Ru(II) Complexes for Chemotherapy of Malaria and Cancer

用于疟疾和癌症化疗的 Ru(II) 配合物

• 批准号: 7059753
• 负责人: ROBERTO A SANCHEZ-DELGADO
• 金额: $ 11.76万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059753
• 关键词: DNA; antimalarial agents; antineoplastics; chemical aggregate; chloroquine; cytotoxicity; drug design /synthesis /production; drug resistance; heme; hydrolysis; malaria; metal complex; neoplasm /cancer; neoplastic cell; pharmacokinetics; ruthenium; spectrometry

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.

由于疟疾和癌症的高发病率，需要有效且安全的新化疗方法。 我们的长期目标是发现基于金属的抗疟疾和抗肿瘤药物的新线索，并 阐明它们的作用机制。具体假设是一个分子中的组合 氯喹 (CQ)、Ru(II) 和 π 键合配体可能会产生多功能化合物，对特定的药物有效 CQ 耐药性疟疾和顺铂耐药性肿瘤的靶标。我们的假设基于：1) Ru-CQ 复合物对 CQ 耐药性恶性疟原虫具有活性，并表现出与特定相关的抗肿瘤活性 运输特性，通常针对 DNA。 2) pi-键合芳烃对于稳定性和传递至关重要 金属络合物，它们促进血红素聚集抑制所需的 pi 相互作用，这是主要模式 CQ 的作用以及 DNA 嵌入，与抗疟疾和抗癌活性相关。 3）CQ增强 抗癌药物对多重耐药细胞系的细胞毒性，因此金属抗肿瘤剂 结合 CQ 可能对抵抗耐药肿瘤更有效。基于这些考虑， 该提案的主要重点是合成 CQ 和 pi 键配体的新型 Ru 配合物，设计为 (i) 以血红素聚集为目标，并通过金属介导降低疟疾耐药性； (ii) 促进抗癌 CQ 诱导细胞分化产生的选择性细胞毒性活性，以及​​特定的转运特性 Ru 复合物的形成导致有效的 DNA 结合。具体目标是： 1. 含有CQ和π键配体且具有足够传输性能的Ru配合物的合成， 用于降低抵抗力，并能够促进与血红素、蛋白质和 DNA 的相互作用，作为目标 生物作用。 2.通过简单的体外研究抑制血红素聚集作为抗疟疾作用的主要模式 分析，允许选择先导化合物，并作为我们的机制假设的测试。 3. Ru-CQ 配合物的水解随 pH 变化及其相互作用的光谱研究 与血红素、DNA 和蛋白质一起，提供抗疟疾或抗癌活性的进一步迹象，并 进一步检验我们关于这些新型金属衍生的转运特性和作用机制的假设 药物。