SYNTHESIS OF TUBULIN BINDING ANTITUMOR AGENTS

微管蛋白结合抗肿瘤剂的合成

• 批准号: 2012376
• 负责人: STEVEN D. BURKE
• 金额: $ 17.58万
• 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 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2012376
• 关键词: antimitotics; antineoplastic antibiotics; chemical binding; drug design /synthesis /production; molecular rearrangement; pyrans; tubulin; vinca alkaloids

DESCRIPTION: The proposed research combines methodology and total synthesis. The targets chosen for total synthesis are halichondrin and rhizoxin. Both natural products are relatively scarce and demonstrate potent antimitotic activity by binding to the vinca domain on tubulin. In vivo activity against vinblastine and vincristine resistant cell lines has led to the selection of rhizoxin for Phase II clinical evaluation, and halichondrin B is currently in preclinical development. As a key strategy in both syntheses, two-directional chain synthesis is being applied. Three new methods for the synthesis of polysubstituted hydropyrans are also proposed. Planned variations of the Claisen rearrangement include a tandem glycolate ester enolate Claisen/ring-closing metathesis sequence, a desymmetrization of C2-symmetric substrates via a dioxanone rearrangement, and asymmetric catalysis of the dioxanone Claisen rearrangement by cationic metal complexes. Based on the second method, a short synthesis of KDO, a membrane component of Gram-negative bacteria, is proposed.

描述：拟议的研究结合了方法论和总体 合成. 选择用于全合成的靶标是软海绵素， 根霉素。 这两种天然产品都相对稀缺， 通过与微管蛋白上的长春花结构域结合而具有有效的抗有丝分裂活性。 在 对长春碱和长春新碱耐药细胞系的体内活性 导致选择根霉素进行II期临床评价， 软海绵素B目前处于临床前开发阶段。 作为一项关键战略 在这两种合成中，都应用了双向链合成。 三 还介绍了合成多取代氢吡喃的新方法， 提出了 克莱森重排的计划变化包括串联 乙醇酸酯烯醇化物Claisen/闭环复分解序列 通过二氧杂环己酮重排使C2-对称底物去对称化， 阳离子对二氧环己酮Claisen重排反应的不对称催化作用 金属配合物 基于第二种方法，对KDO进行了简短的综合， 革兰氏阴性菌的膜组分，提出。