Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.737708
Title: Catalytic organometallic anticancer complexes
Author: Coverdale, James P. C.
ISNI:       0000 0004 7223 9651
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2017
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Abstract:
Half-sandwich complexes of ruthenium, iridium, and more recently osmium, have shown promise as anticancer agents. Many of these ‘piano-stool’ complexes appear to target the redox balance in cells. Separately, similar complexes have been investigated for the catalysis of hydrogenation reactions, with many examples achieving high turnover frequencies and enantioselectivities. This thesis is concerned with achieving in cell catalysis to increase drug potency and generate selectivity for cancer cells. A series of eighteen Os(II) and Ir(III) complexes, of the type [M(ηx-arene)(diamine)] (Os-arene: p-cymene, biphenyl, or m-terphenyl; Ir-arene: Cp*, CpxPh, or CpxBip), were synthesised and fully characterised. The structures were derived from a Ru(II) transfer hydrogenation catalyst [Ru(η6-p-cymene)(TsDPEN)], TsDPEN = N-tosyl-diphenyl-ethylenediamine. The complexes were isolated as 16-electron amido catalysts, which were highly stable in solution and upon storage, unlike their 16-electron Ru(II) counterparts, and were highly active for asymmetric transfer hydrogenation of ketones. Os complexes afforded enantiomerically-pure alcohols with high conversion and enantioselectivity (> 99%) at rates exceeding those of the existing Ru catalyst. Two Os and Ir complexes were explored for the conversion of NADH to its oxidised form (NAD+) under physiologically-relevant conditions. Antiproliferative activities determined in 14 human cell lines correlated with experimentally-determined hydrophobicities. Typically, Os catalysts were found to be more active than their Ir counterparts, though were internalised by cancer cells to a lesser degree, suggestive of a more potent in-cell mechanism of action. Structural modifications identified an apparent inert site of substitution on the sulfonamide substituent. Furthermore, their potency towards cancer cells was increased in combination with L-buthionine sulfoximine, an inhibitor of glutathione synthesis. Acute in vivo toxicities were determined in zebrafish, and all compounds investigated exhibited lower toxicities than the Pt anticancer drug, cisplatin. The complexes were shown to generate reactive oxygen species (ROS) in cancer cells, and similarly generated ROS in zebrafish. Transfer hydrogenation catalysis was explored under physiologically-relevant conditions using sodium formate as a biologically-compatible hydride source. Osmium complexes catalysed the reduction of pyruvate, a key metabolite in cells, to either L-lactate or D-lactate, selectively (ca. 83% ee). Upon co-administration of the catalyst and sodium formate, cancer cell proliferation was decreased by up to 13× (relative to cells treated with the catalyst alone), while no sodium formate effect was determined in non-cancerous cells. Importantly, the treatment of cells with a particular enantiomer of the Os catalyst and sodium formate facilitated the in cell reduction of pyruvate to D-lactate, providing, to the best of my knowledge, the first example of a synthetic catalyst carrying out asymmetric transfer hydrogenation chemistry in cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.737708  DOI: Not available
Keywords: QD Chemistry
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