ISOLATION OF NOVEL MECHANISM-BASED ANTITUMOR AGENTS

拟议研究的总体目标是发现新的自然 具有显著临床有用抗癌活性的产品。这个 该计划的具体目标是： 1.每年获得20-40种具有良好体外活性的提取物 拓扑异构酶I抑制、拓扑异构酶II抑制或DNA损伤 生物测定，活性提取物在初步筛选后会枯萎。 在弗吉尼亚大学进行，作为核心活动的一部分 这组人，在SmithKline Beecham进行了初步筛选 药品，或来自我们与之合作进行的筛选 来自世界各地的各种同事。 2.使用生物测定指导对每种活性提取物进行分级 分级方案，并选择性地分离纯活性化合物 其中一项生物检测的活性表明。 3.确定所有活性化合物的结构 化学操作、光谱技术和X射线的结合 事实证明，结晶学最适合具体的问题。 4.重新分离足够数量的所有活性化合物，以便进一步 实验室计划1的生物学评估(SmithKline Beecham ParmPharmticals)。 5.与实验室计划4合作(桑德伯格博士，华盛顿大学 弗吉尼亚)在设计和合成新的适当类似物方面 分离的活性化合物。 6.酌情与集团其他成员合作，提供协助 作为临床候选药物的活性化合物的开发。

The overall objective of the proposed research is to discover new natural products with significant clinically useful anticancer activity. The specific aims of the program are: 1. To acquire 20-40 extracts per year which show good in vitro activity in topoisomerase I inhibition, topoisomerase II inhibition, or DNA damaging bioassays, The active extracts will come wither from preliminary screening carried out at the University of Virginia as part of the core activities of this Group, preliminary screening carried out at SmithKline Beecham Pharmaceuticals, or from screening carried out by us in collaboration with various colleagues around the world. 2. To fractionate each of the active extracts using a bioassay-directed fractionation scheme, and to isolate pure active compounds with selective activity in one of the bioassays indicated. 3. To determine the structures of all active compounds by whichever combination of chemical manipulation, spectroscopic techniques,a nd X-ray crystallography proves most appropriate to the specific problem. 4. To reisolate adequate amounts of all active compounds for further biological evaluation by Laboratory Program 1 (SmithKline Beecham Parmaceuticals). 5. To collaborate with Laboratory Program 4 (Dr. Sundberg, University of Virginia) in the design and synthesis of appropriate analogs of newly isolated active compounds. 6. To collaborate with other members of the Group as appropriate to assist in the development of active compounds as clinical candidates.