MACROLIDE TOTAL SYNTHESIS

大环内酯全合成

• 批准号: 3283923
• 负责人: Amos B Smith
• 金额: $ 23.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1991-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3283923
• 关键词: actins; antineoplastic antibiotics; binding proteins; chemical carcinogen; chemical structure function; cytochalasins; cytoskeleton; drug design /synthesis /production; ketal; ketones; macrolide antibiotics; saltwater environment; stereoisomer; tissue /cell culture

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.

该研究项目的总体目标是开发 有效的合成程序， 复杂的大环内酯类天然产物。 具体目标包括 latrunculin A，尖藻素，20，21-二脱氢尖藻素， 海兔毒素、脱溴海兔毒素和颤毒素A。 latrunculins（A和B）代表一类新的高效的 特异性结合细胞骨架蛋白的大环内酯类， 从而破坏培养细胞中的微丝组织 而不影响微管系统。 作用方式， 虽然仍然未知，但与显示的活动非常相似 细胞松弛素是唯一已知的 肌动蛋白丝，并专门破坏 微丝状结构 然而，latrunculins是10到 比细胞松弛素活性高100倍。 Acutiphycin和20，21-二脱氢Acutiphycin是大环内酯类， 从淡水藻类的亲脂性提取物中分离， Acutissima. 3它们对KB显示出细胞毒性 和NIH/3 T3细胞，以及在 体内抗小鼠刘易斯肺癌3 阿氏毒素、脱溴阿氏毒素和阿氏毒素A， 从藻类中分离出来，是一种有效的肿瘤促进剂， 复杂的大环内酯结构。 上述每种大环内酯 从这个角度来看， 合成化学和生物效能（即，抗肿瘤或 肿瘤促进剂活性）。 除了上述相当具体的合成目标， 这项研究计划的基本和长期目标是 更好地理解分子 负责这些生物特性的结构， 大环内酯相关 因此，当我们发展我们的程序方法时， 就上述每一个目标，我们亦会推出多项 模型系统，这将是经得起建设和 随后的筛选，这样，最终我们将能够 剖析出负责特征的关键结构特征 观察到的生物活动。 一旦这些特征被 确定，设计新的和可能更有效的代理人 应该是可行的。