開發針對MraY的核甘抗生素

Abstract

我們成功得針對核苷類分子進行合成路徑之設計，保護基的選擇上針對兩種不同的胺基上，分別以羧基苯甲基(Cbz)保護三唑(triazole)尾端胺基及以叔丁氧羰基將胺基(Boc)保護aminoribose的胺基，使合成步驟得以簡單、方便。 我們討論重點分為三個方向，第一，五號位置立體位向的重要性，第二，修飾aminoribose分子結構，第三，討論各種脂質(lipid)對於MraY的抑制效果。第一點，目前在文獻上並沒有對此位置立體位向的報導，而由我們的實驗結果，立體位向的R或S，會有些微影響抑制效果。第二點，試著討論將aminoribose結構換成尾端胺基的五個碳直鏈結構，修改前抑制活性好於修改後，且我們將尾端放上帶有許多亞胺基甲二胺(guanidine)會使抑制活性上升，我們認為雖然抑制活性比不上原有核醣結構之分子，但可以簡化多合成步驟的aminoribose，可以快速方便得到核甘類分子。第三點，以各種脂質討論對於MraY抑制效果的影響，我們認為抑制效果會受脂質長短與結構影響，可能有精確的活性位置。本論文中，最有效抑制分子為在濃度是1微莫耳濃度時，抑制百分比可達60 %。此分子已較天然物抑制劑略有效，因本開發之分子可做為有潛力之分子而做未來進一步研發的基礎。

In this study, we have successfully developed a synthetic approach toward the preparation of structurally complex nucleoside analogues. Based on our strategy, several protecting groups were applied to let us practically prepare these molecules, and the click chemistry was employed to conveniently conjugate a functionalized tag, allowing for the rapidly lipid diversity. With a general and flexible synthetic approach in hand, we raised three interesting questions: (1) What is the role of chiral center at the C5 position? (2) Is it possible to replace the aminoribose moiety with a simple fragment to shorten the reaction steps? (3) Can we apply a proper functionalized tag to rapidly discover a new and potent lipid moiety in nucleosides to improve its inhibition activity against bacterial MraY? In our results toward MraY inhibition study, the chiral center at the C5 position of nucleosides showed only moderate, not dramatic influence to the inhibition potency, Secondly, the structurally complex aminoribose moiety could be replaced with a simple fragment with a five-carbons-chain bearing an amine or guanidine at the end. It may shed a light to develop a new moiety with a more convenient chemistry to accelerate the development of MraY antibiotics. Thirdly, in our nucleoside analogues, the length and structure of the lipid really affected the inhibition potency against MraY. More detail study like a structure activity relationship will be examined in the future. Currently, the best compound showed an approximately 60% inhibition potency against MraY at the concentration at 1 M. Its activity was slightly better than that of natural product, Tunicamycin (46% inhibition) at the same inhibition assay platform.