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Half-sandwich organo-osmium anticancer complexes
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Zhang, Xin (2019) Half-sandwich organo-osmium anticancer complexes. PhD thesis, University of Warwick.
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Abstract
Cancer has become a public health problem worldwide. The side-effects and drug-resistance of current anticancer drugs such as cisplatin make it desirable to develop next-generation cancer therapy. Recently, half sandwich ruthenium, iridium and osmium complexes have exhibited promising anticancer potency, of which [Os(η6 -p-cymene)(4-(2- pyridylazo)-N,N-dimethylaniline)I]+ ([2-I]+ , also known as FY26) showed 49× higher cytotoxicity than cisplatin towards 809 cancer cell lines. The potency of [2-I]+ was influenced by the concentration of intracellular tripeptide glutathione (γ-L-Glu-L-Cys-Gly, GSH). This thesis explores the chemical related mechanism of action of [2-I]+ and mainly studies the reactions of [2-I]+ with GSH.
Complexes related to the reaction of [2-I]+ with GSH under physiological conditions were synthesized and characterized, including the chlorido [2- Cl]+ , hydroxido [2-OH]+ and thiolato adduct 2-SG. For these osmium complexes, their extinction coefficients, retention times and mass spectra were determined and the proportionality between HPLC peak and concentrations is established. These studies provides the basis for the following exploration of the chemical behaviour of [2-I]+ .
[2-I]+ is inert under physiological conditions, but the presence of GSH dramatically increases (> 100×) the extent of hydrolysis of [2-I]+ . AVI similar behaviour was also observed for chlorido analogue [2-Cl]+ , but not for the imino analogue [2-impy-I]+ , which indicates the importance of the azo ligand. Meanwhile, acidic conditions inhibited the promotion of hydrolysis of [2-I]+ by GSH, which might be due to the deprotonation of GSH. Combined with DFT calculations, a novel mechanism of action based on deprotonated GS- attack on the -N=N- azo bond to activate inert organo-osmium azopyridine complexes is proposed.
More surprisingly, free radicals O2- , •OH and •H are detected in reactions of osmium azopridine complexes ([2-I]+ , [2-Cl]+ and [2-OH]+ ) with GSH by EPR in presence of a spin trap, but no radicals were observed for the imino analogue or free azopryridine ligand. These results highlight the importance of azo bond and the osmium centre. Meanwhile, an N2 atmosphere and acidic conditions hampered the free radical generation. A mechanism in which osmium azopyridine complexes induce electron transfer from GSH to O2 and produce GSSG and O2 - is proposed.
The sulfenylhydrazide intermediate in the reaction of [2-I]+ with GSH was captured by Os LIII-edge X-ray absorption spectroscopy. This result supports a mechanism involving attack of deprotonated GS- on the azo bond of [2-I]+ to activate hydrolysis and produce free radicals. The studies in this thesis provide insights to a novel mechanism of action of this class of half-sandwich organo-osmium anticancer complexes.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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Library of Congress Subject Headings (LCSH): | Organoosmium compounds, Cancer -- Treatment, Antineoplastic agents | ||||
Official Date: | July 2019 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Sadler, P. J. | ||||
Format of File: | |||||
Extent: | 325 leaves : illustrations (some colour) | ||||
Language: | eng | ||||
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