Optimizing Protic Ruthenium Anticancer Compounds for Singlet Oxygen Production and Enhanced Photocytotoxicity

优化质子钌抗癌化合物以产生单线态氧并增强光细胞毒性

• 批准号: 10579670
• 负责人: Elizabeth Tabitha Papish
• 金额: $ 42.37万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579670
• 关键词: Bacteria; Bacterial Infections; Biochemical; Biological; Biological Assay; Biology; Biomedical Engineering; Breast Cancer Cell; Cancerous; Cause of Death; Cell Culture Techniques; Cell Death; Cells; Chemicals; Chemistry; Cisplatin; Clinical Trials; Complex; DNA Binding; DNA Probes; Disease; Drug Controls; Electrons; Event; Exhibits; FDA approved; Feedback; Funding; Generations; Goals; Investigation; Lead; Learning; Ligand Binding; Ligands; Light; Location; MCF7 cell; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Metals; Methods; Normal Cell; Oncology; Oxidative Stress; PUVA Photochemotherapy; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Photosensitivity; Phototherapy; Phototoxicity; Physiological; Platinum; Prodrugs; Production; Property; Public Health; Publications; Reactive Oxygen Species; Relapse; Reporting; Research; Role; Ruthenium; Ruthenium Compounds; Series; Singlet Oxygen; Structure; Students; Techniques; Testing; Tissues; Toxic effect; Training; Treatment Efficacy; Work; absorption; analog; anti-cancer; anticancer research; base; cancer cell; cancer stem cell; cancer type; career; cell type; cellular targeting; chemical property; chemical stability; chemotherapy; cytotoxic; deprotonation; design; graduate student; hydroxyl group; hydroxypyridine; improved; indexing; innovation; lipophilicity; nanomolar; neoplastic cell; new therapeutic target; non-compliance; novel; pathogen; protonation; quantum; rational design; scaffold; side effect; symposium; trend; tumor; undergraduate student; uptake

Abstract. Metallodrugs are commonly prescribed to treat cancer, but they have significant off target effects because they kill all quickly dividing cells, including healthy cells. There is a need for new targeted therapies. Light activated ruthenium (Ru) based drugs are promising because they allow for spatial and temporal control of drug activation using the FDA approved technique of photodynamic therapy (PDT). One light-activated Ru complex, TLD-1433 has shown promising results for treatment of bladder cancer in Phase II clinical trials, showing the promise of this approach. Herein, new protic Ru complexes have been synthesized and studied which demonstrate light activation and selective toxicity towards breast cancer cells vs. normal cells. This application aims to determine the influence of pi expansive ligands, electron withdrawing groups, and hydroxy bearing pyridinol ligands on PDT. This can determine the factors leading to an ideal PDT agent with favorable uptake, localization within appropriate cellular targets, and a high yield of toxic singlet oxygen. The long-term goal of this work is to design highly cytotoxic and selective prodrugs that are initially inert but generate cytotoxic species (singlet oxygen) in the presence of tissue penetrating red light. These prodrugs can target cancer cells due to a combination of enhanced uptake and high levels of oxidative stress present in cancerous cells. Three hypotheses motivate this work. First, hydroxy substituted ligands can enhance the uptake of Ru(II) compounds due to the formation of neutral species via ligand deprotonation at physiological pH which leads to improved uptake. Second, hydroxy groups appear to enhance singlet oxygen formation once they are deprotonated in a series of Ru(II) complexes. This application probes the generality of this trend with new scaffolds. Third, the use pi extended co-ligands can enhance both uptake and singlet oxygen formation. New synthetic targets are proposed to test these hypotheses and to look for synergistic enhancements of phototoxicity index values. Three specific aims will probe these hypotheses. Aim 1 involves the design new PDT agents to maximize photocytotoxicity using ligands to enhance lipophilicity, red shift light absorption, and increase singlet oxygen production. Aim 2 involves investigations into the photocytotoxicity and uptake of these novel protic Ru compounds in both cancerous and normal cells. Aim 3 will involve measuring singlet oxygen and reactive oxygen species formation in solution and in cells as well as probing for DNA binding. The proposed research will establish a new generation of Ru PDT agents with selective toxicity towards breast cancer cells and other susceptible cell types. There is potentially a high impact for drug developers beyond the oncology field, in that we are elucidating how protic ligands impact uptake and singlet oxygen formation, and this can be used to target other diseases including potentially bacterial infections. This project will be used to train a diverse group of undergraduate and graduate students in collaborative anticancer research with students in chemistry and in biological engineering. The work from this project will be disseminated via publications and presentations at conferences.

抽象的。金属药物通常用于治疗癌症，但它们具有显著的脱靶效应 因为它们会杀死所有快速分裂的细胞，包括健康细胞。需要新的靶向治疗。 基于光活化钌（Ru）的药物是有希望的，因为它们允许对药物的空间和时间控制。 使用FDA批准的光动力疗法（PDT）技术进行药物活化。一个光激活Ru 复合物，在II期临床试验中，PIB-1433显示出治疗膀胱癌的有希望的结果， 展示了这种方法的前景。本文合成并研究了新型质子钌配合物 其表现出光活化和对乳腺癌细胞相对于正常细胞的选择性毒性。这 本申请旨在确定π膨胀配体、吸电子基团和羟基 PDT上带有吡啶醇配体。这可以确定导致理想的PDT剂的因素， 摄取，在适当的细胞靶内定位，以及高产量的有毒单线态氧。长期 本工作的目标是设计高细胞毒性和选择性的前药，其最初是惰性的，但产生细胞毒性 种（单线态氧）的存在下，组织穿透红光。这些前药可以靶向癌细胞 这是由于增强的摄取和癌细胞中存在的高水平氧化应激的组合。三 假设激发了这项工作。首先，羟基取代的配体可以增强Ru（II）化合物的吸收 由于在生理pH下通过配体去质子化形成中性物质， 摄取。第二，一旦羟基基团在一个非质子化反应中去质子化，它们似乎会增强单线态氧的形成。 Ru（II）配合物。本申请用新支架探索了这种趋势的普遍性。三是利用 π延伸的共配体可以增强摄取和单线态氧形成。新的合成目标是 建议测试这些假设，并寻找协同增效的光毒性指数值。三 具体目标将探讨这些假设。目标1涉及设计新的PDT药物， 使用配体增强亲脂性、红移光吸收和增加单线态氧的光细胞毒性 生产目的二是研究这些新型质子钌的光毒性和摄取 癌细胞和正常细胞中的化合物。目标3将涉及测量单线态氧和活性氧 在溶液和细胞中的物种形成以及探测DNA结合。该研究将建立 对乳腺癌细胞和其他易感细胞具有选择性毒性的新一代Ru PDT试剂 类型这对肿瘤学领域以外的药物开发人员可能有很大的影响，因为我们正在阐明 质子配体如何影响吸收和单线态氧的形成，这可以用于靶向其他疾病 包括潜在的细菌感染。该项目将用于培养一批多样化的本科生和 研究生与化学和生物工程专业的学生合作进行抗癌研究。 该项目的成果将通过出版物和在会议上的介绍加以传播。