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（紫杉）物种中分离的物质。 紫杉醇 作为有丝分裂纺锤体毒素具有有趣的活性。 不像 紫杉醇是典型的纺锤体毒物（如秋水仙碱、长春碱）， 在其促进微管蛋白聚合成微管的能力方面， 在没有GTP的情况下，稳定微管结构， 在Ca的存在下和在低温下解聚。 通过 这种影响，紫杉醇处理的细胞被阻断在中期和细胞分裂相， 复制被抑制。 毫无疑问，这些特征 紫杉醇具有抗白血病和抗肿瘤活性， 显示出对黑色素瘤和卵巢肿瘤有希望的活性。 这项工作的广泛目标是通过综合 紫杉碱和紫杉醇的现有化学合成方法 功能和立体化学复杂的碳多环， 不寻常的环（特别是那些含有中等环）， 表现出有趣的生物学和医学活性。 另外这款 研究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 Taxinine：这项工作将继续进行，特别强调 C型环的特点。 虽然紫杉碱缺乏 与紫杉醇相关的重要生物活性，它具有许多 结构方面与紫杉醇，因此代表了相关的初步 目标 紫杉碱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：紫杉碱的合成路线之一 下一个赠款期的高优先级将提供一个中间 紫杉醇计划的重要性。 它参与了一系列针对 将对紫杉醇进行研究。 紫杉醇C-13的纯手性合成 侧链已完成，将尝试将其附加到 巴卡亭III，从而完成紫杉醇的部分合成， 巴卡亭III是一个接力目标。 3. 紫杉醇类似物的制备 生物学意义和相关研究：合成工作 和部分合成紫杉醇类似物， 通过研究微管蛋白的制备， 光亲和性和荧光标记物，用于生产 抗紫杉醇的抗体，用于进一步定义的类似物 结构/活性关系，并与潜在的更容易 可获得的药物和亲水性类似物和前药。 此外，本发明还提供了一种方法， 某些关键紫杉烷的X射线晶体结构将被 得到了 其中几种调查途径将产生 全合成研究中感兴趣的信息。