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Solid-and Solution-Phase Synthesis of Natural Product-Based Libraries

基于天然产物的文库的固相和溶液相合成

基本信息

批准号：
14103013
负责人：
TAKAHASHI Takashi
金额：
$ 64.4万
依托单位：
Tokyo Institute of Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

项目摘要

Biologically active natural products have served as effective biochemical probes for discovery of not only new drug targets but also new biomarkers. The synthesis of small molecules based upon the structure of biologically active natural products would be an effective and promising way for identification of new biochemical probes. Combinatorial chemistry can assist the high-speed synthesis of these focused liberties. The combinatorial approach might not be an economic route in comparison with the traditional approach based on elucidating the best fragment at each diverse site because fully combinatorial liberties contain many redundant compounds. However, in traditional approach the compounds composed of the best fragments would not often exhibit the strongest biological activity in cell-based assay since cell-permeability of the small molecules would largely influence their biological activity. In this research project, we investigated the development of effective approaches for the solid- and solution-phase synthesis of natural product-based libraries.Research for the solid-phase synthesis of natural product-based libraries resulted in the syntheses of 25 aurilide derivatives, 122 macrosphelide A derivatives, 74 clavulone derivatives, 24 aeruginosin derivatives. In addition, bidirectional solid-phase semisynthesis of vancomycin derivatives was accomplished based on donor-bound glycosylation strategy. On the other hand, for the solution-phase synthesis of natural product-based libraries, we investigated one-pot sequential glycosylation approaches, that are effective not only for high speed synthesis of target oligosaccharides but also for the synthesis of combinatorial libraries. As the results, we succeeded in the development of one-pot glycosylation for the synthesis of a heptasaccharide exhibiting phytoalexin elicitor activity, core 2 type glycosyl amino acids and sialo-containing glycosyl amino acids.

具有生物活性的天然产物不仅可以作为发现新的药物靶点，而且可以作为发现新的生物标志物的有效生物化学探针。利用天然产物的结构合成具有生物活性的小分子化合物是一种有效的、有前途的生物化学探针的合成方法。组合化学可以帮助这些集中的自由的高速合成。与基于阐明每个不同位点的最佳片段的传统方法相比，组合方法可能不是一种经济的途径，因为完全组合的自由基包含许多冗余化合物。然而，在传统的方法中，由最好的片段组成的化合物在基于细胞的测定中通常不会表现出最强的生物活性，因为小分子的细胞渗透性将在很大程度上影响它们的生物活性。本研究课题主要研究了天然产物库的固相和液相合成方法，合成了25个金内酯衍生物、122个大环内酯A衍生物、74个棒酮衍生物、24个红曲霉素衍生物。此外，基于供体结合糖基化策略，实现了万古霉素衍生物的双向固相半合成。另一方面，对于基于天然产物的文库的液相合成，我们研究了一锅顺序糖基化方法，该方法不仅对目标寡糖的高速合成有效，而且对组合文库的合成也有效。作为结果，我们成功地开发了一锅糖基化法，用于合成表现出植物防御素激发子活性的七糖、核心2型糖基氨基酸和含唾液酸的糖基氨基酸。