De novo design of conformational-freedom restricted cyclic amino acids and their application to medicinal chemistry

2021 Fiscal Year Final Research Report

• Project/Area Number: 17H03998
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Nagasaki University
• Principal Investigator: Tanaka Masakazu 長崎大学, 医歯薬学総合研究科(薬学系), 教授 (00227175)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 有機化学 / 生体分子 / 薬学 / 分子認識 / ペプチド / タンパク質 / ２次構造

Outline of Final Research Achievements

We developed efficient synthetic methods for optically active small-ring size alpha,alpha-disubstituted alpha-amino acids, and analyzed the secondary structure of their peptides. Chiral centers at the side-chain of small-ring size amino acid homopeptides controlled their helical-screw directions on a case-by-case basis. Using cyclic alpha,alpha-disubstituted alpha-amino acids-containing arginine-based peptides, pDNAs could be efficiently introduced into cells. Cyclic alpha,alpha-disubstituted alpha-amino acids-containing helical peptides catalyzed enantioselective 1,4-addition reaction of cyclic enones, and also helical peptides with an N-terminal thiourea moiety catalyzed highly enantioselective 1,4-addition reactions between nitroalkenes and dialkyl malonates.

Free Research Field

薬化学

Academic Significance and Societal Importance of the Research Achievements

中分子に分類されるペプチド等を用いた創薬科学が注目されている。ペプチドの配座自由度を制限する各種の小員環状ジ置換アミノ酸を設計合成し、その短鎖ペプチドのヘリックス２次構造を調べた。グアニジノ基を持つヘリックス構造のペプチドは、DNAを効率よく細胞の中に輸送でき遺伝子を発現できることが分かった。また、環状ジ置換アミノ酸を導入してヘリックス構造を安定化したペプチドは、不斉反応の優れた触媒となり光学活性な生成物を与えることが分かった。