Benzo[i]phenanthridines: TOP1-Targeting Antitumor Agents

描述(申请人提供)：拓扑异构酶I(TOP1)是一种通过瞬间断裂一条DNA链来改变DNA拓扑结构的酶。Top1靶向抗癌剂通过捕获流产的酶-DNA可裂解复合体，将TOP1转化为细胞毒物来发挥其细胞毒活性。喜树碱(CPT)是第一个被发现的TOP1毒物。这种生物碱的溶解性差，其内酯部分的代谢不稳定，以及其水解物与人血清白蛋白的高结合亲和力是阻碍这种第一代TOP1靶向抗癌药物临床开发的障碍之一。尽管有这些缺点，临床上仍有两种CPT的衍生物(伊立替康和拓扑替康)。这项建议的重点是促进苯并[I]菲啶及其相关化合物作为一类新型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，有一些化合物1)增强了化学和代谢稳定性，2)能够克服影响CPT类似物细胞毒活性的已知耐药机制。第二代TOP1靶向抗癌药物中的这些属性可能为更广泛的临床应用以及改善疗效提供基础。这项建议的具体目的是1)评价选择苯并[i]菲啶、氮杂并[i]菲啶和氮杂二苯并[c，h]肉桂酚作为能够克服与外排转运体相关的多药耐药性的新型TOP1靶向药物，如BCRP，以及MDR1(P-糖蛋白)、MRP1和LRP；2)评估使用各种人类肿瘤细胞系的体内疗效，包括表达MDR1和BCRP的肿瘤细胞；3)表征ARC-111(氮杂并[i]菲类似物)和ARC-31(氮杂并[c，h]Cinnoline)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效力有所不同。我们的实验室已经确定了几个结构上与苯并[I]菲并[I]菲相关的化合物，它们在TOP1靶向活性和细胞毒性方面与CPT相似。本实验室观察到的苯并[i]菲、氮杂并[i]菲和氮杂并[c，h]肉桂酚等化合物在体外和体内具有良好的生物活性，为进一步了解这些具有潜在临床应用价值的药物奠定了基础。

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.