ELUCIDATION OF THE PANCRATISTATIN CYTOTOXIC PHARMACOPHORE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景和理论基础 该项目的最终目标是为癌症治疗提供新的治疗剂。从斜纹夜蛾鳞茎中提取的生物碱(+)-泛影抑素具有良好的抗肿瘤和抗病毒活性，目前正在接受美国国家癌症研究所的临床前评估。然而，由于可从隔离中获得的材料数量有限，这项研究已被搁置。生物碱的有限可获得性也困扰了阐明其作用机制以及结构活性研究的努力，这可能是识别更有效和/或毒性更低的类似物的关键。因此，发现一条高效而灵活的化学路线，不仅可以制备天然产物本身，而且可以制备不同的类似物库，这将极大地促进这种先导化合物的进一步发展，因此它一直是科学界长期追求的目标。 方法 这项工作集中于一种实用的合成基于泛影抑素的系列化合物，该化合物具有可变的分子截断部分。一旦合成，这些化合物就被评估在体外和体内的抗癌活性。根据获得的合成孔径雷达信息，构建了泛影抑素药效团，并将其用于开发一系列类似物：(A)改善活性/毒性曲线，(B)改善水溶性，(C)简化结构，适合于即将到来的临床试验的大规模生产。 结果 在INBRE项目的前几年，我们开发了一种高非对映选择性的芳基铜酸盐与g-烷氧基-a，b-烯酸酯的加成，探索了它的范围，发现它的潜在应用不仅限于这个项目，而且在合成有机化学中具有普遍的用途。我们成功地将该方法应用于一种关键中间体的合成，该中间体指向具有简化结构的Pancatistatin类似物的聚焦文库，特别是具有较少环数的化合物。INBRE基金还使我们能够通过使用高度集中的化合物文库进行筛选来鉴定几种有效的生物活性化合物。这项工作涉及大量学生，并对他们进行药物发现过程的教育，发表在排名靠前的药物发现期刊上。 进一步研究 将积极利用已开发的合成物来制备和生物学评价简化的胰岛抑素类似物的库，以及药物发现小组的进一步发现，涉及大量学生。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and Rationale This project is aimed at the ultimate goal of providing new therapeutic agents for the treatment of cancer. The alkaloid (+)-pancratistatin, extracted from Pancratium littorale bulbs, displays promising antineoplastic and antiviral activity and is currently undergoing preclinical evaluation by the US National Cancer Institute. However, the studies have been put on hold due to the limited quantity of material available from isolation. The alkaloid's limited availability has also plagued efforts towards the elucidation of its mechanism of action as well as structure  activity studies, which could be crucial for the identification of more potent and/or less toxic analogues. Therefore, the discovery of an efficient and flexible chemical route enabling preparation of not only the natural product itself, but also a diverse library of its analogues will tremendously facilitate further development of this lead compound, hence it has been a long-sought objective of the scientific community. Methods This work focuses on a practical synthesis of pancratistatin-based series of compounds with variable truncated portions of the molecule. Once synthesized, the compounds are evaluated for in vitro and in vivo anticancer activity. Based on the obtained SAR information the pancratistatin pharmacophore is constructed and used for the development of a series of analogs with (a) improved activity/toxicity profiles, (b) improved water solubility, and (c) simplified structures, amenable to a large-scale production for the forthcoming clinical trials. Results In the previous years of the INBRE project we developed a highly diastereoselective arylcuprate addition to g-alkoxy-a,b-enoates, explored its scope and found that its potential applicability is not limited to this project, but rather has a general utility in synthetic organic chemistry. We successfully applied the methodology to the synthesis of a key intermediate toward a focused library of pancratistatin analogues with simplified structures, specifically the compounds with a reduced number of rings. The INBRE funds also allowed us to identify several potent biologically active compounds through screening efforts using highly focused compound libraries. This work, which involves a great number of students and educates them about the drug discovery process, was published in the highly ranked drug discovery journals. Further Study Utilization of the developed synthesis to prepare and biologically evaluate a library of simplified pancratistatin analogues as well as further discoveries of the drug discovery group, involving a large number of students, will be actively pursued.