Design/Synthesis/Mechanisms of Drugs for Tumor Hypoxia

该项目的总体目标是设计、合成并进一步开发几个具有对缺氧细胞选择性毒性的共同特征的小分子药物。这种方法是基于实体肿瘤的缺氧比正常组织严重得多的事实。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剂对正常组织的毒性更小，因此具有更好的治疗比率。我们将跟进当前计划在确定低氧激活的前体药物替拉帕扎明的类似物的最佳物理化学性质(溶解性、亲脂性、还原电位、自由基稳定性、DNA靶向性)方面取得的进展，目前正在进行第三阶段临床试验。特别是，我们将准备和探索3-取代类似物的用途，以优化其中的许多性质。我们将制备和表征有效的烷基化反应的新型前药 专为从大肠杆菌和梭状芽孢杆菌中分离的硝基还原酶、β-葡萄糖醛酸酶和β-半乳糖苷酶激活而设计的试剂。这些酶的基因将由厌氧细菌生孢梭菌选择性地传递给缺氧的肿瘤细胞，这种治疗方法被称为梭状芽胞杆菌导向的酶前药物疗法(CDEPT)。我们将探索细胞毒素和触发单元在前药中的位置，以优化前药/酶的相互作用，并将确定前药及其释放的效应器的适当脂亲性，以实现最佳的血管外扩散，为这一令人兴奋的新载体递送系统开发前药。我们将研究对缺氧诱导转录因子1α(HIF-1α)活性上调的细胞具有致命性的化合物。这是细胞适应低氧环境的途径的重要组成部分，以及在其存在或存在的情况下优先对细胞产生毒性的药物。 由其上调的下游酶的存在，预计将选择性地对缺氧细胞以及过度表达HIF-1α的有氧细胞产生毒性。我们将评估HITS作为治疗药物的潜在开发(例如，溶解性、扩散特性、合成简易性、新颖性)。然后，我们将准备选定的铅小分子的小系列类似物，以确定适合高级开发的类别。

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.