各校計畫成果

活動簡介

生物偶聯物在多種與生物相關的領域具有廣泛應用，通常是透 過自然界中常見的親核基團（如硫醇與胺基）的偶聯反應合成而成。 因此，已有多種針對特定親核基團的化學選擇性交聯試劑被開發出 來，以生成所需的生物偶聯物。受到現有試劑親核基團相容性有限的 限制所啟發，我們在此報導 1,4-二氟-2,5-二硝基苯 (p-DFDNB) 作為 一種統一的交聯試劑，可作為「多功能雜原子親核樞紐」（Versatile Heteroatom Nucleophile Hub, VHNH），能夠透過連續的化學與區位 選擇性親核芳香取代（SNAr）反應與硫醇和胺基進行偶聯，進而構 築出硫醇–硫醇、胺–胺與胺–硫醇等多樣化的生物偶聯物。VHNH 策略能夠與廣泛的含硫醇或胺基的受質相容，包括小分子、藥物、天 然生物分子以及功能性標籤。此外，該方法還能構建帶有多樣化功能 性標籤的翻譯後修飾蛋白質。總體而言，VHNH 策略提供了一個簡 便且多功能的平台，用於構築各式各樣的生物偶聯物。

Bioconjugates are broadly applied in biologically relevant fields and are commonly prepared through the coupling of naturally occurring nucleophiles such as thiols and amines. To this end, numerous chemoselective crosslinking reagents targeting specific nucleophiles have been developed. Addressing the limited nucleophile scope of existing reagents, we introduce 1,4-difluoro-2,5-dinitrobenzene (p-DFDNB) as a unified crosslinker that functions as a versatile heteroatom nucleophile hub (VHNH). Through sequential chemo- and regioselective nucleophilic aromatic substitution (SNAr) reactions with thiol and amine nucleophiles, this reagent enables the modular synthesis of thiol–thiol, amine–amine, and amine–thiol bioconjugates. The VHNH platform is compatible with a wide spectrum of thiol- and amine-containing substrates, ranging from small molecules and pharmaceuticals to biomolecules and functional tags, and further facilitates the generation of post-translationally modified proteins bearing diverse functional groups. Collectively, the VHNH strategy establishes a simple yet broadly applicable approach for constructing diverse bioconjugates.