Glycorandomization/Neoglycorandomization for Anticancer Discovery

虽然众所周知，具有重要药用价值的天然产品的糖键通常定义了它们的 相应的生物活性，直到最近，改变这些基本碳水化合物的有效方法 ，从而系统地探索它们基于碳水化合物的结构-活性关系 (Sar)，是缺乏的。近年来，我们开发了两种策略来快速糖基化天然 产品-体外糖随机化(一种化学酶过程)，最近， 新糖链正规化(基于化学选择-连接的过程)。作为伊利诺伊大学实验计划2 威斯康星州国家合作药物发现小组(UW NCDDG)，这份提案概述了一个系统的 应用这两种独特的战略实现多种天然产物母体的多样化 支架(包括来自UW NCDDG计划1的一些支架，沈教授) 抗癌活动。具体地说，拟议的研究旨在评估以下各项的一般适用性 化学酶和化学选择性结扎为基础的糖核糖化显著增强可及性 以天然产品为基础的多样性，结合独特的筛选和下游分析 UW NCDDG的能力，将呈现出可能是迄今为止生物学上最广泛的关联 天然产物的活性及其所附碳水化合物的特定贡献。更多 重要的是，按照NCDDG的要求，还选择了父支架，以显著偏向 最终结果是在预定的资助期内确定有希望的抗癌线索 多样性指令将在小说的不断咨询的基础上具体演变 UW NCDDG的筛查/生物学分析/临床成分。

While it is known that the sugar attachments of pharmaceutically important natural products often define their corresponding biological activity, until recently, efficient methods to alter these essential carbohydrate appendages, and thereby systematically explore their carbohydrate-based structure-activity relationships (SAR), was lacking. In recent years, we have developed two strategies to rapidly glycosylate natural products - in vitro glycorandomization (a chemoenzymatic process) and, more recently, neoglycorandomization (chemoselective-ligation based process). As Lab Program 2 of the University of Wisconsin National Cooperative Drug Discovery Group (UW NCDDG), this proposal outlines a systematic application of these two unique strategies toward diversification of a wide range of natural product parent scaffolds (including a number from UW NCDDG Program 1, Professor Shen) with previously indicated anticancer activities. Specifically, the proposed studies are designed to assess the general applicability of chemoenzymatic and chemoselective ligation-based glycorandomization to significantly enhance accessible natural product-based diversity and, in conjunction with the unique screening and downstream analysis capabilities of the UW NCDDG, will present perhaps the broadest correlation to date between the biological activity of natural products and the specific contributions invoked by their attached carbohydrates. More importantly, as mandated by the NCDDG, the parent scaffolds were also selected to significantly bias the ultimate outcome toward the identification of promising anticancer leads within the intended funding period and diversity directives will specifically evolve based upon the constant consultation of the novel screening/biological analysis/clinical components of the UW NCDDG.