Design/Synthesis/Mechanisms of Drugs for Tumor Hypoxia

肿瘤缺氧药物的设计/合成/机制

• 批准号: 7222671
• 负责人: WILLIAM A DENNY
• 金额: $ 15.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7222671
• 关键词: Clostridium; NAD(P)H oxidoreductase; alkylating agents; alkylation; analog; antineoplastics; beta galactosidase; beta glucuronidase; chemical structure function; combination therapy; cytotoxicity; drug design /synthesis /production; enzyme induction /repression; enzymes; free radicals; gene delivery system; gene therapy; hypoxia; intermolecular interaction; physical property; prodrugs; tirapazamine; tissue /cell culture; transcription factor

The overall objective of this project is to design, synthesize and further develop several series of small-molecule drugs that have the common feature of being selectively toxic to hypoxic cells. This approach is based on the fact that hypoxia is much more severe in solid tumors than normal tissue. We will explore several approaches to the development of such drugs, which have the promise of being less toxic than current cytotoxic agents to normal tissue, and therefore having better therapeutic ratios. We will follow up progress made in the current program in defining optimal physicochemical properties (solubility, lipophilicity, reduction potential, radical stability, DNA targeting) of analogs of the hypoxia-activated prodrug tirapazamine now in Phase III clinical trials. In particular, we will prepare and explore the utility of 3-substituted analogs to optimize many of these properties. We will prepare and characterize novel prodrugs of potent alkylating agents, designed for activation by nitroreductase, beta-glucuronidase and beta-galactosidase enzymes isolated from the bacteria Escherischia coli and from Clostridium species. The genes for these enzymes will be delivered selectively to hypoxic tumor cells by the anaerobic bacterium Clostridia sporogenes, in a therapy approach called Clostridia-directed enzyme-prodrug therapy (CDEPT). We will explore the positioning of the cytotoxin and trigger units within the prodrug to optimize prodrug/enzyme interactions, and will determine the appropriate lipophilicities of the prodrugs and their released effectors for optimum extravascular diffusion, in developing prodrugs for this exciting new vector delivery system. We will study compounds that are lethal to cells with upregulated activity of hypoxia-induced transcription factor 1alpha (HIF-1alpha). This is an important component of the pathway by which cells adapt to low-oxygen environments, and drugs that are preferentially cytotoxic in its presence or in the presence of downstream enzymes upregulated by it, are expected to be selectively toxic to hypoxic cells as well as to aerobic cells over-expressing HIF-1alpha. We will evaluate hits in terms of their potential development as therapeutic drugs (e.g., solubility, diffusional properties, ease of synthesis, novelty). We will then prepare small series of analogs of selected lead small molecules, to identify classes suitable for advanced development.

本项目的总体目标是设计、合成和进一步开发几个系列的小分子药物，这些药物具有对缺氧细胞选择性毒性的共同特征。这种方法是基于这样一个事实，即实体瘤中的缺氧比正常组织严重得多。 我们将探索几种方法来开发这样的药物，这有希望比目前的细胞毒性药物对正常组织的毒性更小，因此具有更好的治疗比。 我们将跟进目前项目中所取得的进展，以确定目前处于III期临床试验中的缺氧激活前药替拉扎明类似物的最佳理化性质（溶解度、亲脂性、还原电位、自由基稳定性、DNA靶向）。特别是，我们将准备和探索3-取代类似物的效用，以优化许多这些属性。 我们将制备和表征新的前体药物的有效烷基化 试剂，设计用于通过从土栖大肠杆菌和梭菌属分离的硝基还原酶、β-葡萄糖醛酸酶和β-半乳糖苷酶激活。这些酶的基因将通过厌氧细菌产孢梭菌选择性地传递到缺氧肿瘤细胞，这种治疗方法称为梭菌导向酶前药治疗（CDEPT）。我们将探索定位的细胞毒素和触发单元内的前药，以优化前药/酶的相互作用，并将确定适当的亲脂性的前药和其释放的效应器最佳的血管外扩散，在开发前药这个令人兴奋的新载体传递系统。我们将研究对缺氧诱导转录因子1 α（HIF-1 α）活性上调的细胞具有致死性的化合物。这是细胞适应低氧环境的途径的重要组成部分，并且药物在其存在或存在时优先具有细胞毒性。 被其上调的下游酶的存在，预期对缺氧细胞以及过表达HIF-1 α的需氧细胞具有选择性毒性。我们将根据其作为治疗药物的潜在发展来评估命中（例如，溶解性、扩散性质、易于合成、新奇）。然后，我们将准备小系列的类似物的选择铅小分子，以确定类适合先进的发展。