Synthesis and functional analysis of ion channel selective inhibitors based on polycyclic ethers

2015 Fiscal Year Final Research Report

• Project Area: Chemical Biology using bioactive natural products as specific ligands: identification of molecular targets and regulation of bioactivity
• Project/Area Number: 23102016
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Tohoku University
• Principal Investigator: Sasaki Makoto 東北大学, 生命科学研究科, 教授 (80235267)
• Co-Investigator(Renkei-kenkyūsha): FUWA HARUHIKO 東北大学, 大学院生命科学研究科, 准教授 (90359638) ; KONOKI KEIICHI 東北大学, 大学院農学研究科, 准教授 (40292825)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: ポリ環状エーテル / ガンビエロール / 電位依存性カリウムイオンチャネル / 阻害剤 / 機能解析 / 光親和性標識化分子プローブ / 天然物リガンド

Outline of Final Research Achievements

Gambierol is a structurally complex marine polycyclic ether natural product that exhibits potent inhibitory activity against voltage-gated potassium ion channels (Kv channels) with specific subtype selectivity. In order to clarify skeletal structure-activity relationship, hepta-, tetra-, and tricyclic analogues of gambierol were synthesized and tested for inhibitory activity against Kv1.2 channel, which was stably expressed in Chinese hamster ovary (CHO) cells. It was revealed that tetracyclic analogue of gambierol comprising the right-hand EFGH-ring with a triene side chain is the minimal structural unit for inhibitory activity against Kv1.2 channels. Furthermore, we designed and synthesized photoaffinity probe based on the structure of the tetracyclic analogue to identify the binding site of the ligand on Kv channels.

Free Research Field

天然物合成化学