Enantiodivergent Synthesis of (+) and (-) Pancratistatin

( ) 和 (-) Pancratistatin 的对映异构合成

• 批准号: 6593475
• 负责人: ALEXANDER KORNIENKO
• 金额: $ 14.47万
• 依托单位: NEW MEXICO INST OF MINING & TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-09 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6593475
• 关键词: alkaloids; antineoplastic antibiotics; chemical addition; chemical structure function; cyclization; drug design /synthesis /production; stereochemistry; xylose

DESCRIPTION (provided by applicant): 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 development of an efficient chemical route enabling gram-quantity preparation of (+)-pancratistatin will tremendously facilitate further biological and medicinal evaluation of this compound and its analogs, hence it has been a long-sought objective of the scientific community. The work proposed in this application focuses on a practical enantiodivergent synthesis of (+)-pancratistatin and enantiomeric (-)-pancratistatin from D-xylose. The latter compound has not been synthesized in enantiomerically pure form, in spite of recent data revealing the possibility of similar activity in the enantiomeric pancratistatin series. The proposed synthesis of the two pancratistatin enantiomers follows two diverging synthetic pathways leading to each target enantiomer. The key step in both pathways is a ring-closing metathesis process, which represents a novel strategy for assembling the multi-functionalized ring C of pancratistatin skeleton. The flexibility of the proposed synthetic scheme will allow for thorough optimization of the synthesis in search for high efficiency and practicality. Additionally, the fact that L-xylose is commercially available as well will make it possible to reach (+)-pancratistatin via either of the two pathways.

描述(申请人提供)：该项目旨在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，发展一条能够克量制备(+)-泛抑素的有效化学路线将极大地促进该化合物及其类似物的进一步生物学和药用评价，因此它一直是科学界追求已久的目标。本申请中提出的工作集中在以D-木糖为原料合成(+)-pancatistatin和(-)-pancatistatin的实用对映体发散合成方法。尽管最近的数据显示，在对映体泛曲抑素系列中有类似的活性，但后一种化合物还没有以对映体纯净的形式合成。两个泛影抑素对映体的合成遵循两条不同的合成路线，通向每个目标对映体。这两条途径的关键步骤都是关环复分解过程，这代表了一种组装泛素骨架的多功能环C的新策略。所提出的合成方案的灵活性将允许对合成进行彻底的优化，以寻求高效和实用。此外，L-木糖也可以在商业上获得，这将使通过这两种途径中的任何一种途径获得(+)-胰抑素成为可能。