Novel Indenoisoquinoline Topoisomerase I Inhibitors

描述：(申请人提供)：拓扑异构酶I是一个重要的靶标 用于癌症治疗的新化疗药物的开发 在人类身上。尽管喜树碱类拓扑异构酶I的一些成员 抑制剂目前在临床上用作抗癌药物， 喜树碱受到许多先天限制，包括化学成分 内酯开环和快速可逆性导致的代谢不稳定 药物清除时对拓扑异构酶I的抑制。由于这些限制， 喜树碱的有效化疗需要长时间静脉滴注和 长时间持续暴露。 我们研究组的初步研究与其他人合作，已经 导致合成了一类新的拓扑异构酶I抑制剂， 吲哚异喹啉。酶抑制研究的组合，在体外 细胞毒性在人类癌细胞培养和体内动物研究中的结果 已经提供了令人信服的证据表明吲哚异喹啉将克服 喜树碱的一些局限性。该计划的主要目标之一是 目前提出的研究计划将是设计和合成更多 有效的吲哚异喹啉作为潜在的拓扑异构酶I抑制剂 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来合成，该反应是在 P1‘S课题组。席夫碱与邻苯二甲酸的缩合反应 Anlidrides将提供3-芳基-4-羧基异喹啉，并对其进行修饰 通过多种方法合成新的吲哚异喹啉类化合物 生物活动。 增强其抗癌活性的策略之一是 吲哚异喹啉将与氨基烷基和多氨基烷基侧相连。 链连接到吲哚异喹啉上。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的提高 当3‘-氨基烷基取代基连接到氮原子上时的活性 吲哚异喹啉。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)带正电荷的离子键， 带负电荷的侧链的质子化氨基 插入前DNA骨架的磷酸二酯；3)稳定性 通过离子键合形成插层络合物。其中一些化合物被提出 在本申请中的目的是探索以下效果：i) 在侧链上加入多个氨基，将靶向更多 2)改变氨基之间的距离 基团和吲哚异喹啉核；3)连接氨基烷基侧 与吲哚异喹啉体系不同区域的链；以及4)修饰 吲哚异喹啉骨架，使其更接近于 喜树碱。 虽然人拓扑异构酶I的几种晶体结构在共价和 最近发表了与DNA的非共价络合物，目前还没有 拓扑异构酶三元络合物的晶体结构 I、DNA和一种抑制剂。我们将尝试合成一种构象 限制性三元络合物，其中缓蚀剂共价结合到 DNA裂解后的寡核苷酸。这应该会促进结晶 用于X射线结构测定的络合物。

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.