Ru(II) Complexes for Chemotherapy of Malaria and Cancer

Brooklyn College, New York NY

Investigators

Linked publications & trials

Abstract

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