SYNTHESES OF ANTITUMOR AGENTS CALYCULIN AND SCYTOPHYCIN

抗肿瘤剂花萼蛋白和细胞霉素的合成

• 批准号: 3192203
• 负责人: SATORU MASAMUNE
• 金额: $ 20.86万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-08 至 1993-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3192203
• 关键词: amides; antineoplastics; carcinoma; chemical structure function; cyanides; drug design /synthesis /production; fibroblasts; oxazoles; saltwater environment; skin neoplasms; stereochemistry; tissue /cell culture

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.

这一建议具体针对两者的综合 海洋天然产物calyculin A（1），C50 H81 N4015 P，isolated 从海绵Discodermia calyx，1和scytophycin C（2）， C45 H74 NO10，来自蓝绿色的红蓝蓝线藻 pseudohofmanni Bharadwaja。 两种靶分子都表现出 显著的抗肿瘤活性。 例如，calyculin在高 对肿瘤细胞具有细胞毒性（IC 50：1.75 x 10-3 μ g/ml;L1210），而 藻毒素对KB人的最小毒性剂量 表皮样癌和NIH/3 T3小鼠成纤维细胞系， 1 ng/mL和0.65 ng/mL。 该项目，如其 的前身，涉及潜在的抗肿瘤剂的合成 它们满足两个标准：（1）它们从自然界中的可用性 资源是非常有限的，更重要的是，（2）他们 包括合成上有吸引力的结构单元， 通过应用新的 开发合成方法和/或试剂。 Calyculin A和 Scytophycin C确实显示了这些特征，因此 代表了令人兴奋的合成目标。 1和2都主要由聚酮化合物和大量的1，3-二醇组成 在结构和立体化学上变化的单元。 有效 这些重复单元的构建现在看来是实用的（甚至 对于复杂的分子，如1和2），使用一整套 纯手性试剂，其中大多数已经在 去年的立体选择性羟醛缩合反应和烯丙基硼化。 除了这个聚酮化合物问题之外，calyculin A还包含一个聚酮化合物。 具有相当不寻常骨架的带有磷酸酯的新型螺环缩酮， 恶唑，腈和酰胺官能团，而scytophycin C是 其独特特征在于存在N-甲基甲酰胺， 组 功能组组装在最后阶段的两个 合成提出了一项具有挑战性的任务， 被提议。 天然产品继续提供测试 概念、综合策略和方法的基础。 期间 它们进一步帮助识别基本 有待调查的问题。