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Doctoral Degrees (Chemistry)

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

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    Derivatised phenanthroline transition metal chelates : targeted chemotherapeutic agents.
    (2024) Hunter, Leigh André.; Akerman, Matthew Piers.
    The derivatisation of 1,10-phenanthroline at the 2-position afforded two classes of compounds with two different bridging groups in this study. The first group comprised two amide-bridged tetradentate N4-donor ligands and were chelated to copper(II), nickel(II) and palladium(II). The ligand chelation occurred with concomitant deprotonation of the amide N-H, resulting in a monoanionic ligand and monocationic complexes when coordinated to the divalent metal ions. The ligands N-(quinolin-8-yl)-1,10-phenanthroline-2-carboxamide, HL1, and N-(pyridin-2-ylmethyl)-1,10-phenanthroline-2-carboxamide, HL2, were characterised by NMR, IR and UV/vis spectroscopy as well as mass spectrometry. The second class of compounds were imine-bridged copper(II) chelates. These chelates were synthesised via a templating condensation reaction between various salicylaldehyde derivates and 1,10-phenanthrolin-2-ylmethanaminium chloride, yielding eight additional copper(II) chelates. The metal chelates were characterised by IR, UV/vis and EPR spectroscopy, and mass spectrometry. HL1, [Cu(L4)(NO3)] and [Cu(L7)](NO3) were further studied by X-ray diffraction. The copper(II) chelates exhibit two different solid-state structures with the nitrate counter ion coordinated to the metal centre in [Cu(L4)(NO3)], but in the outer coordination sphere for [Cu(L7)](NO3). The paramagnetic copper(II) chelates were studied with EPR spectroscopy, which confirmed the square planar coordination geometries of these chelates in solution. The metal chelates were designed to be chemotherapeutic agents, exerting their cytotoxicity through DNA intercalation and, for the copper(II) chelates, DNA cleavage through the catalytic production of ROS. The ability of the copper(II) chelates to catalyse the production of hydroxyl radical in situ in the presence of ascorbic acid and hydrogen peroxide was studied via a hydroxyl radical assay using Rhodamine B as an analogue for the aromatic DNA bases. Competitive binding studies determined the affinity of the metal chelates towards ct-DNA, [Cu(L1)](PF6) has the highest binding constant: 5.91 × 106 M-1. DFT calculations were performed on the ligands and metal chelates to determine the geometry-optimised structures, vibrational frequencies, 1H and 13C NMR chemical shifts and electronic transitions. The B3LYP/6-311G (d,p) level of theory was used for the ligands, copper(II) and nickel(II) chelates and the B3LYP/LanL2DZ level of theory for the palladium(II) chelates. The TD-DFT method was used for the energy calculations. The experimental and calculated results were compared where possible, and a reasonable correlation was found. The cytotoxicity of five amide-based chelates was evaluated against four human cancer cell lines, namely A549, TK-10, HT29 and U251, using an MTT assay. The screened chelates exhibited favourable anticancer activity with the mean IC50 values against the four cancer cell lines ranging from ca. 12 to 35 μM. Importantly, it was found that the combination of the copper(II) ion and the ligand was essential for enhanced cytotoxicity. The complex [Cu(L1)](PF6) was identified as the lead drug candidate based on the high DNA affinity and cytotoxicity. This compound was most cytotoxic towards the glioblastoma cell line U251 with an IC50 value of 7.59 μM. The imine-based chelates were screened against three human cancer cell lines: MDA-MB, HELA, and SHSY5Y, and a healthy human cell line, HEK293. The selectivity index of these chelates for neoplastic versus the healthy cell line was calculated. The imine-based chelates showed a high selectivity towards the triple-negative breast cancer MDA-MB, an order of magnitude more toxic to the tumour cell than the healthy one. This selectivity index is significantly improved over that of cisplatin. A gel mobility shift assay investigated the interactions between the copper(II) chelates and plasmid DNA. The in vivo biodistribution of [Cu(L1)](PF6) was determined using the copper-64 radiolabelled analogue of [Cu(L1)]Cl and microPET-CT scanning. The initial biodistribution studies suggested that the complex has good serum stability and showed that there was no significant accumulation in any organs. The subsequent study involved a xenograft model using the A549 cell line and showed significant uptake and retention of the complex in the tumour. The cytotoxicity of the chelate when synthesised with the non-radioactive isotopes of copper and the uptake of the radiolabelled equivalent in a tumour model suggest that this complex could have application as a “theranostic agent”.
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    Targeting the tumour extracellular environment through rational modification of the SNX class of HSP90 inhibitors.
    (2023) Mathenjwa, Gciniwe Sindiswa.; Akerman, Matthew Piers.; Veale, Clinton Garenth Lancaster.; Bode, Moira Leanne.
    HSP90 remains a valuable target for cancer therapy. Unfortunately, targeting intracellular HSP90 has proven not to be a viable chemotherapeutic approach. Compensatory HSR induction and HSP70 overexpression are the main limitations of this approach. A growing body of evidence suggests that targeting the extracellular environment would be of advantage and devoid of the drawbacks observed with intracellular HSP90 inhibition. As a result, the development of extracellular HSP90 inhibitors represents a novel opportunity for cancer therapeutics. In view of this hypothesis, we aimed to design and synthesise extracellular inhibitors and to assay these compounds against HSP90. To develop extracellular HSP90 inhibitors, cell-impermeable analogues of the well-developed benzamide HSP90 inhibitor (SNX 2112) were designed, synthesised and biologically evaluated. The desired target compounds were synthesized using developed methodology, as well as modified methodology. In Chapter 3 we compared and evaluated a variety of reported synthetic methods to deliver the analogues of SNX 2112. Interested in a general procedure for the synthesis of our analogues, we initially attempted to afford both the methyl and the trifluoromethyl containing analogues via a β- triketone mediated procedure. Despite the success observed with the methyl analogues, the instability of a trifluoromethyl containing β-triketone, deemed this procedure not feasible for this class of compounds. Our continued effort towards a general procedure led to the investigation of a tosylhydrazone mediated tetrahydroindazolone condensation; unexpectedly attempts to synthesise the methyl containing analogues via this procedure led to a 1—5 nitrogen to carbon tosyl migration, which was further investigated for varying substrates, and these results are explained in detail in this thesis. It then became apparent that each of the reported methods had its merits and shortcomings, there was no one best method, rather the synthetic approach was mainly determined by the C-3 substituent. The key intermediates were then converted into the desired targeted compounds by tethering the HSP90 pharmacophore to flexible alkyl groups, attached to polar sulfonate and phosphonate functionalities. Hypothetically, introduction of polar alkyl groups, would inhibit cell penetration thus limiting them to the extracellular environment. Based on the goals of our study we were interested in three biological evaluations; to confirm that our modified compounds were still capable of inhibiting HSP90s ATPase activity, to evaluate if our modifications reduced intracellular HSP90 activity, whether they stimulated the pro-oncogenic HSR, and to evaluate their cytotoxicity. Preliminary biological assessment of our compounds was consistent with our hypothesis. Here we showed that our compounds did not inhibit intracellular HSP90, and did not stimulate HSP70 expression, a marker of induction of the compensatory HSR. Furthermore, our analogues displayed cytotoxicity in the nanomolar range against the HeLa cell line. These preliminary data support the feasibility of targeting extracellular HSP90 as a novel anticancer strategy.