INDOLEQUINONE TOPOISOMERASE INHIBITORS/ANTITUMOR AGENTS

第一阶段项目的目标是综合和评价 吲哚醌和吡咯并亚氨基醌生物碱， 与天然产物BE 10988和Makaluvamines相似， 预期作为人拓扑异构酶I和II的抑制剂。 拓扑异构 II是许多临床上有用的抗肿瘤药物的靶点，例如 蒽环类、VP-16和m-AMSA，而拓扑异构酶I是 目前在临床试验中的几种药物，如喜树碱和 CPT-11 我们的初步研究发现，简单的4，7- 在5-位具有氨基官能团的吲哚醌提供了双 两种酶的抑制作用以及对 人类肿瘤细胞。 只有少数拓扑异构酶I和I的双重抑制剂 II以前已经描述过了。 一系列类似物将在 合成并评价拓扑异构酶I和II的抑制作用 活性以及对人肿瘤细胞系的体外细胞毒性 该数据将被用于绘制抑制之间的相关性。 拓扑异构酶活性和细胞毒性，以及提供结构- 设计和合成具有放射性物质的同系物的活动数据 优化生物活性。 本研究的长期目标是 用于临床的新类似物的鉴定 用于治疗人类癌症，这将在世界范围内产生巨大的 市场潜力。 拟议的商业应用：许多临床有用 抑制剂通过抑制拓扑异构酶II起作用，并且几种 抑制拓扑异构酶I的类似物目前处于临床试验中。一 拓扑异构酶I和II的双重抑制剂将利用 作用于两种不同的酶靶点的能力，从而提供 在某些对一种作用模式有抗性的肿瘤中的治疗效果。 具有改善的治疗特性的新的抗肿瘤剂在很大程度上是有用的。 全世界的商业需求。

The goal of this Phase I project is the synthesis and evaluation of indolequinone and pyrroloiminoquinone alkaloids having structural similarity to the natural products BE 10988 and the makaluvamines, intended as inhibitors of human topoisomerase I and II. Topoisomerase II is the target of many clinically useful antineoplastic agents, such as anthracyclines, VP-16 and m-AMSA, while topoisomerase I is the target of several agents currently in clinical trials, such as camptothecin and CPT-11. Our preliminary studies have found that simple 4,7- indolequinones having amino functionality at the 5-position afford dual inhibition of both enzymes, as well as in vitro cytotoxicity against human tumor cells. Only a few dual inhibitors of topoisomerases I and II have previously been described. A series of analogues will be synthesized and evaluated for inhibition of topoisomerase I and II activities, as well as in vitro cytotoxicity against human tumor cell lines This data will be utilized to draw correlations between inhibition of topoisomerase activity and cytotoxicity, as well as afford structure- activity data for the design and synthesis of congeners possessing optimized biological activities. The long term goal of this study is the identification of novel analogues to be utilized in the clinical setting for the treatment of human cancers, which would have enormous worldwide market potential. PROPOSED COMMERCIAL APPLICATION: Many clinically useful antineoplastic agents act via inhibition of topoisomerase II, and several analogues which inhibit topoisomerase I are currently in clinical trials. A dual inhibitor of both topoisomerases I and II would take advantage of the ability to act at two distinct enzymatic targets, thus affording therapeutic effects in certain tumors resistant to one mode of action. New antitumor agents with improved therapeutic properties are in great commercial demand worldwide.