4'-Substituted nucleoside analogs as anticancer drugs

描述（由申请人提供）： 本申请的目的是合理设计、合成和评价某些核苷类似物，以努力发现用于治疗实体瘤以及血液恶性肿瘤的新药剂。该项目的主要研究人员多年来一直参与这项工作，最近负责发现一种新药（氯法拉滨），该药物于2004年12月被FDA批准用于治疗儿童急性淋巴细胞白血病，目前正在成人临床试验中评估其在实体瘤和血液恶性肿瘤中的活性。最近，我们发现了一种在2'-和4'-位置修饰的先导化合物，其对小鼠实体瘤异种移植物表现出优异的活性。在这一系列中，只有少数类似物具有抗癌活性作为疾病靶标，本提案的目标是彻底评估这种类型修饰的潜力。该申请包括两个具体目标。在目标1中，我们将设计和合成在4'-碳上具有修饰的新型核苷类似物。基于我们对核苷代谢的广泛了解，目前用于治疗癌症的类似物，可用的蛋白质结构数据，dCyd激酶的计算建模以及我们和其他人过去已经制备的那些化合物，合理设计了目标化合物。所有新化合物将针对一组人实体瘤细胞系进行细胞毒性测试。将评价细胞毒性化合物对正常细胞的毒性，并且将合成足够量的具有显著选择性的化合物用于体内研究，以确定对许多人实体瘤异种移植物的抗肿瘤功效。在具体目标2中，我们将评估具有有希望活性的新药物的代谢和作用机制，以便我们可以了解这些化合物与现有药物的不同之处。生物学评价的结果将用于新化合物的迭代合理设计。这项资助申请是一项高度综合的工作，涉及核苷类似物的设计和合成，核苷类似物的代谢和作用机制的生物化学评价以及人类肿瘤异种移植物中新药的评价。该资助申请的重点是在现有抗癌药物类别的基础上发现新的抗癌药物，预计将产生临床候选药物，并增加我们对这一重要类别作用机制的了解。在这个计划中，我们将设计，合成，并评估新的核苷类似物作为抗癌药物的基础上，一个新的先导化合物在动物模型系统中的活动。该项目的主要研究人员多年来一直参与抗癌药物发现，最近负责发现了一种新药（氯法拉滨），该药物最近获得FDA批准用于治疗儿童急性淋巴细胞白血病，目前正在成人临床试验中评估其在实体瘤和血液恶性肿瘤中的活性。

DESCRIPTION (provided by applicant): The goal of this application is to rationally design, synthesize, and evaluate certain nucleoside analogs in an effort to discover new agents for the treatment of solid tumors as well as hematological malignancies. The key investigators of this project have been involved in this endeavor for many years and have recently been responsible for the discovery of a new drug (clofarabine) that was approved by the FDA for the treatment of childhood acute lymphocytic leukemia in December of 2004 and is currently being evaluated in adult clinical trials for activity in solid tumors and hematological malignancies. Recently, we have discovered a lead compound that is modified at the 2'- and 4'-positions that has demonstrated excellent activity against solid tumor xenografts in mice. Only a few analogs in this series have been made with anticancer activity as the disease target, and it is the goal of this proposal to thoroughly evaluate the potential of this type of modification. The application consists of two specific aims. In aim 1 we will design and synthesize novel nucleoside analogs with modifications at the 4'-carbon. The target compounds are rationally designed based on our extensive knowledge of nucleoside metabolism, the analogs that are currently used in the treatment of cancer, available protein structural data, computational modeling with dCyd kinase and those compounds that have been made in the past by us and others. All new compounds will be tested for cytotoxicity against a panel of human solid tumor cell lines. Cytotoxic compounds will be evaluated for toxicity to normal cells, and those compounds with significant selectivity will be synthesized in sufficient quantities for in vivo studies to determine antitumor efficacy against numerous human solid tumor xenografts. In specific aim 2 we will evaluate the metabolism and mechanism of action of new agents with promising activity so that we can learn how these compounds differ from existing agents. The results of the biological evaluations will be used in the iterative rational design of new compounds. This grant application is a highly integrated effort involving expertise in the design and synthesis of nucleoside analogs, the biochemical evaluation of the metabolism and mechanism of action of nucleoside analogs, and the evaluation of new agents in human tumor xenografts. The grant application is focused on the discovery of new anticancer agents based on an established anticancer drug class, and is expected to lead to a clinical candidate as well as to increase our understanding of the mechanisms of action of this important class. In this proposal we will design, synthesize, and evaluate new nucleoside analogs as anticancer agents based upon a new lead compound with activity in animal model systems. The key investigators of this project have been involved in anticancer drug discovery for many years and have recently been responsible for the discovery of a new drug (clofarabine), which was recently approved by the FDA for the treatment of childhood acute lymphocytic leukemia and is currently being evaluated in adult clinical trials for activity in solid tumors and hematological malignancies.