SYNTHESES OF ANTITUMOR AGENTS CALYCULIN AND SCYTOPHYCIN

这一提议专门针对这两者的综合 海洋天然产物Calyculin A(1)，C50H81N4015P，分离得到 从海绵花瓣1和镰刀菌素C(2)中， C45H74NO10，来自蓝绿藻Scytonema 伪霍夫曼尼·巴拉德瓦贾。两个目标分子都表现出 具有显著的抗肿瘤活性。例如，在很高的 对肿瘤细胞的细胞毒作用(IC50：1.75×10-3mug/ml；L1210)，而 镰刀菌素对KB人的最小毒性剂量 表皮样癌和NIH/3T3小鼠成纤维细胞系 1 ng/m L和0.65 ng/m L。这个项目，就像它的 前身，关注潜在抗肿瘤药物的合成 它们满足两个标准：(1)它们的天然可用性 来源严重有限，更重要的是，(2)他们 由综合吸引力的结构单元组成， 它的建设似乎是可行的，通过应用新的 开发了合成方法和/或试剂。Calyculin A和 单胞菌素C确实表现出这样的特征，因此 代表令人兴奋的合成目标。 1和2主要由聚酮和大量的1，3-二醇组成 在结构和立体化学上不同的单元。高效的 这些重复单元的建造现在看起来是可行的(甚至 对于像1和2这样的复杂分子)，使用全套 同种手性试剂，其中大多数是在 过去一年的立体选择性羟醛反应和烯丙基硼化反应。 除了这个聚酮问题外，毛盏花素A还包括一个 新奇的螺环酮，一个相当不寻常的骨架，含有磷酸盐， 恶唑、腈和酰胺官能团，而镰刀菌素C是 以N-甲基甲酰胺的存在为唯一特征的 一群人。在两者的最后阶段进行官能团组装 对于哪种可行的方法，合成提出了一项具有挑战性的任务 都被提出了。天然产品继续提供测试 概念、综合策略和方法的依据。在.期间 他们的综合追求进一步帮助识别基本 尚待调查的问题。

This proposal is specifically aimed at the synthesis of the two marine natural products calyculin A (1), C50H81N4015P, isolated from the sponge Discodermia calyx, 1 and scytophycin C(2), C45H74NO10, from the blue-green alga Scytonema pseudohofmanni Bharadwaja. Both target molecules exhibit remarkable antitumor activity. For instance, calyculin in highly cytotoxic to tumor cells (IC50:1.75 x 10-3 mug/ml;L1210), while the minimum toxic doses of scytophycins against KB human epidermoid carcinoma and NIH/3T3 mouse fibroblast cell lines are 1 ng/mL and 0.65 ng/mL, respectively. This project, like its predecessor, concerns the synthesis of potential antitumor agents which meet two criteria: (1) their availability from natural sources is severely limited and more importantly, (2) they comprise synthetically attractive structural units, the construction of which appears feasible by the application of newly developed synthetic methods and/or reagents. Calyculin A and Scytophycin C do indeed display such characteristics and hence represent exciting synthetic targets. Both 1 and 2 consist largely of polyketides and numerous 1,3-diol units varying in structure and stereochemistry. The efficient construction of these repeating units now appears practical (even for complex molecules such as 1 and 2), using a full set of homochiral reagents, most of which have been developed over the past year for the stereoselective aldol reaction and allylboration. In addition to this polyketide problem, calyculin A comprises a novel spiro ketal of a rather unusual skeleton bearing phosphate, oxazole, nitrile, and amide functionalities, while scytophycin C is uniquely characterized by the presence of a N-methylformamide group. Functional group assembly in the final stages of both syntheses present a challenging task for which workable methods are proposed. Natural products continue to provide the testing grounds for concepts, synthetic strategies and methods. During the synthetic pursuit they further help identify fundamental problems yet to be investigated.