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Doctoral Degrees (Chemistry)

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    Cytotoxic and mechanistic studies of novel phenanthroline-derived oxovanadium(IV) complexes.
    (2022) Barry, Kristy-Lyn.; Munro, Orde Quentin.
    In this work, a new series of ternary oxovanadium(IV) complexes of the type [VO(ONO)(DPQ/DPPZ)], [VO(ONN)(PHEN/DPQ)](PF6) and [VO(ONN)(DPPZ)](Cl) have been synthesised and characterised for the purpose of developing novel anticancer agents. ONO represents a tridentate Schiff base ligand derived from salicylaldehyde and various 4-substituted-2-aminophenols. ONN represents a tridentate Schiff base ligand derived from 1-methyl-2-imidazolecarboxaldehyde and various 4-substituted-2-aminophenols. PHEN represents 1,10-phenanthroline, DPQ represents dipyrido[3,2-d:2′,3′-f]quinoxaline and DPPZ represents dipyrido[3,2-a:2′,3′-c]phenazine. The bidentate N,N-donor polypyridyl co-ligands were incorporated to enhance DNA binding and to stabilise the vanadium(IV) metal centre. The known N,N-bidentate ligands were synthesised and characterised by ESI-mass, 1H and 13C NMR spectroscopy. The tridentate O,N,O′ and O,N,N′ ligands were synthesised and characterised by ESI-mass, NMR, IR, and UV/visible spectroscopic techniques, elemental analysis and single crystal X-ray crystallography. Single crystal X-ray diffraction, 1H NMR and DFT simulations confirmed the O,N,N′ ligands in this work form dimeric hydrogen-bonded supramolecular structures that are stable in solution. The oxovanadium(IV) complexes were characterised by elemental analysis, UV/visible, FT-IR and EPR spectroscopy as well as mass spectrometry. Elemental analysis and mass spectrometry confirmed the identity and purity of the complexes. EPR spectroscopy confirmed the monomeric VIVO-bound species. IR and UV/visible spectroscopy confirmed coordination of the ligands to the metal centre. Highresolution solid-state structures were elucidated for the cationic complexes with PHEN coligands and the 4-chloro and 4-tert-butyl derivatives of the [VO(ONO)(DPQ)] complexes. The crystal structures of the complexes showed a monomeric vanadium(IV) species with the bidentate N,N-donor co-ligand and respective dianionic O,N,O′- or monoanionic O,N,N′-tridentate Schiff base ligand coordinated to the oxovanadium centre in a distorted octahedral geometry. The respective neutral VIVO3N3 and monocationic VIVO2N4+ species were formed. A least-squares fit of the solid-state and DFT-simulated (B3LYP-/6-311G(dp)) structures of the oxovanadium chelates indicate the experimental and simulated structures are in good agreement. DFT-simulated structures were determined for those complexes where X-ray data are not available. The geometry-optimised structures for the neutral and cationic complexes all indicate that the respective bidentate polypyridyl ligands are free from steric hindrance by the tridentate ligand and should be available to bind DNA, which is their proposed cellular target. DFT simulations indicated the neutral complexes have larger HOMO-LUMO energy gaps than the corresponding cationic complexes, suggesting that the neutral complexes are more stable with respect to ligand substitution than the cationic complexes. Experimental mass spectrometry and UV/visible spectroscopy confirmed slower solvolysis processes for the neutral complexes versus the cationic analogues. 51V NMR studies indicate partial oxidation of the vanadium(IV) species in DMSO to VVO2(ONO/ONN)(DMSO) analogues. The cationic complexes with PHEN and DPQ co-ligands were deemed suitable to proceed with absorption DNA binding studies. The cytotoxicity screening of the oxovanadium complexes in this work revealed that, in general, the neutral complexes with DPQ co-ligands are cytotoxic against the triple-negative breast cancer MDA-MB and neuroblastoma SH-SY5Y tumour cell lines and non-toxic towards the cervical cancer HeLa cell line. The charge of the complexes was found to influence the cytotoxic properties. The cationic complexes with PHEN and DPQ co-ligands are cytotoxic towards the HeLa cell line as well as the MDA-MB and SH-SY5Y cell lines. The neutral DPQ and cationic complexes with PHEN and DPQ co-ligands were found to be more cytotoxic towards MDA-MB cell lines than cisplatin and the cationic complexes were found to be more cytotoxic towards the HeLa cell line than cisplatin. Steric bulk of the Schiff base functional group influences cytotoxicity with larger functional groups, such as tert-butyl and sulfonyl, leading to lower cytotoxicity. The N,N-donor co-ligand and steric bulk of the Schiff base functional group also influenced the selectivity index of the cationic complexes. The cationic oxovanadium-DPQ complex with a methyl substituent on the tridentate ligand is significantly more toxic to the carcinoma cell lines than the healthy renal cell line HEK293. In comparison, the cationic oxovanadium-PHEN analogue with a methyl substituent and the cationic oxovanadium-DPQ analogue with a bulky tert-butyl substituent are less selective in their cytotoxicity. The DNA binding studies show that the neutral and cationic DPQ compounds do have an affinity for DNA. A positive correlation between antitumour activity and DNA binding affinity was found. The [VO(ONN)(DPQ)](PF6) analogue with a bulky tert-butyl substituent has a lower intrinsic ct-DNA binding constant than the [VO(ONN)(DPQ)](PF6) analogue with a methyl substituent (1.3 × 104 M–1 and 2.8 × 104 M–1 respectively). The cationic DPQ derivatives also bind more strongly to DNA than the cationic complexes with PHEN co-ligands. The steric effect is also evident in the neutral complexes. The [VO(ONO)(DPQ)] complex with a tert-butyl substituent has a lower apparent binding constant than the [VO(ONO)(DPQ)] complex with no substituents on the Schiff base ligand. The cationic charge also led to a higher apparent binding constant for the [VO(ONO)(DPQ)](PF6) complex with a tert-butyl functional group than for the corresponding neutral [VO(ONO)(DPQ)] analogue with a tert-butyl functional group. Absorption and fluorescence spectroscopic and DNA viscosity studies indicate at least a partial DNA intercalative ability for the cationic oxovanadium-DPQ derivatives and the neutral oxovanadium-DPQ complexes with less bulky substituents. Molecular docking studies further highlighted the affinity of the metal chelates towards DNA, including interactions between DNA and the tridentate ligand. The lowest energy molecular docking poses range from ca. -48 to -67 kJ mol–1. Gel electrophoresis studies showed the cationic vanadium complexes with DPQ co-ligands (unlike the neutral DPQ and cationic PHEN analogues) were able to cleave plasmid DNA without adding external oxidising or reducing reagents. Experimental data suggest a singlet oxygen pathway is the most likely. It was also shown that the combination of metal ion and ligand is needed to induce DNA cleavage. The neutral [VO(ONO)(DPQ)] derivative with a methyl functional group on the Schiff base was shown to oxidatively cleave supercoiled plasmid DNA in the presence of H2O2 through the generation of hydroxyl radicals. EPR spintrapping studies with DMPO further support the idea that hydroxyl radicals are formed from reaction of the oxovanadium complex and H2O2. In summary the charge of the complex, type of substituent on the tridentate ligand and the identity of the N,N-donor heterocyclic ligand affected the stability, cytotoxic properties, selectivity, DNA binding, DNA cleavage abilities and DNA cleavage mechanism of the oxovanadium compounds in this study.