Ru(II) Complexes for Chemotherapy of Malaria and Cancer

Brooklyn College, New York NY

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Abstract

Because of the high incidence of malaria and cancer, effective and safe new chemotherapies are needed. Our long-term goal is to discover new leads for metal-based anti-malarial and anti-tumor agents and to elucidate their mechanisms of action. The specific hypothesis is that the combination in one molecule of chloroquine (CQ), Ru(ll) and pi-bonded ligands may lead to multifunctional compounds, effective for specific targets in CQ-resistant malaria and in cisplatin-resistant tumors. We base that hypothesis on: 1) Ru-CQ complexes are active against CQ-resistant P. falciparum and display anti-tumor activity related to particular transport properties, generally targeting DNA. 2) pi-Bonded arenes are essential for stability and delivery of metal complexes and they promote pi-interactions required by heme aggregation inhibition, the primary mode of action of CQ, and by DNA intercalation, relevant for anti-malarial and anti-cancer activity. 3) CQ enhances the cytotoxicity of anti-cancer drugs against multi-resistant cell lines and thus metal anti-tumor agents incorporating CQ may be more efficacious against resistant tumors. Based on these considerations, the primary focus of the proposal is the synthesis of new Ru complexes of CQ and pi-bonded ligands, designed to: (i) target heme aggregation and a metal-mediated reduction of resistance in malaria;and (ii) promote anticancer activity by selective cytotoxicity by cell differentiation induced by CQ, and specific transport properties of the Ru complex leading to effective DNA binding. The specific aims are: 1. The synthesis of Ru complexes containing CQ and pi-bonded ligands with adequate transport properties, for reducing resistance, and ability to promote ir-interactions with heme, proteins, and DNA, as targets for biological action. 2. Studies of inhibition of heme aggregation as the primary mode of anti-malarial action, by simple in vitro assays, allowing the selection of lead compounds, and serving as a test for our mechanistic hypothesis. 3. Spectroscopic studies of the hydrolysis of Ru-CQ complexes as a function of pH, and of their interaction with heme, DNA, and proteins, to provide further indications of anti-malarial or anti-cancer activity, and to further test our hypothesis concerning ttransport properties and mechanisms of action of these novel metal-derived drugs.