Coverdale, James P. C. (2017) Catalytic organometallic anticancer complexes. PhD thesis, University of Warwick.

Preview

PDF WRAP_Theses_Coverdale_2017.pdf - Submitted Version - Requires a PDF viewer. Download (5Mb) | Preview

Request Changes to record.

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.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Antineoplastic agents, Organometallic compounds -- Synthesis, Organoosmium compounds, Organoiridium compounds, Catalysis, Hydrogenation
Official Date:	November 2017
Dates:	Date Event November 2017 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Sadler, P. J. ; Wills, Martin
Format of File:	pdf
Extent:	viii, 258 leaves : illustrations, charts
Language:	eng

Request changes or add full text files to a record

Repository staff actions (login required)

View Item

Downloads