Novel Indenoisoquinoline Topoisomerase I Inhibitors

新型茚并异喹啉拓扑异构酶 I 抑制剂

• 批准号: 6514869
• 负责人: MARK S CUSHMAN
• 金额: $ 20.55万
• 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/6514869
• 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：（申请人提供）：拓扑异构酶I是一个重要的靶点 用于开发治疗癌症的新型化疗药物 在人类身上。虽然拓扑异构酶I的喜树碱类的一些成员 抑制剂目前在临床上用作抗癌剂， 喜树碱具有许多固有的局限性，包括化学上的局限性， 以及由于内酯开环和快速可逆性导致的代谢不稳定性 拓扑异构酶I抑制作用。由于这些限制， 使用喜树碱的有效化疗需要长时间的静脉输注， 长期和持续的接触。 我们研究小组与其他人合作进行的初步研究， 导致一类新的拓扑异构酶I抑制剂的合成， 茚并异喹啉。体外酶抑制研究的组合 在人类癌细胞培养物和体内动物研究中的细胞毒性结果 已经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的主要目标之一， 目前提出的研究计划将是设计和合成更多的 作为潜在的拓扑异构酶I抑制剂的有效茚并异喹啉 在人类癌症治疗中的临床应用。新化合物 将使用一种新的缩合反应合成， P1的研究小组。Schiff碱与同酞菁的缩合反应 酸酐将提供3-芳基-4-羧基异喹啉，其将被修饰 通过多种方法得到新的茚并异喹啉， 生物活动。 增强抗癌活性的策略之一是， 茚并异喹啉将连接氨基烷基和多氨基烷基侧 链连接到茚并异喹啉。最近的结果显示， 拓扑异构酶I抑制活性和体外抗癌活性增加 当3 '-氨基烷基取代基连接到氨基烷基的氮原子上时， 茚并异喹啉。这种活动的增加被认为是理所当然的 以：1）促进细胞摄取; 2）带正电荷的， 带负电荷的侧链的质子化氨基 嵌入前DNA骨架的磷酸二酯;和3）稳定化 的插层复合物的离子键合。提出的一些化合物 本申请中的方法被设计为探索以下效果： 在侧链中引入多个氨基， 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 链到茚并异喹啉体系的不同区域;和4）修饰 茚并异喹啉骨架，使其更接近于 喜树碱 虽然人拓扑异构酶I的几种晶体结构以共价键和 与DNA的非共价复合物最近已经发表，没有 由拓扑异构酶组成的三元配合物的晶体结构 我，DNA，和抑制剂。我们将尝试合成一个构象 限制性三元复合物，其中抑制剂与 DNA裂解后的寡核苷酸。这将有助于结晶， 配合物的X射线结构测定。