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

抽象的。金属药物通常是用来治疗癌症的，但它们有显著的偏离目标的效果 因为它们杀死了所有快速分裂的细胞，包括健康细胞。有必要进行新的靶向治疗。 基于光活化Ru(Ru)的药物很有希望，因为它们允许对 使用FDA批准的光动力疗法(PDT)技术激活药物。一个光激活的Ru 复杂的TLD-1433在第二阶段临床试验中显示出治疗膀胱癌的良好结果， 展示了这种方法的前景。本文合成并研究了新的质子型Ru络合物 与正常细胞相比，它们对乳腺癌细胞表现出光激活和选择性毒性。这 应用目的是确定pi膨胀配体、电子引出基团和羟基的影响。 PDT上含有吡啶酚配体。这可以确定导致理想的PDT试剂具有良好的因素 摄取，在适当的细胞靶点定位，以及高产量的有毒单线态氧。长期的 这项工作的目标是设计高度细胞毒性和选择性的前体药物，这些药物最初是惰性的，但会产生细胞毒性 物种(单线态氧)在组织穿透红光的情况下。这些前药可以靶向癌细胞。 这是由于癌细胞摄取增强和氧化应激水平高所致。三 假说推动了这项工作。首先，羟基取代配体可以促进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种，从而导致改善 领悟。其次，羟基一旦被去质子化，似乎就能促进单线态氧的形成。 系列Ru(II)络合物。这个应用程序通过新的脚手架探索了这种趋势的普遍性。第三，使用 PI扩链共配体可以促进氧的摄取和单线态氧的形成。新的合成目标是 建议检验这些假说，并寻找光毒性指数值的协同增强作用。三 《特定目标》将探讨这些假说。目标1涉及设计新的PDT试剂以最大限度地 利用配体增强亲脂性、红移光吸收和增加单线态氧的光细胞毒性 制作。目的2研究这些新型质子Ru的光细胞毒性和摄取 癌细胞和正常细胞中的化合物。目标3将包括测量单线态氧和活性氧。 在溶液和细胞中的物种形成以及DNA结合的探测。拟议的研究将确立 对乳腺癌细胞和其他敏感细胞具有选择性毒性的新一代Ru PDT试剂 类型。除了肿瘤学领域之外，药物开发商可能会产生很大的影响，因为我们正在澄清 质子酸配体如何影响摄取和单线态氧的形成，这可以用来针对其他疾病 包括潜在的细菌感染。该项目将用于培养一批不同的本科生和 与化学和生物工程专业的研究生合作进行抗癌研究。 该项目的工作将通过出版物和在会议上的发言来传播。

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.