SYNTHESIS OF TAXININE AND TAXOL

紫杉碱和紫杉醇的合成

• 批准号: 3181752
• 负责人: CHARLES S SWINDELL
• 金额: $ 14.07万
• 依托单位: BRYN MAWR COLLEGE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-05-01 至 1993-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3181752
• 关键词: X ray crystallography; alkaloids; antileukemic agent; antineoplastics; diterpenes; drug design /synthesis /production; drug metabolism; fluorescence; medicinal plants; microtubules; neoplasm /cancer pharmacology; paclitaxel; plant extracts; polymerization; stereochemistry; tubulin

Taxol and taxinine are members of the taxane diterpene family, natural substances which are isolated from various Taxus (yew) species. Taxol possesses intriguing activity as a mitotic spindle poison. Unlike classical spindle poisons (e.g. colchicine, vinblastine), taxol is unique in its ability to promote the polymerization of tubulin into microtubular structures in the absence of GTP, and to stabilize microtubules toward de-polymerization in the presence of Ca and at low temperatures. Through this affect, taxol treated cells are blocked in metaphase and cellular replication is inhibited. Undoubtedly, these characteristics underlie the anti-leukemic and anti-tumor activities exhibited by taxol; taxol has shown promising activities against melanoma and ovarian tumors. The broad objectives of this work are to augment through the synthesis of taxinine and taxol existing methodology for the chemical synthesis of functionally and stereochemically complex carbon polycycles possessing unusual skeleta (especially those containing medium rings) which might exhibit interesting biological and medicinal activity. In addition, this work should make available synthetic and semi-synthetic taxol analogues of potential value to clinical and biological investigations. The following are specific goals of this application: 1. Synthesis of Taxinine: This work will continue with special emphasis on the elaboration of the C-ring features. Although taxinine lacks the important biological activity associated with taxol, it shares many structural aspects with taxol and so represents a relevant preliminary target. The synthesis of taxinine will provide a standard by which to judge the success of the overall taxane synthesis strategy. 2. Synthesis of Taxol: One of the routes to taxinine which will receive high priority in the next grant period will provide an intermediate of importance to the taxol plans. Its involvement in a sequence targeted at taxol will be investigated. A homochiral synthesis of the taxol C-13 sidechain has been completed and attempts will be made to attach it to baccatin III, thereby completing a partial synthesis of taxol and making baccatin III a relay target. 3. Preparation of Taxol Analogues of Biological Significance and Related Studies: Work toward the synthesis and partial synthesis of taxol analogues of interest in biological studies will be extended by investigating the preparation of tubulin photoaffinity and fluorescent labels, substrates for the production of antibodies against taxol, analogues for further definition of structure/activity relationships and with potential as more readily accessible drugs and hydrophilic analogues and pro-drugs. In addition, X-ray crystallographic structures for certain key taxanes will be obtained. Several of these avenues of investigation will yield information of interest in total synthesis studies.

紫杉醇和紫杉宁是紫杉烷二萜家族的成员，天然 从各种红豆杉 (红豆杉) 物种中分离出来的物质。 紫杉醇 作为有丝分裂纺锤体毒物，具有有趣的活性。 不像 经典纺锤体毒物（如秋水仙碱、长春花碱），紫杉醇是独一无二的 其促进微管蛋白聚合成微管的能力 在没有 GTP 的情况下形成结构，并稳定微管 在 Ca 存在下和低温下解聚。 通过 这种影响，紫杉醇处理的细胞被阻断在中期和细胞 复制受到抑制。 毫无疑问，这些特征是 紫杉醇表现出的抗白血病和抗肿瘤活性；紫杉醇有 对黑色素瘤和卵巢肿瘤显示出有希望的活性。 这项工作的主要目标是通过综合 紫杉碱和紫杉醇的化学合成现有方法 功能和立体化学复杂的碳多环具有 不寻常的骨骼（尤其是那些含有中等环的骨骼）可能会 表现出有趣的生物和医学活性。 此外，这 工作应提供合成和半合成紫杉醇类似物 对临床和生物学研究具有潜在价值。 以下是本申请的具体目标： 1. 合成 紫杉宁：这项工作将继续进行，特别强调 C 形环特征的详细阐述。 虽然紫杉宁缺乏 与紫杉醇相关的重要生物活性，它具有许多共同点 与紫杉醇的结构方面，因此代表了相关的初步 目标。 紫杉宁的合成将提供一个标准 判断整个紫杉烷合成策略是否成功。 2. 紫杉醇的合成：获得紫杉宁的途径之一 下一个资助期的高度优先将提供中间 紫杉醇计划的重要性。 它参与了一个针对的序列 紫杉醇将被研究。 紫杉醇 C-13 的同手性合成 侧链已完成，将尝试将其附加到 浆果赤霉素III，从而完成紫杉醇的部分合成并制备 浆果赤霉素 III 是一个中继目标。 3.紫杉醇类似物的制备 生物学意义及相关研究：合成工作 以及生物领域感兴趣的紫杉醇类似物的部分合成 将通过研究微管蛋白的制备来扩展研究 光亲和和荧光标记，用于生产的底物 抗紫杉醇的抗体，类似物的进一步定义 结构/活动关系和潜力更容易 易接近的药物和亲水性类似物和前药。 此外， 某些关键紫杉烷的 X 射线晶体结构将 获得。 其中一些调查途径将产生结果 全合成研究中感兴趣的信息。