NUCLEAR TARGETS FOR NATURAL PRODUCTS DRUG DISCOVERY

该实验室计划的长期目标是确定 适合作为抗肿瘤药物开发的化合物。在项目期间 在此期间，目标包括： (1)利用酵母为基础的筛选DNA损伤剂来鉴定 机械上独特的物种，其行为表明其潜在的效用 抗肿瘤药物。 (2)利用拓扑异构酶I作为新的基因座 分离额外拓扑异构酶I抑制剂的抗肿瘤药物 功能，产生大量已识别的结构类似物 使用组合化学技术的缓蚀剂，并开发了几种 可用于鉴定这些拓扑异构酶的次级鉴别器 I类抑制剂可能是有用的抗肿瘤药物。 (3)获得更有效的DNA聚合酶β抑制剂 可能完成对假设的检验，即这些代理人可以 增强抗肿瘤药物的细胞毒活性 通过造成DNA损伤，并证明这种抑制物有能力 增强博莱霉素、埃斯帕米星等药物的抗肿瘤活性 和Calicheamicin (4)确定研究概述中确定的先导化合物的优先顺序 并在数量上获得了最有希望的化合物 足以在实验动物模型/初始阶段进行抗肿瘤评估 临床前发展 (5)加强我们寻找新抗肿瘤药物的前景 从已有的植物样本中准备额外的植物提取物。

The long term objective of this Laboratory Program is the identification of compounds suitable for development as antitumor agents. During the project period, objectives include: (1) utilizing yeast-based screens for DNA damaging agents to identify mechanistically unique species whose behavior suggests potential utility as antitumor agents. (2) utilizing topoisomerase I as a locus for the development of new antitumor agents by isolating additional inhibitors of topoisomerase I function, producing large numbers of structural analogues of identified inhibitors using combinatorial chemistry techniques, and developing several secondary discriminators that can be used to identify those topoisomerase I inhibitors likely to be of utility as antitumor agents. (3) obtaining more potent inhibitors of DNA polymerase beta so that it is possible to complete the testing of the hypothesis that these agents can potentiate the cytotoxic activity of activity of antitumor agents that act by creating DNA lesions, and demonstrate the ability of such inhibitors to potentiate the antitumor activity of agents such as bleomycin, esperamicin and calicheamicin (4) prioritizing the lead compounds identified by the studies outlined above and obtaining the most promising compounds in quantitities sufficient for antitumor evaluation in experimental animal models/initial preclinical development (5) enhancing our prospects for identifying novel antitumor agents by preparing additional plant extracts from plant samples already in hand.