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.

由于疟疾和癌症的发病率很高，因此需要有效且安全的新化学疗法。 我们的长期目标是发现基于金属的抗疟疾和抗肿瘤代理的新潜在客户，以及 阐明他们的作用机理。具体假设是一个分子的组合 氯喹（CQ），RU（LL）和PI键合配体可能会导致多功能化合物，对特定有效 CQ耐药疟疾和顺铂耐药性肿瘤的靶标。我们以：1）RU-CQ为基础 复合物对耐CQ的恶性疟原虫具有活性，并显示与特定有关的抗肿瘤活性 运输特性，通常针对DNA。 2）PI键入的领域对于稳定和交付至关重要 金属配合物，它们促进了血红素聚集抑制所需的PI互操作，主要模式 CQ的作用以及通过DNA插入的作用，与抗恶性和抗癌活性有关。 3）CQ增强 抗癌药对多耐药细胞系的细胞毒性，因此是金属抗肿瘤剂 结合CQ可能更有效地抵抗抗性肿瘤。基于这些考虑， 该提案的主要重点是综合了新的CQ和PI键合配体的RU复合物 至：（i）靶血红素聚集和金属介导的疟疾耐药性降低； （ii）促进抗癌 通过CQ诱导的细胞分化和特定的转运特性，通过选择性细胞毒性进行活性 RU复合物导致有效的DNA结合。具体目的是： 1。含有CQ和PI键合配体的RU复合物的合成，具有足够的运输特性， 为了降低抗性和促进与血红素，蛋白质和DNA相互作用的能力，作为目标的目标 生物行动。 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 测定，允许选择铅化合物，并作为我们机械假设的测试。 3。ru-CQ复合物水解作为pH的函数及其相互作用的光谱研究 使用血红素，DNA和蛋白质，以提供抗癌症或抗癌活性的进一步指示，并提供 进一步检验了我们关于这些新金属衍生的Transport特性和作用机制的假设 毒品。