Benzo[i]phenanthridines: TOP1-Targeting Antitumor Agents

描述（由申请人提供）：拓扑异构酶I （TOP1）是一种通过短暂断裂一条DNA链来改变DNA拓扑结构的酶。靶向TOP1的抗癌药物通过捕获流产的酶- dna可切割复合物，将TOP1转化为细胞毒素，发挥其细胞毒性活性。喜树碱（CPT）是第一个被发现的TOP1毒物。这种生物碱的溶解度差，其内酯部分代谢不稳定，其水解产物与人血清白蛋白的高结合亲和力是阻碍第一代top1靶向抗癌药物临床发展的障碍。尽管存在这些缺点，临床上仍有两种CPT衍生物（伊立替康和拓扑替康）在使用。本提案的重点是推进苯并[i]菲菲啶及其相关化合物作为一类新的top1靶向抗癌药物的开发。我们的假设是，在这类非喜树碱top1靶向药物中，存在以下化合物：1)具有增强的化学和代谢稳定性；2)能够克服影响CPT类似物细胞毒性活性的已知耐药机制。第二代靶向top1的抗癌药物的这些特性可能为更广泛的临床应用和提高疗效提供基础。该提案的具体目的是：1)评估选择苯并[i]菲菲啶、氮杂苯并[i]菲菲啶和氮杂苯并[c，h]喹啉作为新型top1靶向药物，能够克服与外排转运体（如BCRP）、MDR1 （p -糖蛋白）、MRP1和LRP相关的多药耐药；2)利用多种人类肿瘤细胞系（包括表达MDR1和BCRP的细胞系）评估体内疗效；3)表征ARC-111 （azabenzo[i]菲苯胺类似物）和ARC-31 （azabenzo[c，h]肉桂碱）的代谢和生物利用度。虽然ARC-111和ARC-31具有强大的top1靶向活性和细胞毒性，但这些化合物在体内的相对功效不同。我们的实验室已经确定了几种与苯并[i]菲菲啶结构相关的化合物，它们在top1靶向活性和细胞毒性方面与CPT相似。在我们的实验室中观察到的苯并[i]菲菲啶、偶氮苯并[i]菲菲啶和偶氮苯并[c，h]肉桂碱的特殊体外和体内生物活性，为我们提出的研究奠定了基础，以促进我们对这些潜在临床有用药物的理解。

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.