Molecules by Assembly-Line Synthesis: Conformational Control and Biological Activity Study

Aggarwal的流水线合成代表了一种独特的方法，使我们能够使用手性锂化氨基甲酸酯或酯作为构建单元，通过硼酸酯的迭代同系化来构建碳链。该反应在大多数情况下显示出高效和完全的立体控制，并且其潜在的适用性已被进一步证明与生物活性天然产物的全合成。在这个项目中，我们建议将这种方法扩展到合成侧链上含有大取代基的构象设计分子。我们将通过X射线、先进的核磁共振和计算分析来研究它们的三维结构，并确定远离主链的构象控制的程度。该研究将为我们提供如何将可变大小的分子片段定位在精确位置的知识。为了证明这种构象控制研究的潜力，我们将靶向螺旋结构与特定位置的特定基团进行最佳结合，以破坏癌症中涉及的蛋白质-蛋白质相互作用。我们希望流水线合成沿着构象控制研究，能使我们快速构建一系列具有生物活性的化合物，并促进新药的发现。

Aggarwal's assembly-line synthesis represents a unique method that allows us to build a carbon chain by iterative homologation of boronic esters using chiral lithiated carbamates or esters as building blocks. The reaction shows high efficiency and complete stereocontrol in most cases, and its potential applicability has been further demonstrated with total syntheses of biologically active natural products. In this project, we propose to extend this methodology to the synthesis of conformationally designed molecules containing large substituents on side chains. We will investigate their three-dimensional structures by X-ray, advanced NMR and computational analysis, and determine the extent of conformational control remote from the main chain. This study will give us the knowledge of how to position molecular fragments with variable size in a precise position. In order to demonstrate the potential of this conformational control study, we will target helical structures with specific groups at specific places for optimum bonding to disrupt protein-protein interactions involved in cancer. We hope that the assembly-line synthesis along with conformational control study will enable us to rapidly build a series of biologically active compounds and facilitate new drug discovery.