異羥肟酸類鐵載體結合物的合成及其應用

Synthesis of Hydroxamate Siderophore Conjugates and Their Applications

何宇軒(Yuxuan He)

指導教授 ： 王宗興

國立臺灣大學/理學院/化學研究所/碩士(2016年)

https://doi.org/10.6342/NTU201602325

摘要

鐵對生命至關重要。細菌會分泌一系列結構多樣的鐵載體以獲得足夠的鐵。而鐵載體介導的攝取系統是微生物中最重要的鐵供給來源之一，在宿主中尤為重要。此主動運輸系統以引起相當程度的關注，而又以“Trojan Horse”策略介導的物質遞送更為人知。由於此攝取系統具一定程度的物種依賴性，每個鐵載體只能針對一定種類細菌。因此，我們試圖開發一個簡易通用的異羥肟酸類鐵載體合成法。更具體地，我們設計和合成了一系列的通用的合成單元。又此基礎上，合成了aerobactin和avaroferrin以驗證設計的可行性。此外，考慮其對三價鐵的高親和性的特點，建立了對aerobactin的直接修飾方法並合成一系列aerobactin-fluorophore conjugates。細菌標註的初步成果表明我們修飾策略的可行性。據此可以準備更多不同的綴合物以進一步研究此鐵攝取系統。

關鍵字

異羥肟酸類鐵載體 ； 綴合物 ； 鐵攝取 ； aerobactin ； avaroferrin

並列摘要

Iron is vital to life. Bacteria secreted siderophores, a diverse class of iron chelator, to acquire sufficient iron. The siderophore-mediated iron uptake system is one of the most important iron supply in microorganisms, especially inside a host. The potential of this active transport system has been well aware, and typically the “Trojan Horse” strategy is for substance delivery. Since this uptake system is somewhat species dependent, each siderophore only target a narrow spectrum of bacteria. Therefore, we tried to develop a facile and divergent synthesis of hydroxamate siderophores, the majority of this class of natural product. To be more specific, we designed and prepared the versatile building blocks. On the basis of that, we synthesized the aerobactin and avaroferrin as examples to verify the viability of the design. Furthermore, taking advantage of the high affinity for ferric iron, a direct modification method for aerobactin have been established and a series of aerobactin-fluorophore conjugates were also synthesized. The preliminary positive result of bacteria labelling indicated the plausibility of our modification strategy. Therefore, a lot of other conjugates can be prepared in the future to probe the possibility of this iron uptake system.

並列關鍵字

Hydroxamate siderophore ； conjugate ； iron uptake ； aerobactin ； avaroferrin

參考文獻

(24) Xu, C.; Zhang, S.; Kaplan, D. I.; Ho, Y.-F.; Schwehr, K. A.; Roberts, K. A.; Chen, H.; DiDonato, N.; Athon, M.; Hatcher, P. G. Environ. Sci. Technol. 2015, 49, 11458.

(42) Bodanszky, M.; Martinez, J.; Priestley, G. P.; Gardner, J. D.; Mutt, V. J. Med. Chem. 1978, 21, 1030.

(46) Diarra, M.; Lavoie, M.; Jacques, M.; Darwish, I.; Dolence, E.; Dolence, J.; Ghosh, A.; Ghosh, M.; Miller, M.; Malouin, F. Antimicrob. Agents Chemother. 1996, 40, 2610.

(1) Neilands, J. B. Annu. Rev. Biochem. 1981, 50, 715.

(3) Hider, R. C.; Kong, X. Nat. Prod. Rep. 2010, 27, 637.