Masters Degrees (Chemistry)

Permanent URI for this collectionhttps://hdl.handle.net/10413/6597

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The chemotherapeutic potential of bidentate pyrrolide-imine gold (III) chelates.
(2014) Chiazzari, Victoria A.; Akerman, Matthew Piers.; Munro, Orde Quentin.
Abstract available in PDF file.
Heteroleptic copper (II) chemotherapeutic agents.
(2019) Mbatha, Njabulo Khethinkosi.; Akerman, Matthew Piers.; Xulu, Bheki Alex.
In this study, a range of heteroleptic copper(II) chelates were synthesized as chemotherapeutic agents. Two primary heteroleptic copper(II) chelates, [Cu(L)(H2O)2]NO3 and [Cu(L1)(H2O)2]NO3 were successfully synthesized and characterized. These complexes had Schiff base ligands HL and HL1 coordinated, both with an N,N’,O donor atom set which were synthesized by the reaction of 2-aminophenol with 2-pyridinecarbaldehyde for HL and the condensation of salicylaldehyde with 8-aminoquinoline for HL1. Both Schiff base ligands were synthesized via the eco-friendly solid state technique. The reaction between (CuNO3)2 and Schiff base HL yielded [Cu(L)(H2O)2]NO3 which was further reacted with three co-ligands: 1,10-phenantroline (phen), 1,10-phenantroline-5-amine (phen-NH2) and dipyrido[3,2-a:2′,3′-c]phenazine (dppz) to afford three secondary heteroleptic copper(II) chelates. The secondary heteroleptic copper(II) complexes have been synthesized using a mechanochemical technique that is eco-friendly, efficient, simple and afforded excellent yields. The co-ligand dppz was prepared from the reaction of 1,10-phenanthroline-5,6-dione with o-phenylenediamine. The complex [Cu(phen-NH2)2Cl]Cl was synthesized by reacting CuCl2 with 1,10-phenantroline-5-amine. The ligands have been characterised by mass spectrometry (MS), IR and NMR spectroscopy, while the chelates have been characterised by EPR, MS, elemental analysis as well as UV/vis spectroscopy. The solid state structures of three heteroleptic complexes were elucidated using single crystal X-ray diffraction. X-ray crystallography showed that [Cu(L)(H2O)2]NO3 and [Cu(L1)(H2O)2]NO3 complexes had square pyramidal geometries with various combinations of N and O-donor ligands. The solution state coordination geometry of copper(II) complexes [Cu(L)(H2O)2]NO3, [Cu(L)(phen)]NO3, [Cu(L)(phen-NH2)]NO3 and [Cu(L)(dppz)]NO3 were found to be trigonal bipyramidal using EPR spectroscopy. The DNA binding affinities of the chelates were measured using fluorescence competitive binding assays. The binding affinities range from 2.79 × 105 M-1 for [Cu(L)(H2O)2]NO3 to 5.31 × 106 M-1 for [Cu(phen-NH2)2(Cl)]Cl. The order of all complexes in terms of increasing binding strength is: [Cu(L)(H2O)2]NO3 < [Cu(L)(phen)]NO3 < [Cu(L)(dppz)]NO3 < [Cu(L)(phen-NH2)]NO3 < [Cu(phen-NH2)2(Cl)]Cl. The five copper(II) chelates synthesized were screened against a panel of four human cell lines. These cell lines are: HEK293 (healthy embryonic kidney cells) which was used as a control, MDA-MB (triple negative cancer cells), HELA (cervical cancer cells) as well as SHSY5Y (human neuroblastoma cells). From the cell screening, the EC50 values were calculated. The complex [Cu(L)(dppz)]NO3 had the lowest EC50 values while [Cu(L)(H2O)2]NO3 had the highest EC50 values. The results showed that four complexes are highly cytotoxic towards tumour cells, more so than the well-known chemothepeutic agent cisplatin. The complex [Cu(L)(H2O)2]NO3 showed lower cytotoxicity, however, it has greater selectivity towards tumour cells. The cytotoxicity of the compounds varies with different cells; hence each has a unique cytotoxicity profile and could be used for a specific type of cancer. There is little correlation between the binding affinities of complexes and their cytotoxicity, this suggest that the mechanism of action could include the production of ROS in vitro, which are known to cleave the DNA and induce apoptosis. Significantly, all the complexes synthesized in this work showed lower toxicity towards the healthy cell line than the tumour cell lines. It was also shown that the combination of the Schiff base ligand and co-ligand was an important factor in the cytotoxicity. The redox activity of copper and the production of reactive oxygen species (ROS) are likely key in the cytotoxicity of the complexes.
Structural, physical and biological studies of transition metal Schiff base complexes.
(2013) De Ponte, Justine C.; Munro, Orde Quentin.; Akerman, Matthew Piers.
The aims of this work were first to synthesize and fully characterize compounds that may function as bleomycin analogues and, second, to test their anticancer activity in vitro. Three novel tetradentate O,N,N,O Schiff base ligands, H₃L¹, H₂L³ and H₂L³ were synthesized by condensation of three different 1,3-diaminoalkane bridging units with two equivalents of (2,4-dihydroxy–phenyl)-(phenyl)methanone. These ligands contain two neutral imine nitrogen donors and two anionic phenolate oxygen donors for the coordination of metal ions. The choice of ligand was guided by the fact that Cu(II) bleomycin analogues with ligands employing O,N,N,O donor atom sets are able to cleave double-stranded DNA via oxygen radical formation. Using these ligands, six novel metal complexes of copper(II), nickel(II) and zinc(II) were synthesized and fully characterised. Two novel ligand crystal structures and six novel metal complex crystal structures are reported in this work. The X-ray structures of the two structurally characterized nickel(II) complexes [Ni(L²)] and [Ni(L³)] adopted the same nominally square planar coordination geometry, with the metal ion bound by the pairs of imine nitrogen and ortho-phenolic oxygen atoms of the ligand’s tetradentate donor atom set. The Ni–N and Ni–O distances averaged 1.892(3) Å and 1.845(2) Å, respectively. However, when reacted with Cu(II) and Zn(II), the ligands favored the formation of multinuclear complexes as a result of metal ion bridging by ionized oxygen donor atoms (either the phenolic oxygen atoms or an alkoxide oxygen atom of the 2-hydroxy substituted alkane bridge in the case of H₃L¹) of the polyfunctional ligands. For the di- and trinuclear copper(II) complexes, the mean Cu–N and Cu–O distances averaged 1.953(3) Å and 2.082(3) Å, respectively. For the dinuclear zinc(II) complex, the mean Zn–N and Zn–O distances averaged 2.074(3) Å and 2.042(3) Å, respectively. Electron spin resonance (ESR) measurements on the paramagnetic trinuclear copper(II) complexes confirmed that the trinuclear solid state structures remain intact in fluid solution (DMF) and that two of the three copper(II) ions are antiferromagnetically coupled, leaving the third as an S = ½ center with a hyperfine coupling constant to the I = 3/2 Cu nucleus of 14.80 G. Super-hyperfine coupling (15.13 G) to two N atoms was also evident, consistent with one of the terminal copper(II) centers (O,N,N,O donor atom set) being the site of the unpaired spin density in the molecule. Density functional theory (DFT) simulations were used to determine the electronic structures of the diamagnetic mononuclear nickel(II) complexes. The simulations reproduced the structures of [Ni(L²)] and [Ni(L³)] accurately with similarity coefficients for the two complexes of 0.982 and 0.990, respectively. The simulated electronic spectra (TD-DFT) of the nickel(II) complexes showed reasonably good agreement with the experimental spectra and were useful for the assignment of the low-lying MLCT state (near 400 nm) for the complexes as well as the higher-lying π-π* transitions between 300–350 nm. All of the metal complexes and one ligand were sent to MINTEK¹ (Project AuTEK) for anticancer screening. The copper(II) complexes (bleomycin analogues capable of generating hydroxyl radicals in vivo) showed significant cytotoxicity against the human cancer cell lines A549, DU145, HT-29, and U21. The trinuclear complexes were the most cytotoxic with mean IC₅₀ values of 6(2) and 7(1) μM for [Cu₃(L²)₂Cl₂(DMF)₂] and [Cu₃(L³)₂(H₂O)₂]Cl₂, respectively. The nickel(II) complexes [Ni(L²)] and [Ni(L³)] were comparatively inactive with mean IC₅₀ values of >50 and 35(16) μM, respectively, consistent with the fact that they do not readily generate reactive oxygen species in a cellular environment.
Synthesis and characterisation of gold-based compounds as potential DNA intercalators.
(2016) Moodley, Desigan.; Akerman, Matthew Piers.
Abstract available in PDF file.
Synthesis and characterisation of novel oxovanadium(IV) Schiff base complexes: A study of their electronic spectral properties, peroxide binding affinities, DFT-calculated geometries and spectra, and cytotoxicity towards human carcinoma cells.
(2012) Bartlett, Malcolm Alan.; Munro, Orde Quentin.; Akerman, Matthew Piers.
A series of five, tetradentate Schiff-base ligands were synthesised and chelated to vanadyl to form oxovanadium(IV) complexes. The ligands, 4,4’-{benzene-1,2-diylbis[nitrilo(1E)phen-1-yl-1ylidene]}- dibenzene-1,3-diol (H2L1), 4,4’-{ethane-1,2-diylbis[nitrilo(1E)phenyl-1-yl-1-ylidene]}dibenzene-1,3-diol (H2L2), 4,4’-{propane-1,2-diylbis[nitrilo(1E)phen-1-yl-1-ylidene]}dibenzene-1,3-diol (H2L3), 4,4’-{(2- hydroxypropane-1,3-diyl)bis[nitrilo(1E)phen-1-yl-1-ylidene]}dibenzene-1,3-diol (H2L4) and 4,4’-{2,2- dimethylpropane-1,3-diyl)bis-[nitrilo(1E)phen-1-yl-1-ylidene]}-dibenzene-1,3-diol (H2L5), characterised by TOF-MS, IR, electronic absorption, 1H and 13C NMR spectroscopy. The ligand H2L5 was also characterised by XRD. The ligands were shown to have a bis-zwitterionic structure in the solid state, and possibly also in solution. Complexes were characterised by Elemental Analysis, TOF-MS, IR, electronic absorption spectra, EPR and 51V NMR spectroscopy. They form mononuclear complexes, with one ligand binding a single vanadyl ion. EPR spectroscopy was performed on both the powdered form and solutions of the complexes. All the complexes displayed axial symmetry, with increasing distortion from an ideal square pyramidal geometry as the size and bulk of the central chelate ring was increased. Isotropic g0 values suggest solvent interaction with the vanadium ion for the coordinating solvent DMSO. Additional distortion on the coordination geometry, presumably from the benzyl groups of the compounds, causes the isotropic hyperfine coupling constants to be greater than expected. Furthermore, the ability of the complexes to bind peroxide species was investigated by following the addition of H2O2 to the complexes using 51V NMR spectroscopy to observe shielding changes at the vanadium nucleus, and 1H NMR spectroscopy to monitor the bulk magnetic susceptibility, via a modified Evan’s NMR method. Similar experiments were done with sodium hydroxide for comparison. As expected, the oxoperoxovanadium(V) complexes were more stable than their progenitor oxovanadium(IV) complexes. Additionally, increasing the distortion from the ideal pseudo square-pyramidal coordination geometry for the vanadyl ion resulted in a greater increase in the apparent stability of the peroxocomplexes. This latter effect is further enhanced by the addition of a hydrogen-bonding group in close proximity to the vanadium nucleus. DFT calculations of the optimized geometries, natural bond orbitals, electronic absorption and infra-red frequencies were performed for both the ligands and the complexes; nuclear magnetic resonance calculations were performed for the ligands as well. The B3LYP/6-311G (d,p) and B3LYP/LANL2DZ level of theories were used for the ligands and complexes respectively, except for electronic transitions, which were calculated using TD-SCF methods for both ligands and complexes. Calculated and experimental results were compared where possible, and showed reasonable agreement for all calculations performed. The exception to this was for the NMR calculations for the ligands, which were poorly simulated. Finally, the in vitro biological activity of the complexes was evaluated for cytotoxicity against the human tumour cell lines: A549, U251, TK-10 and HT29, via an MTT assay. All complexes showed promising anticancer activity, as evidenced by their low IC50 values for the cell lines A549, U251 and TK-10, which are in general, lower than that observed for cisplatin. They did, however, express negligible activity against the HT29 colon adenocarcinoma cell line; showing an apparent selectivity for certain cell lines. These oxovanadium(IV) complexes, thus warrant further evaluation as chemotherapeutic agents.

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Browsing Masters Degrees (Chemistry) by Author "Akerman, Matthew Piers."