ELUCIDATION OF THE PANCRATISTATIN CYTOTOXIC PHARMACOPHORE

胰酶抑制素细胞毒性药效团的阐明

• 批准号: 7960231
• 负责人: ALEXANDER KORNIENKO
• 金额: $ 12.87万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960231
• 关键词: Alkaloids; Antineoplastic Agents; Antiviral Agents; Biomedical Research; Chemicals; Chemistry; Clinical Trials; Communities; Computer Retrieval of Information on Scientific Projects Database; Development; Funding; Goals; Grant; Institution; Laboratories; Lead; National Cancer Institute; New Mexico; Pancratistatin; Plague; Preparation; Research; Research Personnel; Resources; Route; Series; Source; Structure; Testing; Therapeutic Agents; Toxic effect; United States National Institutes of Health; Work; analog; base; cancer therapy; cytotoxic; flexibility; improved; in vivo; large scale production; mouse model; novel; novel therapeutics; pharmacophore; preclinical evaluation; water solubility

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目的最终目标是提供治疗癌症的新治疗剂。从 Pancratium littorale 球茎中提取的生物碱 (+)-pancratistatin 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，由于隔离可用的材料数量有限，这些研究已被搁置。 生物碱的有限可用性也困扰着阐明其作用机制以及结构活性研究的努力，这对于鉴定更有效和/或毒性更低的类似物可能至关重要。因此，发现一种高效、灵活的制备(+)-pancratistatin及其类似物的化学路线将极大地促进该先导化合物的进一步开发，一直是科学界长期追求的目标。 该项目的重点是基于 pancratistatin 的系列化合物的实际合成，这些化合物具有 (a) 芳香族部分的可变结构和 (b) 分子的截短的环醇部分。对这两个系列的抗肿瘤活性进行了评估，并在适当的小鼠模型中进一步测试了活性化合物的体内情况。 所使用的化学基于本实验室先前开发的新型2-脱氧-2-芳基conduritols F的合成以及高度非对映选择性的芳基铜酸酯加成至¿-烷氧基-Ф,Ф-烯酸酯。 这项工作的长期目标包括完善 pancratistatin 细胞毒性药效团，以开发类似物，这些类似物具有 (a) 改善的活性/毒性特征，(b) 改善的水溶性，以及 (c) 简化的结构，适合于即将进行的临床试验的大规模生产。