開發蒎烯雙醇衍生物對硼酸的可控籠閉策略

Abstract

近年來，硼酸在化學生物學以及生物醫學中的應用逐漸受到重視。在醫療上，硼可做為癌症放射治療的重要試劑。此外，美國食品藥物管理局至今也已批准了五樣硼酸藥物。在化學生物學中，硼酸可作為醣類傳感器、生物正交探針以及藥物運送奈米粒子。然而，硼酸也會和生物體中其他親核基形成非專一性結合，進而造成脫靶效應，限制其在生物體內的應用。 在本研究中，我們設計了由δ-蒎烯雙醇衍伸的可控侷限硼酸保護基，進而在特定條件下釋放硼酸分子，以增加其對生物標靶的專一性。為了進一步實現可控釋放，我們在δ-蒎烯雙醇上引入了觸發單元，分別為4-(2-硝基苄氧基)苯基與4-(4-硝基苄氧基)苯基。當此兩種觸發單元經由觸發後，可生成不穩定的酚，進而釋放出硼酸分子。此外，我們也探討了pH值以及取代基的立體障礙對於δ-蒎烯雙醇衍生物所形成硼酯的穩定性影響。結果顯示，將苯環作為立體障礙引入δ-蒎烯雙醇，對於形成的硼酯抗水解能力至關重要，進而使硼酯在廣泛的 pH 值條件下仍能保持穩定。然而，當引入具有推電子性質的酚，δ-蒎烯雙醇可進行1,6-消去反應，應而降低硼酯的穩定性。綜合上述，我們可藉由觸發在δ-蒎烯雙醇上形成不穩定的酚，來對硼酸進行可控釋放。最終，我們將光可控侷限保護基應用於抗癌藥物伊沙佐米的前驅藥策略中。在經由365 nm光解後，此光籠化抑制劑可順利釋放伊沙佐米並抑制蛋白酶體活性。未來此策略將可進一步應用於硼酸在生物系統中的可控釋放。

In recent years, the application of boronic acids in biomedical fields and chemical biology has received increasing attention. For biomedical, boron is an important reagent for radiotherapy in cancer. In addition, the FDA has approved five boronic acid-containing drugs to date. In chemical biology, boronic acids can be applied to saccharide sensors, bioorthogonal probes, and drug delivery nanoparticles. However, it should be noted that boronic acids may also non-specifically bind with other nucleophiles in the biological system, limiting their application in the body. In this study, we developed a controllable caging strategy for boronic acids using δ-pinanediol derivatives, allowing for the release of boronic acids under specific conditions to increase their specificity for biological targets. To achieve controllable release, we introduced trigger units, namely 4-[(2-nitrophenyl)methoxy]phenyl and 4-[(4-nitrophenyl)methoxy]phenyl, on the δ-pinanediol. Upon triggering, each of these trigger units can form a free phenol group, which destabilize the boronic ester, thereby releasing boronic acid molecules. Furthermore, we investigated the effects of pH value and substituents on the stability of boronic esters formed by δ-pinanediol derivatives. The results showed that the introducing of a bulky phenyl moiety in δ-pinanediol derivatives is crucial for the hydrolytic resistance of the boronic esters, which can remain stable in a wide range of pH values. However, with an electron-donating phenol group, δ-pinanediol can undergo 1,6-elimination, thereby reducing the stability of boronic esters. In short, we can control the release of boronic acids by triggering, through an unstable phenol on δ-pinanediol derivatives. Finally, we applied the controllable photocage strategy to prepare the prodrug of anti-cancer drug Ixazomib. After 365 nm irradiation, the photocaged prodrug can successfully release Ixazomib, thereby inhibiting proteasomal activity. In the future, our strategy can be further applied to the controllable release of boronic acids in biological systems.