Development of silicon-containing units as expanded bioisosters

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K15137
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: HASHIMOTO Yuichi 東京大学, 定量生命科学研究所, 教授 (90164798)
• Co-Investigator(Renkei-kenkyūsha): FUJII shinya
• Research Collaborator: FUJII shinya
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ケイ素 / バイオアイソスター / 核内受容体 / 構造展開 / 構造変換

Outline of Final Research Achievements

Application of silyl functionalities is one of promising strategies for development of novel and distinctive biologically active compounds. Exchange of carbon atom of various biologically active compounds to silicon atom, that is called sila-substitution, have been intensively investigated, and the results suggest that sila-substitution is effective for alteration of activity profiles. In addition to the simple C/Si exchange, by focusing on the intrinsic characteristics of silicon being different from those of carbon, several novel approaches for utilizing silicon atom in medicinal chemistry have been proposed. Thus, the results indicate that the usage of silicon-containing unit increases possible options of structural development and has great potential for enlarging the chemical space of medicinal chemistry.

Free Research Field

生物有機化学

Academic Significance and Societal Importance of the Research Achievements

新規な汎用性のあるバイオアイソスターの開発は医薬化学の重点課題の一つである。本研究において、(1)光や熱に不安定なシスオレフィンを安定なケイ素に代替できることを示し、また、(2)ケイ素の特性（電気陰性度／脂溶性／結合長／分極性／分子間力など）によって、活性変換（アゴニスト・アンタゴニスト）や標的選択性の変換、新たな活性の付与、等が可能であることを示した。本研究成果により、生物活性物質・医薬シーズの分子設計戦略に多様性を付与し、そのケミカルスペースの拡大に貢献することができたと考える。