SYNTHESIS OF ANTITUMOR AGENTS AND RELATED CHEMISTRY

抗肿瘤剂的合成及相关化学

• 批准号: 6603723
• 负责人: STEVEN D. BURKE
• 金额: $ 23.84万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603723
• 关键词: antimitotics; antineoplastic antibiotics; bridged cyclic compound; diene; drug design /synthesis /production; macrolide antibiotics; pyrans; sialate; stereochemistry; tubulin; vinca alkaloids

DESCRIPTION: (Principal Investigator's Abstract) Explicit goals of this research include: 1. To complete a highly convergent, relatively short total synthesis of the anticancer agent halichondrin B, which is potently active against several resistant human solid tumor xenografts, but is limited by scarcity from further advancement in NCI preclinical studies. 2. To further develop a powerful synthesis of 6,8-dioxabicyclo(3.2.1)octanes by intermolecular acetalization/intramolecular diene metathesis, for application to sialic acid syntheses (KDN, N-acetylneuraminic acid (Neu5Ac), and KDO). The last of these targets will require development of a means to distinguish between enantiotopic vinyl groups in the metathesis desymmetrization. 3. To explore the conversion of bridged 6,8-dioxabicyclo(3.2.1)octane derivatives to 1,7-dioxaspiro(5.5)decane spiroketals, which are ubiquitous structural components in insect pheromones, anticancer and antibiotic natural products. 4. To develop a new synthetic approach to the annonaceous acetogenins using catalytic ring closing metathesis to construct the bis(tetrahydrofuran) core, exemplified by a total synthesis of squamotacin. Quick access to the enantiomerically pure, C2-symmetric core will provide ready access to several additional potent antitumor agents in this class, which show potency ten to the 8th power to ten to the 10th power times that of adriamycin against several tumor cell lines. 5. To exploit, at the strategic level, symmetry and novel strategies for symmetry-breaking to simplify complex targets and to provide short and efficient syntheses thereof.

描述：(首席调查员摘要) 这项研究的明确目标包括： 1.完成高度收敛、相对较短的全合成 抗癌剂灯盏花素B，它对几种 耐药的人实体瘤异种移植，但受到进一步稀缺的限制 NCI临床前研究进展。 2.进一步开发6，8-二恶二环(3.2.1)辛烷的高效合成方法 分子间缩合/分子内双烯歧化，应用 唾液酸合成(KDN、N-乙酰神经氨酸(Neu5Ac)和KDO)。这个 这些目标中的最后一个将需要开发一种手段来区分 歧化去对称化反应中对映体间的乙烯基团。 3.探讨桥联6，8-二恶二环(3.2.1)辛烷的转化 1，7-二氧螺并(5.5)正庚烷螺酮的衍生物，它们普遍存在 昆虫信息素、抗癌和天然抗生素中的结构成分 产品。 4.开发一种合成番荔枝内酯的新方法 催化闭环复分解以构建双(四氢呋喃)核， 以斯堪美辛的全合成为例。快速访问 对映体纯净的C2对称核心将提供对几个 这一类中其他有效的抗肿瘤药物，其效力为10% 8次方到10次方是阿霉素的10倍 肿瘤细胞系。 5.在战略层面开发对称性和新颖的战略 对称破缺以简化复杂的目标，并提供简短和 它们的有效合成。