第一部分: SC79衍生物的合成 第二部分:合成含有氨基乙烯基(甲基)半胱胺酸和羊毛硫氨酸的常見大環核醣體合成和轉譯後修飾肽次結構

Abstract

第一部分: SC79衍生物的合成 蛋白激酶B的激活劑SC79被發現在蛋白激酶信號通路能增強磷酸化作用但抑制膜轉位。迄今為止，關於SC79作用機制的發現尚未有所報導. 在本研究中，我們想要透過在SC79的未結合位進行修飾並結合螢光基團，在未來能用於探討其反應機制。 第二部分: 合成含有氨基乙烯基(甲基)半胱胺酸和羊毛硫氨酸的常見大環核醣體合成和轉譯後修飾肽次結構 現今，已經發現了許多含有氨基乙烯基(甲基)半胱氨酸(Avi(Me)Cys)和羊毛硫氨酸(Lan)的天然肽。Avi(Me)Cys和羊毛硫氨酸似乎在抗菌活性中扮演重要的角色，有助於形成更剛性的結構，並將胜肽鎖在活性構型使目標結合並抑制蛋白酶降解。在本研究中，我們回顧了Avi(Me)Cys的化學合成並嘗試透過硫醇-炔反應和柯提斯重排反應合成Avi(Me)Cys。此外，我們試圖完成grisemycin的全合成和cacaoidin中的羊毛硫氨酸環，並且兩者皆使用了固相肽合成法去建立肽的骨架。在grisemycin的大環中，Z-AviCys基團的合成涉及到路易斯酸催化的縮合反應和硫與氧原子間的立體電子效應。預期得到的大環將與線性肽前體進行反應，以達到griemycin的全合成。至於cacaoidin中的羊毛硫氨酸環，我們針對結果進行討論，以了解羊毛硫氨酸環中的脫氫丙氨酸(Dha)未能形成的原因。

Part 1. Synthesis of SC79 Derivatives An Akt activator, SC79, was reported to enhance phosphorylation but inhibit membrane translocation in the Akt signaling pathway. To date, the mechanism of SC79 action is not fully understood. In this study, we explored the possibility of modifying SC79 on its unbinding sites to conjugate it with fluorophore to explore its mechanism in the future. Part 2. Synthesis of Common Macrocyclic RiPPs Sub-structures Containing Avi(Me)Cys and Lanthionine Nowadays, many Avi(Me)Cys- and Lan-containing natural peptides have been found. Both the Avi(Me)Cys moiety and lanthionine appear to play important roles in antimicrobial activities, ensuring a more rigid structure and locking the peptide in the active conformation for target binding while inhibiting proteolytic degradation. In this study, we reviewed the chemical synthesis of Avi(Me)Cys moiety and attempted to synthesize the AviCys residue through a thiol-yne reaction and subsequent Curtius rearrangement. Additionally, we attempted to achieved the total synthesis of grisemycin and the Lan ring in cacaoidin. Both of them were incorporated using solid-phase peptide synthesis. The solid-supported chemical synthesis technique was utilized to construct the peptide backbone. The formation of the Z-AviCys building block in the macrocycle of grisemycin involved a Lewis-acid prompted condensation and stereo-electronic effects between sulfur and oxygen atom. The resultant macrocycle is expected to react with linear peptide precursor to achieve synthesis of grisemycin in the future. As for the Lan ring in cacaoidin, we discussed some observations to understand why Dha formation didn’t proceed in the Lan ring.