Titanium-gold-based chemotherapeutics for prostate and kidney cancer

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DESCRIPTION (provided by applicant): Kidney cancer is among the most common cancers and prostate cancer is a major cause of morbidity and mortality in men in the US. There is a clear need to increase the number of chemotherapeutic options for these cancers to use alone or in combination with targeted agents. Metallo-drugs are important tools in current cancer therapy. Platinum-derived drugs, commonly used, have failed in renal and prostate cancers. Titanium-based drugs have high preclinical activity and hold potential for anticancer therapy, especially for metastatic renal, metastatic breast and prostate cancers. However, their mode of action remains unclear. Recent studies indicate that gold complexes also display considerable anti-tumor properties both in vitro and in vivo against cisplatin-resistant cancer cell lines with different mode of action than cisplatin itself. Preliminary results demonstrate that compounds containing both titanium and gold have significant anti-tumor properties in vitro against prostate cancer cell lines. The long-term goal of this proposal is to develop heterometallic titanium-gold anticancer chemotherapeutics for the treatment of renal and prostate cancers. Our hypothesis is that the incorporation of two different metals with anti-tumor properties in the same molecule will improve their activity due to: a) interaction of the different metals with multiple biological targts and b) improved chemicophysical properties of the heterometallic compound. We will synthesize new titanium organometallic compounds with phosphine-, and iminophosphorane-modified cyclopentadienyl (Cp) ligands able to further coordinate gold moieties. The anti-tumor properties and mechanism of action of the new titanium and titanium-gold derivatives prepared will be evaluated using different human kidney and prostate cancer cell lines. Aim 1. To synthesise and to determine the stability, in vitro and in vivo anti-tumor activity of titanium and titanium-gold compounds with phosphine- and iminophosphorane-containing ligands. Aim 2: To test the hypothesis that the improved activity of titanium-gold compounds is due to their interactions with multiple biological targets. We will evaluate the interaction of these compounds with different biomolecular targets, including protein kinases, DNA, transport and mitochondrial proteins, and cell death pathways. This research will elucidate the mode of action of promising non-platinum anti-cancer heterometallic derivatives. The knowledge gained from the studies of the kinase inhibitory properties of these compounds will guide the design of more selective or targeted chemotherapeutics for treating humans in the future. We will work in collaboration with Prof. Ramos (University of Hawaii Cancer Center).