The aim of the proposed research is to design new metal complexes that can undergo photoaquation with low energy visible light, such that, when photoactivated, these systems will bind to DNA in a manner similar to the well-known antitumor drug cisplatin, cis-Pt(NH3)2CI2. The action of the new metal complexes will be localized through the sole irradiation of the affected areas, thus circumventing the toxicity towards healthy tissue that is common in cisplatin and many other thermally-activated anticancer drugs. The activation of cisplatin requires the exchange of the two chloride ligands for water molecules resulting in the species which covalently binds to DNA, cis-[Pt(NH3)2(H2O)2]2+ (activated cisplatin). The activation of anti-tumor agents using low energy light has been extensively investigated in a field generally known as photodynamic therapy (PDT). However, PDT agents typically require the production of 1O2, which is ultimately the reactive species. The oxygen requirement by these systems represents an important drawback, since some of the most malignant and drug resistant cancer cells are hypoxic. The goal of this proposal is the design of potential drugs that can be photoactivated with low energy light but whose toxicity does not require the presence of oxygen. Possibilities exist for new drugs based on Ru(ll) complexes, since they are known to undergo efficient photoaquation. The resulting cis-diaqua Ru(ll) species may be able to act in a manner akin to activated cisplatin within the cellular environment. The relevance to public health of the proposed research stems from its potential to discover a new class of drugs that could be potentially useful at targeting only tumor tissue by irradiating the affected areas with low-energy light. Since the compunds sought would only be toxic to cells when irradiated, they would not be harmful toward healthy tissue that is not exposed to light.
| Respondek, Tomasz; Garner, Robert N; Herroon, Mackenzie K et al. (2011) Light activation of a cysteine protease inhibitor: caging of a peptidomimetic nitrile with Ru(II)(bpy)2. J Am Chem Soc 133:17164-7 |
| Garner, Robert N; Gallucci, Judith C; Dunbar, Kim R et al. (2011) [Ru(bpy)2(5-cyanouracil)2]2+ as a potential light-activated dual-action therapeutic agent. Inorg Chem 50:9213-5 |
