SYNTHESIS OF TAXININE AND TAXOL

紫杉醇和紫杉碱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 具有作为有丝分裂纺锤体毒素的耐人寻味的活性。不像 经典纺锤体毒素(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 结构在没有GTP的情况下，并稳定微管 在有钙存在和低温下解聚。穿过 在这种影响下，紫杉醇处理的细胞被阻断在中期和细胞期。 复制被禁止。毫无疑问，这些特点是 紫杉醇表现出的抗白血病和抗肿瘤活性； 显示出良好的抗黑色素瘤和卵巢肿瘤活性。 这项工作的广泛目标是通过合成 紫杉碱和紫杉醇现有的化学合成方法 具有官能化和立体化学的复杂碳多环 不寻常的骨骼(特别是那些含有中环的)，可能 展示有趣的生物和药用活性。此外，这一点 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。 本申请的具体目标如下：1.合成 Taxinine：这项工作将继续，特别强调 阐述了C形环的特点。尽管紫杉碱缺乏 与紫杉醇相关的重要生物活性，它有许多 结构方面与紫杉醇等相关的初步 目标。紫杉碱的合成将提供一个标准，用来 判断整个紫杉烷合成策略的成功与否。2. 紫杉醇的合成：紫杉醇的合成路线之一 在下一个授权期内的高优先级将提供 对紫杉醇计划的重要性。它参与了一系列针对 紫杉醇将被调查。紫杉醇C-13的同手性合成 侧链已完成，将尝试将其连接到 Baccatin III，从而完成紫杉醇的部分合成 巴卡丁三号是接力目标。3.紫杉醇类似物的制备 生物学意义及相关研究：为合成而努力 和部分合成具有生物学意义的紫杉醇类似物 将通过研究微管蛋白的制备来扩大研究范围 光亲和性和荧光标签，用于生产 抗紫杉醇抗体，用于进一步定义的类似物 结构/活性关系，更容易具有潜在的 可获得的药物、亲水性类似物和亲药物。此外, 某些关键紫杉烷的X射线晶体结构将是 获得。这些调查中的几个途径将产生 对总体合成研究感兴趣的信息。

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.