MACROLIDE TOTAL SYNTHESIS

这项研究计划的总体目标是发展 在结构上建造高效的综合程序 复杂的大环内酯类天然产物。具体目标包括 冬虫夏草甲素、麻黄素、20，21-二脱氢麻黄素、 Aplysiatoxin、Dbromoaplysiatoxin和Oscillatoxin A。 Latrunculin(A和B)代表了一类新的高度有效的 与细胞骨架蛋白特异结合的大环内酯类化合物 从而破坏培养细胞中的微丝组织 而不影响微管系统。行动模式， 虽然仍然未知，但与所显示的活动最相似 由细胞松弛素，唯一已知的另一类药物结合 肌动蛋白细丝，并特别干扰 微丝状结构。然而，迟来的是10到10个 比细胞松弛素的活性高100倍。 麻黄素和20，21-二脱氢麻黄素是大环内酯类化合物， 从淡水藻类的亲脂提取物中分离出来， 3它们对KB有细胞毒作用。 和NIH/3T3细胞，以及显著的抗肿瘤活性 体内抗小鼠Lewis肺癌。3 Aplysiatoxin、Dbromoaplysiatoxin和Oscillatoxin A也 从藻类中分离出来的，是有效的肿瘤促进剂，具有 复杂的大环内酯结构。上述每一种大环内酯类化合物 代表了一个极其重要的目标，从这个角度来看 合成化学和生物效力(例如，抗肿瘤或 肿瘤促进活性)。 除了上述非常具体的合成靶点外，更多的 这项研究计划的基本和长期目标是 对分子的更好理解的发展 负责这些生物特性的架构和 相关的大环内酯类。因此，当我们发展我们的程序方法时 对于上述每一项目标，我们还将推出不同的 模型系统将服从于建设和 随后的筛选，这样最终我们将能够 剖析应负责的特征的关键结构特征 用于观察到的生物活动。一旦这些功能被 确定、设计新的和可能更有效的药物 应该是可行的。

The overall objective of this research program is the development of efficient synthetic procedures for construction of structurally complex macrolide natural products. The specific targets include latrunculin A, acutiphycin, 20,21-didehydroacutiphycin, aplysiatoxin, debromoaplysiatoxin and oscillatoxin A. The latrunculins (A and B) represent a new class of highly potent macrolides that specifically bind to cytoskeletal proteins and thereby disrupt microfilament organization in cultured cells without effecting the microtubular system. The mode of action, while still unknown, most closely resembles the activity displayed by the cytochalasins, the only other class of drugs known to bind to actin filaments and to specifically disrupt the mocrofilamentous structures. The latrunculins, however are 10 to 100 times more active than the cytochalasins. Acutiphycin and 20,21-didehydroacutiphycin are macrolides, isolated from the lipophilic extract of the freshwater algae, Oscillatoria acutissima.3 They display cytotoxicity against KB and NIH/3T3 cells as well as significant antineoplastic activity in vivo against murine Lewis lung carcinoma.3 Aplysiatoxin, debromoaplysiatoxin, and oscillatoxin A, also isolated from algae, are potent tumor promoters possessing complex macrolide structures. Each of the above macrolides represents an extremely important target from the point of view of synthetic chemistry and biological potency (i.e., antitumor or tumor promoter activity). In addition to the above quite specific synthetic targets, a more general underlying and long range aim of this research program is the development of a better understanding of the molecular architecture responsible for the biological properties of these and related macrolides. Thus, as we develop our method of procedure for each of the above targets, we will also introduce various model systems which will be amenable to construction and subsequent screening, such that in the end we will be able to dissect out the critical structural feature of features responsible for the observed biological activities. Once such features are identified, the design of new and possible more effective agents should be feasible.