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。 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、灵活的化学路线来制备(+)-泛影抑素及其类似物将极大地促进这一先导化合物的进一步发展，因此它一直是科学界追求已久的目标。本项目专注于一种实用的合成基于泛影抑素的系列化合物，这些化合物具有(A)芳香族部分的可变结构和(B)分子中截短的环醇部分。这两个系列都被评估了抗肿瘤活性，活性化合物进一步在适当的小鼠模型中进行了体内测试。所利用的化学是基于本实验室先前开发的新的2-脱氧-2-芳基持续醇F和高度非对映选择性的芳基铜酸盐与-烷氧基-2-烯酸酯的加成反应。这项工作的长期目标包括提炼胰抑素细胞毒性药效团，以开发类似物，包括(A)改善活性/毒性曲线，(B)改善水溶性，以及(C)简化结构，以便为即将到来的临床试验大规模生产。

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. 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 analogs. Therefore, the discovery of an efficient and flexible chemical route enabling preparation of (+)-pancratistatin and its analogs will tremendously facilitate further development of this lead compound, hence it has been a long-sought objective of the scientific community. This project focuses on a practical synthesis of pancratistatin-based series of compounds with (a) variable structure of the aromatic moiety and (b) truncated cyclitol portion of the molecule. Both series are evaluated for antitumor activity and the active compounds are further tested in vivo in appropriate mouse models. The utilized chemistry is based on the previously developed in this laboratory synthesis of novel 2-deoxy-2-arylconduritols F and a highly diastereoselective arylcuprate addition to ¿-alkoxy-¿,¿-enoates. The long-term objective of this work involves the refinement of the pancratistatin cytotoxic pharmacophore for the development 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.