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Platinum drugs are among the most commonly used chemotherapeutics for the treatment of testicular, head and neck, ovarian, small cell lung, and colorectal carcinomas. Although the current set of platinum chemotherapeutics has proven somewhat successful, the overall success of platinum based drugs is limited due to acquired drug resistance and a limited range of tumor types that are treatable with the current regime. The development of novel cytotoxic platinum based compounds, both trans- and polynuclear, provides for the promising treatment of clinical platinum drug resistant tumors. While the cytotoxic activity of platinum drugs provides for a hopeful outlook, the ultimate factors that affect the success of chemotherapeutics are the fine balance between cytotoxic activity and metabolic deactivation. In general, this work reports the drug design/drug action, and pharmacokinetic consequences of anticancer compounds aimed to fight mechanisms of cisplatin resistance. In the first project, we report the biological and biophysical studies aimed at understanding and improving upon the pharmacokinetic properties of chemotherapeutics; specifically, understanding their interactions with serum proteins. This work resulted in the discovery of using carboxylate ligands to modulate the reactivity of trans-platinum based compounds towards sulfur containing proteins with consequent effects on drug efficacy. In addition, we report an in depth look into the biological consequences of non-covalent platinum drug-protein interactions on drug efficacy, and introduce the use of novel Platinum-NBD fluorescent conjugates as probes for drug metabolism. In the second project we report the design, synthesis, and biological consequences of fluorescent drug derivatives based on the NBD fluorophore, for use in understanding drug action and drug metabolism. As a result of this fluorescent drug labeling, TriplatinNC, a non-covalent platinum based chemotherapeutic, was found to specifically target nucleolar DNA/RNA, due to its high charge, and inhibit ribosomal RNA production in cancer cells. The use of fluorescent derivatization also resulted in the development of a series of novel water-soluble trans-platinum complexes, with greater cytotoxicity than cisplatin. Therefore, these data resulted in the understanding of, and improvement upon the pharmacokinetic profile of platinum chemotherapeutics, as well as the development of novel fluorescent platinum conjugates with novel metabolic and cytotoxic profiles.

Yes / The problems of acquired resistance associated with platinum drugs may be addressed by chemotherapeutics based on other transition metals as they offer the possibility of novel mechanisms of action. In this study, the cellular uptake and induction of apoptosis in A549 human non-small cell lung cancer cells of three promising osmium(II) arene complexes containing azopyridine ligands,[Os(Z6-arene)( p-R-phenylazopyridine)X]PF6, where arene is p-cymene or biphenyl, R is OH or NMe2, and X is Cl or I, were investigated. These complexes showed time-dependent (4–48 h) potent anticancer activity with highest potency after 24 h (IC50 values ranging from 0.1 to 3.6 mM). Cellular uptake of the three compounds as quantified by ICP-MS, was independent of their log P values (hydrophobicity). Furthermore, maximum cell uptake was observed after 24 h, with evident cell efflux of the osmium after 48 and 72 h of exposure, which correlated with the corresponding IC50 values. The most active compound 2, [Os(Z6-p-cymene)(NMe2-phenylazopyridine)I]PF6, was taken up by lung cancer cells pre-dominately in a temperature-dependent manner indicating that energy-dependent mechanisms are important in the uptake of 2. Cell fractionation studies showed that all three compounds accumulated mainly in cellular membranes. Furthermore, compound 2 induced apoptosis and caused accumulation in the S-phase of the cell cycle. In addition, 2 induced cytochrome c release and alterations in mito-chondrial membrane potential even after short exposure times, indicating that mitochondrial apoptotic pathways are involved. This study represents the first steps towards understanding the mode of action of this promising class of new osmium-based chemotherapeutics.

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