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Organometallic osmium arene anticancer complexes
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Fu, Ying (2011) Organometallic osmium arene anticancer complexes. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2596040~S1
Abstract
The interest in the development of anticancer metal complexes for cancer
therapy is growing spurred by the encouraging successful stories of platinum
drugs. Osmium arene chlorido complexes had been found to show anticancer
activity in vitro. In this thesis, the osmium arene iodido complexes were mainly
explored and investigated.
It is found that iodido OsII arene complexes with a general structure: [Os(η6-
arene)(XY)I]PF6 (XY = p-hydroxy or p-dimethylamino phenylazopyridine, arene
= p-cymene or biphenyl) are potently cytotoxic at nanomolar concentrations
toward a panel of human cancer cell lines. In contrast to the chlorido osmium
arene anticancer complexes, the iodido complexes are stable and inert toward
aquation.
More than thirty half sandwich azopyridine OsII arene complexes [Os(η6-
arene)(azopyridine)X]+ (where X is chloride or iodide, the arene is p-cymene or
biphenyl and the pyridine ring of azopyridine ligand bearing a variety of
substituents) were synthesized and characterized. A preliminary structure activity
relationships (SARs) were built up based on the anticancer activity towards
A2780 human ovarian cancer cell line. In general, the introduction of an electronwithdrawing
group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring
significantly increases cytotoxic activity and aqueous solubility. Changing the
arene from p-cymene to biphenyl or the monodentate ligand (X) from chloride to
iodide resulted in a significant increase in the anticancer activity. Studies in
A2780 human ovarian cancer cells suggested that cellular uptake and targeting to
cellular organelles play important roles in determining the anticancer activity.
According to the 60 cancer cell lines screening results from National Cancer
Institute (NCI), the anticancer activity achieved by the most potent OsII arene
azopyridine complex is 100 times more than cisplatin; 1000 times activity was found in some cell lines. The mechanism of action may involve the inhibition of
tubulin polymerization.
One iodido osmium complex was selected for anticancer efficiency evaluation
in vivo: [Os(η6-p-cym)(Azpy-NMe2)I]PF6 (FY026). This complex delayed the
growth of HCT116 human colon cancer xenografts in mice, with negligible
toxicity. It is the first example of in vivo antitumour activity for an organometallic
osmium arene complex. Its activity appears to involve redox mechanisms. Its
potency towards A2780 ovarian and A549 lung cancer cells is increased
significantly when used in combination with L-buthionine-sulfoximine (L-BSO)
indicating that L-BSO can be a good candidate for combination therapy treatment
with iodido osmium complexes.
Further study on the bioisosteres of FY026 was carried out by changing the
azo bond (N=N) to imine bond (CH=N). Sixteen osmium arene iminopyridine
complexes were synthesized, well characterized and showed good anticancer
activity. Different structure-activity relationships comparing iminopyridine
complexes with azopyridine complexes were identified which suggested a
different anticancer mechanism. In contrast to FY026, [Os(η6-p-cym)(Impy-
NMe2)I]PF6 (6) and [Os(η6-p-cym)(Impy-NMe2)Cl]PF6 (14) were found to
undergo hydrolysis and the binding was observed between their hydrolyzed
product (14A) and 9-ethylguanine.
Moreover, a hydride transfer from NADH to form an osmium hydride
intermediate which is involved in a catalytic process resulting in the formation of
NAD+ was discovered. This process might be involved in the anticancer
mechanism of action. A dual mechanism of action was proposed based in the
interaction of these compounds with DNA nucleobase and catalytic oxidation of
NADH.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology |
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Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Osmium compounds -- Therapeutic use | ||||
Official Date: | December 2011 | ||||
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. | ||||
Sponsors: | University of Warwick | ||||
Extent: | ix, 242 leaves : illustrations, charts | ||||
Language: | eng |
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