適用於生物系統中的多功能刺激響應型蒎烯雙醇籠閉分子對硼酸的動態組裝和釋放策略

Abstract

近年來，硼酸在化學生物學中的應用備受關注，並在治療研究、生物探針以及多種化學-生物研究領域取得了顯著的實際進展。然而，硼酸與其他親核試劑會產生非特異性結合，而硼酸酯在生物系統中的固有不穩定性限制了其在體內的應用。 在此我們利用δ-蒎烯雙醇衍生物開發了一種可控的硼酸籠策略，使硼酸能夠在特定刺激下釋放。δ-蒎烯雙醇做為保護基骨架，並引入含有鄰硝基或對硝基的芐基取代基作為觸發單元，這些觸發單元在UV照射或暴露於硝基還原酶後，會形成裸露的酚基或苯胺基團，透過自崩解反應，降低硼酸酯的穩定性，進而釋放出硼酸分子。我們利用這種具有刺激響應性的δ-蒎烯雙醇衍生物與雙硼酸類型的葡萄糖螢光探針結合，藉由可控釋放策略進行細胞內葡萄糖檢測，建立了一個具有優良時空選擇性的光響應硼酸酯探針。另外，我們的缺氧響應籠閉策略使葡萄糖探針能夠選擇性地靶向過度表達硝基還原酶的腫瘤細胞，幫助我們在混合的細胞中分辨癌細胞以及正常細胞。我們期待未來，刺激響應籠閉策略能夠在多種生物環境中可控釋放硼酸，拓展硼酸化學在生物體中的應用性。

In recent years, there has been a growing focus on the application of boronic acids in chemical biology, with significant practical progress made in areas such as therapeutic research, biological probes, and numerous chemical–biological studies. However, boronic acids exhibit nonspecific binding with other nucleophiles, and the inherent lability of boronic esters in biological systems limits their applications in vivo. In this study, we have developed a controllable caging strategy for boronic acids using δ-pinanediol derivatives, enabling the release of boronic acids toward specific stimuli. Trigger units containing o-nitroaryl or p-nitroaryl groups were introduced onto δ-pinanediol. Upon UV irradiation or exposure to nitroreductase, these trigger units form a free phenol or aniline group, acting as self-immolative linkers, which destabilize the boronic ester, thereby releasing boronic acid molecules. Furthermore, we utilized our stimuli-responsive pinanediol cages in combination with a diboronic acid-based fluorescent glucose sensor. Through our controllable release strategies, intracellular glucose detection was conducted with a photoresponsive boronic ester probe with excellent spatiotemporal selectivity. Additionally, our hypoxia-responsive caging strategy has allowed glucose probes to selectively target tumor cells overexpressing nitroreductase, assisting us in distinguishing cancer cells from normal cells in co-cultured cell samples. In the future, stimuli-responsive caging strategies show promising potential for the controllable release of boronic acids in various biological contexts.