Design/Synthesis/Mechanisms of Drugs for Tumor Hypoxia

肿瘤缺氧药物的设计/合成/机制

• 批准号: 6985585
• 负责人: WILLIAM A DENNY
• 金额: $ 14.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985585
• 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.

该项目的总体目标是设计、合成并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有选择性毒性的共同特征。这种方法是基于这样一个事实，即在实体瘤中缺氧比正常组织严重得多。我们将探索几种开发此类药物的方法，这些药物有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率。我们将跟踪当前项目在确定缺氧激活前药替拉帕胺类似物的最佳理化性质（溶解度、亲脂性、还原潜力、自由基稳定性、DNA靶向性）方面取得的进展，这些类似物目前处于III期临床试验中。特别是，我们将准备和探索3取代类似物的效用，以优化许多这些性质。我们将制备和表征新型强效烷基化前药