Novel Indenoisoquinoline Topoisomerase I Inhibitors

新型茚并异喹啉拓扑异构酶 I 抑制剂

• 批准号: 6400690
• 负责人: MARK S CUSHMAN
• 金额: $ 21.34万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-10 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6400690
• 关键词: DNA topoisomerases; antineoplastics; cooperative study; drug design /synthesis /production; enzyme inhibitors; isoquinolines; tissue /cell culture

DESCRIPTION: (provided by applicant): Topoisomerase I is an important target for the development of new chemotherapeutic agents for the treatment of cancer in humans. Although some members of the camptothecin class of topoisomerase I inhibitors are presently in clinical use as anticancer agents, the camptothecins suffer from a number of inherent limitations, including chemical and metabolic instability due to lactone ring opening and rapid reversibility of topoisomerase I inhibition upon drug removal. Because of these limitations, effective chemotherapy with the camptothecins requires long I.V. infusions and prolonged and continuous exposure. Preliminary studies in our research group, in collaboration with others, have resulted in the synthesis of a new class of topoisomerase I inhibitors, the indenoisoquinolines. A combination of enzyme inhibition studies, in vitro cytotoxicity results in human cancer cell cultures, and in vivo animal studies have provided compelling evidence that the indenoisoquinolines will overcome some of the limitations of the camptothecins. One of the main goals of the presently proposed research program will be to design and synthesize more effective indenoisoquinolines as topoisomerase I inhibitors with potential clinical application in the treatment of cancer in humans. The new compounds will be synthesized using a novel condensation reaction that was developed in the P1's research group. Condensation of Schiff bases with homophthalic anliydrides will provide 3-aryl-4-carboxyisoquinolines, which will be modified by a variety of methods to afford new indenoisoquinolines with enhanced biological activities. One of the strategies to be employed to enhance the anticancer activities of the indenoisoquinolines will be to attach aminoalkyl and polyaminoalkyl side chains to the indenoisoquinolines. Recent results have shown a dramatic increase in both topoisomerase I inhibitory activity and in vitro anticancer activity when a 3'-aminoalkyl substituent is attached the nitrogen atom of the indenoisoquinolines. This boost in activity has been rationalized as being due to: 1) facilitated cellular uptake; 2) ionic bonding of the positively charged, protonated amino group of the side chain with the negatively charged phosphodiesters of the DNA backbone before intercalation; and 3) stabilization of the intercalation complex by ionic bonding. Some of the compounds proposed in the present application are designed to explored the effects of: I) incorporating multiple amino groups in the side chain that will target more than one phosphodiester linkage; 2) altering the distances separating the amino groups and the indenoisoquinolines nucleus; 3) attaching the aminoalkyl side chains to different regions of the indenoisoquinoline system; and 4) modifying the indenoisoquinoline framework so that it more closely resembles camptothecin. Although several crystal structures of human topoisomerase I in covalent and non-covalent complex with DNA have recently been published, there are no crystal structures available of ternary complexes consisting of topoisomerase I, DNA, and an inhibitor. We will attempt to synthesize a conformationally restricted ternary complex in which the inhibitor is covalently bound to the oligonucleotide after DNA cleavage. This should facilitate crystallization of the complex for X-ray structure determination.

描述：（由申请人提供）：拓扑异构酶 I 是一个重要的靶标 开发用于治疗癌症的新化疗药物 在人类中。尽管拓扑异构酶 I 的喜树碱类的一些成员 抑制剂目前在临床上作为抗癌药物使用 喜树碱有许多固有的局限性，包括化学 由于内酯开环和快速可逆性导致代谢不稳定 药物去除后拓扑异构酶 I 的抑制作用。由于这些限制， 喜树碱的有效化疗需要长时间静脉注射。输液和 长时间且连续的暴露。 我们的研究小组与其他人合作进行的初步研究已经 导致合成了一类新的拓扑异构酶 I 抑制剂， 茚并异喹啉类。体外酶抑制研究的组合 人类癌细胞培养物和体内动物研究中的细胞毒性结果 提供了令人信服的证据表明茚并异喹啉将克服 喜树碱的一些局限性。该组织的主要目标之一 目前提出的研究计划将是设计和综合更多 有效的茚并异喹啉作为拓扑异构酶 I 抑制剂具有潜力 临床应用在治疗人类癌症中。新化合物 将使用一种新颖的缩合反应来合成，该反应是在 P1的研究小组。席夫碱与同邻苯二甲酸的缩合 酸酐将提供 3-芳基-4-羧基异喹啉，其将被修饰 通过多种方法提供新的茚并异喹啉，具有增强的 生物活性。 增强抗癌活性的策略之一 茚并异喹啉将连接氨基烷基和聚氨基烷基侧 链至茚并异喹啉。最近的结果显示出戏剧性的 拓扑异构酶 I 抑制活性和体外抗癌活性均增加 当 3'-氨基烷基取代基连接到氮原子上时的活性 茚并异喹啉类。这种活动的增加已被合理化为应有的结果 1）促进细胞摄取； 2）带正电的离子键， 带负电荷的侧链质子化氨基 插入前 DNA 主链的磷酸二酯； 3) 稳定性 通过离子键合形成插层络合物。一些提议的化合物 本申请旨在探索以下效果：I) 在侧链中结合多个氨基，可以靶向更多 多于一个磷酸二酯键； 2) 改变氨基之间的距离 基团和茚并异喹啉核； 3) 连接氨基烷基侧 链至茚并异喹啉系统的不同区域； 4）修改 茚并异喹啉框架，使其更类似于 喜树碱。 尽管人类拓扑异构酶 I 的几种晶体结构以共价和 最近发表了与 DNA 的非共价复合物，但尚无 由拓扑异构酶组成的三元复合物的晶体结构 I、DNA 和抑制剂。我们将尝试合成一种构象 限制性三元复合物，其中抑制剂与 DNA切割后的寡核苷酸。这应该有利于结晶 用于X射线结构测定的络合物。