N1-Methylpseudouridine 的合成研究

Abstract

N1-methylpseudouridine 是1976年首次自Streptomyces platensis var. clarensis鉑鏈黴菌培養液中分離出的天然物。和它的衍生物pseudouridine一樣，它也是一種由碳碳鍵連接含氮鹼基和醣而組成的核苷分子。自從covid-19爆發後，N1-methylpseudouridine 在mrnA疫苗的開發上佔有一席之地。現今兩大疫苗公司Pfitzer以及Moderna所開發的mrnA疫苗中，都分別將核酸序列中的U（Uridine）都換成N1-methylpseudouridine，這樣不但仍然保留了可以辨識U的部分，N1-methylpseudouridine所提供的N-1甲基還可以提供RNA序列有力的立體阻礙，防止被近一步氧化，甚至整個序列被水解破壞。由於上述具有潛力的應用，引起了我們合成N1 -methylpseudouridine的興趣。雖然過去在1980年代pseudouridine的取代方便，可以直接透過pseudouridine或是以pseudouridine製備的起始物進行甲基化後得到N1-methylpseudouridine，然而現今酵素合成pseudouridine的成本不但高，來源也不易取得，如果用化學合成此類C-nucleosides 也相當具有挑戰性，因此我們才會想開發N1-methylpseudouridine的全合成。

N1-methylpseudouridine, a derivative of pseudouridine, was first isolated fromStreptomyces platensis var. clarensis in 1976. It is a kind of C-nucleosides thatpossesses a carbon-carbon linkage between a carbohydrate and an N-heterocyclicbase. After the outbreak of COVID-19, research of the replacement of Uridine withN1 -methylpseudouridine in mRNA has proven to be a prospective application to thedevelopment of vaccines in recent years. Consequently, it has engaged us to propose anovel synthetic approach to the total synthesis of N1-methylpseudouridine.