing analogues of these neutral complexes were also prepared by reacting the afore mentioned salicylaldimine complexes with the alkylated PTA scaffold. All the compounds were characterised using an array of techniques including NMR spectroscopy, IR spectroscopy and mass spectrometry. Single crystal X-ray diffraction (XRD) was used to confirm the bidentate coordination mode of the salicylaldimine ligand to the metal centre, as well as the presence of the metal-phosphorus bond for the alkylated PTA complexes. All of the metal complexes were evaluated against the MCF7 breast cancer cell line. The ruthenium and iridium salicylaldimine complexes showed comparable or greater cytotoxicity than cisplatin at 20 µM against the MCF7 cancer cells, as well as greater cytotoxicity than their rhodium counterparts. Three of the salicylaldimine complexes exhibited potent activity (18 < IC₅₀ < 21 M). Selectivity studies showed that two of these complexes had a greater affinity for cancerous cells than for the CHO non- cancerous cells. All the alkylated PTA complexes were less cytotoxic than cisplatin against the MCF7 cancer cells. Preliminary mechanistic studies of the most active complexes suggest ruthenium undergoes solvation prior to 5'-GMP binding, whereas iridium was inert to the solvation process.en_ZA
dc.identifier.apacitationCassells, I. (2017). <i>Synthesis and biological evaluation of salicylaldimine complexes based on an alkylated PTA scaffold</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/25206en_ZA
dc.identifier.chicagocitationCassells, Irwin. <i>"Synthesis and biological evaluation of salicylaldimine complexes based on an alkylated PTA scaffold."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2017. http://hdl.handle.net/11427/25206en_ZA
dc.identifier.citationCassells, I. 2017. Synthesis and biological evaluation of salicylaldimine complexes based on an alkylated PTA scaffold. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Cassells, Irwin AB - Cancer remains one of the largest pandemics in the world, with millions affected by this disease every year. Since the discovery of the anticancer properties of cisplatin and other platinum-based drugs, metal-based chemotherapies have been extensively researched. Due to the elevated levels of toxicity of many platinum-based drugs, a rise in research using other metal-based drugs for the treatment of cancer has been observed. Of these, platinum group metals such as ruthenium, rhodium and iridium have shown great promise over the last several decades. RAPTA-type (ruthenium arene 1,3,5-triaza-7-phosphaadamantane) complexes have shown great promise in vivo for the treatment of certain cancers. Combining RAPTA with other biologically active groups has often resulted in increased potency and selectivity against various cancer cells in vitro. In this study, we investigated the synthesis, characterisation and biological evaluation of salicylaldimine complexes with an alkylated PTA scaffold. All of the metal complexes were screened for their activity against MCF7 breast cancer cells in vitro, in addition, the most active complexes were screened against Chinese Hamster Ovarian (CHO) non-cancerous cells to evaluate their selectivity. A series of salicylaldimine ligands, as well as a benzyl alkylated PTA scaffold were prepared. Complexes of these ligands were synthesised by a reaction with [RuCl(µ-Cl)(p-cymene)]₂, [RhCl(µ-Cl)(Cp*)]₂ or [IrCl(µ-Cl)(Cp*)]₂. In addition to this, new PTA containing analogues of these neutral complexes were also prepared by reacting the afore mentioned salicylaldimine complexes with the alkylated PTA scaffold. All the compounds were characterised using an array of techniques including NMR spectroscopy, IR spectroscopy and mass spectrometry. Single crystal X-ray diffraction (XRD) was used to confirm the bidentate coordination mode of the salicylaldimine ligand to the metal centre, as well as the presence of the metal-phosphorus bond for the alkylated PTA complexes. All of the metal complexes were evaluated against the MCF7 breast cancer cell line. The ruthenium and iridium salicylaldimine complexes showed comparable or greater cytotoxicity than cisplatin at 20 µM against the MCF7 cancer cells, as well as greater cytotoxicity than their rhodium counterparts. Three of the salicylaldimine complexes exhibited potent activity (18 < IC₅₀ < 21 M). Selectivity studies showed that two of these complexes had a greater affinity for cancerous cells than for the CHO non- cancerous cells. All the alkylated PTA complexes were less cytotoxic than cisplatin against the MCF7 cancer cells. Preliminary mechanistic studies of the most active complexes suggest ruthenium undergoes solvation prior to 5'-GMP binding, whereas iridium was inert to the solvation process. DA - 2017 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2017 T1 - Synthesis and biological evaluation of salicylaldimine complexes based on an alkylated PTA scaffold TI - Synthesis and biological evaluation of salicylaldimine complexes based on an alkylated PTA scaffold UR - http://hdl.handle.net/11427/25206 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/25206
dc.identifier.vancouvercitationCassells I. Synthesis and biological evaluation of salicylaldimine complexes based on an alkylated PTA scaffold. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2017 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/25206en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherChemistryen_ZA
dc.titleSynthesis and biological evaluation of salicylaldimine complexes based on an alkylated PTA scaffolden_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMScen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
thesis_sci_2017_cassells_irwin.pdf
Size:
9.18 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Masters