Benzo[i]phenanthridines: TOP1-Targeting Antitumor Agents

描述（由申请人提供）：拓扑异构酶I（TOP 1）是一种通过瞬时断裂一条DNA链来改变DNA拓扑结构的酶。靶向TOP1的抗癌剂通过捕获失败的酶-DNA可切割复合物，将TOP1转化为细胞毒素来发挥其细胞毒性活性。喜树碱（CPT）是第一个被发现的TOP1毒物。这种生物碱的溶解性差，其内酯部分的代谢不稳定性以及其水解产物对人血清白蛋白的高结合亲和力是阻碍这种第一代TOP1靶向抗癌剂的临床开发的障碍之一。尽管存在这些缺点，但临床使用的CPT有两种衍生物（伊立替康和托泊替康）。本提案的重点是推进苯并[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TOP 1靶向药物中，存在1）具有增强的化学和代谢稳定性和2）能够克服影响CPT类似物细胞毒性活性的已知耐药机制的化合物。第二代靶向TOP1的抗癌剂的这些属性可以为更广泛的临床应用以及改善的疗效提供基础。本提案的具体目的是：1）评价选择的苯并[i]菲啶类、氮杂苯并[i]菲啶类和氮杂二苯并[c，h]噌啉类作为新型TOP 1靶向药物，这些药物能够克服与外排转运蛋白（如BCRP）以及MDR 1相关的多药耐药性（P-糖蛋白）、MRP 1和LRP; 2）使用各种人肿瘤细胞系评估体内功效，包括表达MDR 1和BCRP的那些，和3）表征ARC-111（氮杂苯并[i]菲啶类似物）和ARC-31（氮杂二苯并[c，h]噌啉）的代谢和生物利用度。虽然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功效方面不同。我们的实验室已经鉴定了几种与苯并[i]菲啶结构相关的化合物，其在TOP1靶向活性和细胞毒性方面与CPT具有相似的效力。在我们的实验室中观察到的苯并[i]菲啶类、氮杂苯并[i]菲啶类和氮杂二苯并[c，h]噌啉类化合物的体外和体内生物学活性异常，这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.