Generation of macrocyclic molecules regulating DNA-protein interactions

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K15454
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 38040:Bioorganic chemistry-related
• Research Institution: The University of Tokyo (2021); Tokyo University of Agriculture and Technology (2020)
• Principal Investigator: Tanifuji Ryo 東京大学, 大学院理学系研究科(理学部), 助教 (10866205)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 化学-酵素ハイブリッド合成 / マクロ環 / エクテナサイジン743 / 中分子 / 核酸-タンパク質間相互作用

Outline of Final Research Achievements

To modulate DNA-protein interactions selectively, novel macrocyclic mid-sized molecules have been designed inspired by natural product ecteinascidin 743 (ET-743) which is clinically utilized as an anticancer agent for soft tissue sarcoma.
Integration of organic synthesis with enzymatic conversions enabled rapid access to the pentacyclic core scaffold of ET-743. To explore the utility of biosynthetic enzyme, SfmC, 8 types of substrate variants were synthesized and treated with the enzyme. SfmC has highly wide substrate tolerance and converted all of the substrate analogs to the corresponding unnatural type pentacyclic scaffolds.
Designed mid-sized molecules bearing 14-17 membered macrocycles were semi-synthesized from natural product, cyanosafracin B. All of macrocyclic compounds showed DNA alkylation abilities and potent anti-tumor activities as we expected. Further, fine tuning of macrocyclic structure brought about the significant changes in those activities.

Free Research Field

天然物化学、有機合成、酵素合成

Academic Significance and Societal Importance of the Research Achievements

本研究で設計・合成した中分子群は、母骨格にてDNAを可逆的にアルキル化しながら、マクロ環とそれに連結したユニットで核内タンパク質とも相互作用が可能と考えられる。各ユニットを多様化した中分子群の構造と活性の相関を取得は、未だ発展途上と言えるDNA-タンパク質間相互作用の選択的制御法の開発に向けた、合理的な分子設計を可能とする。生合成酵素を活用したハイブリッド合成法により、構造の複雑性に起因する供給における課題も解決可能である。