Synthesis of Peptoid-Based Alpha-Helix Mimetics

Abstract

Peptide analogs have been intensively developed as therapeutic candidates. Among various peptidomimetics, N-substituted glycine oligomers named peptoids are of increasing attention because they have interesting structural and functional features, improved cell permeability, and cellular stability. In particular, various biological functions in many protein-protein interactions have been known to be modulated by protein secondary structures such as alpha-helix. Thus, the development of useful secondary structure mimetics is strongly needed. We herein envisioned developing twisted cyclic peptoids with a rigid scaffold as α-helix mimetics. For the construction of twisted cyclic peptoids, we tried to introduce a rigid column with dual ligation sites in the opposite direction. At first, we used Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), also called click chemistry. The azide-containing peptoids were successively conjugated with 1,4-diethynylbenzene to afford twisted cyclic peptoids with a terphenyl-type aromatic ring. Next, we also employed two different rigid scaffolds with diacid functionalities at the opposite sites, (1,1′:4′,1′′-terphenyl)-3,3′′-dicarboxylic acid and 9,10-dihydro-9,10-dioxo-2,6-anthracenedicarboxylic acid. In the synthesis of twisted cyclic peptoids using macrolactamization, different results were obtained depending on the characteristics of the scaffold. We had better conversion when (1,1′:4′,1′′-terphenyl)-3,3′′-dicarboxylic acid was introduced to linear peptoids than 9,10-dihydro-9,10-dioxo-2,6-anthracenedicarboxylic acid is introduced. Carboxylic acids of scaffolds were successfully macrolactamized with both amino groups of peptoids at the same time in different conditions to give twisted cyclic peptoids as alpha-helix mimetics. Various controlling factors were thoroughly studied in solid-phase dual macrolactamization.;펩타이드 유사체는 질병 치료제로서 집중적으로 개발되어 왔다. 다양한 peptidomimetics 중에서 펩토이드(Peptoids)는 N-subsituted glycine oligomer라는 구조적 특질을 통해 펩타이드보다 우수한 세포 투과성과 세포 안정성을 지닌다는 점에서 학계의 주목을 받고 있다. 특히, 많은 단백질-단백질 상호작용에서 다양한 생물학적 기능은 알파 나선과 같은 단백질 2차 구조에 의해 조절되는 것으로 알려져 있다. 이에 따라 유용한 2차 구조 모방체의 개발의 필요성이 제기되었다. 이 연구에서는 알파 나선 모방체로서 rigid scaffold를 포함하는 twisted cyclic peptoids 를 합성하고자 하였다. Twisted cyclic peptoids의 합성을 위해 두 개의 ligation site가 반대 방향에 존재하는 rigid column을 도입하고자 했다. 먼저, click chemistry라고 불리는 Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC)을 도입했다. 아자이드를 포함하는 펩토이드는 클릭 반응을 통해 terphenyl-type의 방향족 고리를 만들며 성공적인 twisted cyclic peptoids를 합성하였다. 다음으로는, macrolactamization 을 이용하기 위해 (1,1′:4′,1′′-terphenyl)-3,3′′-dicarboxylic acid 와 9,10-dihydro-9,10-dioxo-2,6-anthracenedicarboxylic acid를 각각 합성한 후 rigid scaffold로써 도입하였다. 그 결과, (1,1′:4′,1′′-terphenyl)-3,3′′-dicarboxylic acid가 9,10-dihydro-9,10-dioxo-2,6-anthracenedicarboxylic acid보다 선형 펩토이드에 도입되었을 때 수율이 더 높았다. Scaffold의 카르복실산은 서로 다른 조건에서 동시에 펩토이드의 두 아미노 그룹과 성공적으로 매크로락탐화되어 알파 나선 모방체 twisted cyclic peptoids를 합성하였다.