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The thesis addresses the potential application of ruthenium(II)-cobalt(III) heterodinuclear complexes as a new selective cancer treatment. The selectivity is to be achieved through the use of visible light to trigger activation of the drug. The majority of work conducted relates to the design and synthesis of the bridging ligand for the final ruthenium(II)-cobalt(III) heterodinuclear complex. In Chapter 2, a potential bridging ligand based on a functionalised terpyridine is described. The intention was to bind the ruthenium(II) metal centre to the terpyridine end of the bridging ligand and have a secondary binding domain available for coordination of the cobalt(III) metal centre. However, a reductive step in the synthetic pathway failed to produce the desired product and this potential bridging ligand had to be abandoned. In Chapter 3, two series of bridging ligands are described. The first of these series is based on Jurgen Sauer’s ‘LEGO’ system. In addition to describing the free synthesis of these ligands, their synthesis on a ruthenium(II) metal centre is described. The second series is based on disubstituted-1,2,4,5-tetrazines. These compounds are only able to be directly synthesised as the non-coordinated ligand. Coordination of these ligands to a single ruthenium(II) metal centre is then described. Ruthenium(II) complexes of both ligand series are then exposed to several transition metals and their ability to coordinate a second metal centre investigated. The formation of ruthenium(II)-cobalt(III) heterodinuclear complexes, using the ligand series detailed in Chapter 3, is described in Chapter 4. These complexes are formed by reacting the ruthenium(II) complex of the bridging ligand with either [Co(en)₂(OTf)₂](OTf) or [Co(tren)(OTf)₂](OTf). These heterodinuclear complexes exhibit photo-activated ligand release, which makes them candidates for development as a potential cancer treatment. The non-bridging ligands coordinated to the cobalt(III) metal centre in Chapter 4 were not cytotoxic. In order to make the system biologically active these ligands need to be changed. Chapter 5 describes how nitrogen mustards (a class of cytotoxic DNA alkylators) could be introduced as the non-bridging ligands. This involves the synthetic strategy of forming the cobalt(III) complex of the alcohol precursor of a nitrogen mustard. This precursor complex is then converted into the nitrogen mustard complex and coordinated to the ruthenium(II) bound bridging ligand. The synthetic strategies outlined in this thesis can be applied to a wide range of potential bridging ligands and could potentially lead to a large number of ruthenium(II)-cobalt(III) heterodinuclear complexes being synthesised. One journal article based on this research has been accepted for publication, in the Australian Journal of Chemistry. Three more articles are in preparation.

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Malignant gliomas are the most common primary brain tumors in adults. Patients with these highly malignant tumors have an extremely poor prognosis. The situation with a highly proliferative tumor in a non-proliferating tissue should favor cytostatic treatment but so far the role of conventional chemotherapy has been adjunctive. The concentrations of three sex steroids, estradiol, progesterone and testosterone, were analyzed by radioimmunoassay after celite chromatography in brain tumor samples. Some malignant gliomas had high tissue concentrations of estradiol. Low progesterone levels may suggest steroid consumption. Estramustine (EM), a conjugate of estradiol-17ß and nornitrogen mustard had a dose-dependent antiproliferative effect on several human malignant glioma cell lines. At equimolar concentrations the inhibitory effects of the EM complex were clearly more pronounced than those of estradiol and nornitrogen mustard given alone or in combination. A specific binding protein (EMBP) is important for the cytotoxic action of EM. Using a mouse monoclonal antibody and an indirect antibodyperoxidase technique, EMBP was demonstrated in human glioma cells. Significant amounts of EMBP were also detected in human brain tumor tissue by radioimmunoassay. The mean concentrations (ng/mg protein) in 16 astrocytomas (2.6) and 7 meningiomas (5.1) were higher (p&lt;0.001) than in 18 samples of normal brain (0.5). The presence of the specific binding protein may suggest a selective binding and effect of EM in human brain tumor tissue. Human glioma cells displayed significant uptake, retention and metabolism of estramustine phosphate (EMP). After incubation with ^H-EMP a progressive uptake of radioactivity was recorded during 24 hours. Metabolism of parent EMP into estramustine and estromustine, which is a well known part of the metabolic pathway in man, was also demonstrated. A dose- dependent increase in DNA strand breaks was recorded at EMP- concentrations ranging 10-40 yg/ml. The uptake of ®^Rb, used as a tracer for potassium to study ion transport and membrane permeability, was reduced after incubation with EMP. Scanning electron microscopy gave further evidence for membrane damage. According to flow cytometric analyses exponentially growing glioma cells were accumulated in the G2/M stage and the fraction of Gi/Gq was reduced. EM seems to attack malignant cells in a multifocal fashion on several vital functions including the microtubule, the nucleus, and the cell membrane. The intact EM complex may be important for effects related to microtubule function which add to the cytotoxic potential of its constituents. These experimental findings justify further investigations on the role of sex hormones in brain tumor growth and development and of hormone-linked cytostatics in clinical treatment. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1990, härtill 6 uppsatser.</p> / digitalisering@umu