A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy, 2019 / This thesis describes a study directed towards the synthesis and full characterization of novel [Pt(phen)(Ln-κS)2] complexes where disubstituted acylthioureato ligands (Ln), (also referred herein as N,N-di(alkyl/aryl)-N’-acylthioureato ligands), coordinate to the platinum(II) metal centre in a monodentate fashion through the sulfur donor atom and establishing the driving factors behind this rare coordination mode. The study included a systematically chosen ligand library where the ligands varied mainly on the electronic influence of acyl substituents balanced with minor steric variations on the amino end of the ligand.
[Pt(phen)(Ln-κS)2] complexes were synthesized in excellent yields via a stepwise method where the ligands were first deprotonated using sodium hydride in anhydrous THF and subsequently reacting the resultant solvated salts with the [PtCl2(phen)] precursor under reflux for one hour in a 1:2.2 (precursor/ligand) stoichiometric ratio. The complexes were characterised using FT-IR (ATR) spectroscopy, 1H- and 13C NMR spectroscopy, high-resolution mass spectrometry, UV-vis spectrophotometry, elemental analysis, and single-crystal X-ray diffraction. The complexes were also probed for their solution conformations in correlation with the solid-state structures obtained through single-crystal X-ray diffraction using variable temperature 1H- and 195Pt NMR spectroscopy in order to gain insight into the persistence of intramolecular π-π stacking interactions in solution as a stabilising factor directing the monodentate coordination. This study showed that [Pt(phen)(Ln-κS)2] complexes with acylthioureato ligands bearing aromatic acyl substituents could at least exist in three conformations while complexes with acylthioureato ligands that have non-aromatic acyl substituents could only have one structural conformation at -50 ° C. However, there is no conclusive evidence of the intramolecular π-π stacking interactions in solution at ambient and higher temperatures.
Investigations into whether the electronic effects of acyl substituents could influence the nucleophilicity of the other donor sites in the ligands, particularly oxygen, enough to render their reactivity towards platinum(II) ions more preferable was done using conceptual DFT. The study showed that the sulfur donor atom was tenfold more nucleophilic than any other donor atom in the acylthioureato ligands regardless of acyl substituents making it the most probable site to coordinate with platinum(II) ions.
Mechanistic insights into how the reaction proceeded were probed through a series of individual experiments that involved the metal precursor, the ligands, the [Pt(phen)(Ln-κS)2] complexes, the byproduct [Pt(phen)(Ln-κO,S)]+ complexes and acids of different degrees of acidity. These experiments showed that the synthetic reaction proceeded most likely via solvolysis of the precursor resulting in a solvento complex and subsequent anation of the solvento complex with disubstituted acylthioureato anions to get [Pt(phen)(Ln-κS)2]. [Pt(phen)(Ln-κS)2] could also be obtained by reacting the cationic byproduct [Pt(phen)(Ln-κO,S)]+ with the ligand after deprotonation with base. It was also shown that the [Pt(phen)(Ln-κS)2] complexes dissociated under different acids resulting in different dissociation products via protonation-anation reactions. The nature of the dissociation products depended on the strength of the acid and the coordinating properties of the acids’ conjugate bases. This coordination mode could be extrapolated to include platinum(II) complexes bearing other co-ligands like bipyridine and triphenylphosphine, however in medium to low yields.
A pilot study into the potential antiproliferative activity of [Pt(phen)(L1-κS)2] and [Pt(phen)(L2-κS)2] (where L1 = N,N-di(ethyl)-N’-(1-naphthoylthioureato) and L2 = N,N-di(butyl)-N’-(1naphthoylthioureato) anions) against an A549 lung cancer line showed that these complexes are very active with IC50 values of 6.4 ± 0.9 and 2.4 ± 0.3 μM respectively, killing cancer cells via apoptosis. This study also revealed that these complexes could potentially interact with DNA as a major groove binder.
The knowledge obtained through this study should contribute to the fundamental understanding of the coordination chemistry of disubstituted acylthiourea ligands, chemical and physical properties of various platinum(II) complexes bearing disubstituted acylthiourea ligands coordinated in a monodentate fashion and explore possible applications in the fight against cancer. / TL (2020)
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/29474 |
| Date | January 2019 |
| Creators | Kangara, Edmore F. |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | Online resource (124 leaves), application/pdf |
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