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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:564427 |
| Date | January 2011 |
| Creators | Fu, Ying |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/52695/ |
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