Benzo[i]phenanthridines: TOP1-Targeting Antitumor Agents

苯并[i]菲啶：TOP1 靶向抗肿瘤药物

• 批准号: 6774195
• 负责人: EDMOND J LAVOIE
• 金额: $ 24.49万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774195
• 关键词: DNA topoisomerases; antineoplastics; athymic mouse; camptothecin; cell line; cytotoxicity; drug design /synthesis /production; drug metabolism; drug screening /evaluation; enzyme inhibitors; multidrug resistance; pharmacokinetics; phenanthridines

DESCRIPTION (provided by applicant): Topoisomerase I (TOP1) is an enzyme that alters the topology of DNA by transiently breaking one DNA strand. TOP1-targeting anticancer agents exert their cytotoxic activity by trapping an abortive enzyme-DNA cleavable complex, converting TOP1 into a cellular poison. Camptothecin (CPT) was the first TOP1 poison identified. The poor solubility of this alkaloid, the metabolic instability of its lactone moiety and the high binding affinity to human serum albumin of its hydrolysis product are among the obstacles that hampered clinical development of this first generation of TOP1-targeting anticancer agents. Despite these shortcomings, there are two derivatives of CPT (Irinotecan, and Topotecan) in clinical use. The focus of this proposal is to advance the development of benzo[i]phenanthridines and related compounds as a novel class TOP1-targeting anticancer agents. It is our hypothesis that within this class of noncamptothecin TOP1-targeting agents, there are compounds that 1) have enhanced chemical and metabolic stability and 2) are able to overcome known mechanisms of resistance that do affect the cytotoxic activity of CPT analogues. Such attributes within a second generation of TOP1-targeting anticancer agents may provide the basis for broader clinical utility as well as improved efficacy. The specific aims of this proposal are 1) Evaluate select benzo[i]phenanthridines, azabenzo[i]phenanthridines, and azadibenzo[c,h]cinnolines as novel TOP1-targeting agents capable of overcoming multidrug resistance associated with efflux transporters such as BCRP, as well as MDR1 (P-glycoprotein), MRP1, and LRP; 2) to assess in vivo efficacy using various human tumor cell lines, including those that express MDR1 and BCRP and 3) characterize the metabolism and bioavailability of ARC-111 (azabenzo[i]phenanthridine analogue) and ARC-31 (an azadibenzo[c,h]cinnoline). While ARC-111 and ARC-31 possess potent TOP1-targeting activity and cytotoxicity, these compounds differ in regard to their relative efficacy in vivo. Our laboratory has identified several compounds structurally-related to benzo[i]phenanthridines with similar potency to CPT in TOP1-targeting activity and cytotoxicity. The exceptional in vitro and in vivo biological activities of benzo[i]phenanthridines, azabenzo[i]phenanthridines and azadibenzo[c,h]cinnolines observed in our laboratory form the basis for the studies proposed to advance our understanding of these potentially clinically-useful agents.

描述（由申请人提供）：拓扑异构酶I（TOP1）是一种酶，通过瞬时打破一个DNA链来改变DNA的拓扑。 TOP1靶向抗癌剂通过捕获流产酶-DNA可裂解的复合物，将TOP1转化为细胞毒物，从而发挥其细胞毒性活性。 Camptothecin（CPT）是第一个鉴定出的Top1毒药。这种生物碱的溶解度不佳，其内酯部分的代谢不稳定性以及对其水解产物的人血清白蛋白的高结合亲和力是阻碍了第一代Top1-Targeting抗癌剂的临床发展的障碍之一。尽管存在这些缺点，但在临床用途中仍有两个CPT（Irinotecan和Topotecan）的衍生物。该提案的重点是推进苯并[I]菲类动物和相关化合物的发展，作为一种新型的Top1靶向抗癌剂。我们的假设是，在这类非膜片蛋白TOP1靶向剂中，有一些化合物，即1）具有增强的化学和代谢稳定性，并且2）能够克服确实影响CPT类似物细胞毒性活性的已知抗性机制。第二代靶标的抗癌药物中的这种属性可能为更广泛的临床实用性和提高疗效提供基础。 The specific aims of this proposal are 1) Evaluate select benzo[i]phenanthridines, azabenzo[i]phenanthridines, and azadibenzo[c,h]cinnolines as novel TOP1-targeting agents capable of overcoming multidrug resistance associated with efflux transporters such as BCRP, as well as MDR1 (P-glycoprotein), MRP1, and LRP; 2）使用各种人类肿瘤细胞系评估体内功效，包括表达MDR1和BCRP的细胞和3）表征Arc-1111（Azabenzo [I] thanthroththridine Allogue）和Arc-31（Azadibenzo [azadibenzo [C，H] pinnnoline）的代谢和生物利用度。尽管ARC-111和ARC-31具有有效的TOP1靶向活性和细胞毒性，但这些化合物在体内的相对疗效方面有所不同。我们的实验室已经确定了几种与苯并[I]凤凰的结构相关的化合物，其效力与CPT相似，在Top1靶向活性和细胞毒性中。苯并[i]苯拥丁，阿扎本佐[I]苯拥汀和阿扎迪本佐[C，H]辛诺林在我们的实验室中观察到的研究的基础的特殊体外和体内生物学活性尤其是促进我们对这些潜在的临床持续使用的人的理解，旨在促进我们在实验室中观察到的基础。