Development of Structural Optimization Process Accelerating Drug Discovery based on Natural Products

Natural products are attractive drug lead compounds. But rarely can natural products be used as-is as drugs, often requiring chemical modifications. Chemical modifications of structurally complex natural products are difficult due to multistep synthesis, complexity of purification operation and determination of those structures. To overcome this difficulty, we have a developed structural optimization process accelerating natural product drug discovery. This process contains parallel synthesis of a large number of analogues using chemoselective and clean reactions and in situ evaluation of biological activities, thereby simplifying the synthetic operations and providing seamless access to biological activity evaluation. Here, we describe our studies on the optimization of natural products exhibiting antibacterial activity, MraY inhibitory natural products and polymyxin. In the MraY inhibitory natural products study, a library of a series of natural products was synthesized and evaluated simultaneously for enzyme inhibitory activity and antibacterial activity to rapidly obtain analogues with high antibacterial activity. In the polymyxin study, analogues overcoming resistance were obtained by combining peptide scanning and library synthesis. This structural optimization process can be applied to a variety of natural products and is particularly powerful in cases, where it is difficult to design rational analogues, and we hope that it will lead to the creation of innovative new drugs based on natural products.