Laboratory of Medicinal Chemical Biology, Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou 215123, China.
J Med Chem. 2022 Jan 13;65(1):333-342. doi: 10.1021/acs.jmedchem.1c01493. Epub 2021 Dec 29.
Although a myriad of bioorthogonal prodrugs have been developed, very few of them present both fast reaction kinetics and complete cleavage. Herein, we report a new bioorthogonal prodrug strategy with both fast reaction kinetics (: ∼10 M s) and complete cleavage (>90% within minutes) using the bioorthogonal reaction pair of -oxide and boron reagent. Distinctively, an innovative 1,6-elimination-based self-immolative linker is masked by -oxide, which can be bioorthogonally demasked by a boron reagent for the release of both amino and hydroxy-containing payload in live cells. Such a strategy was applied to prepare a bioorthogonal prodrug for a camptothecin derivative, SN-38, resulting in 10-fold weakened cytotoxicity against A549 cells, 300-fold enhanced water solubility, and "on-demand" activation upon a click reaction both and . This novel bioorthogonal prodrug strategy presents significant advances over the existing ones and may find wide applications in drug delivery in the future.
尽管已经开发出了无数种生物正交前药，但它们中的大多数都具有快速反应动力学和完全裂解的特点。在此，我们报道了一种新的生物正交前药策略，该策略使用生物正交反应对-氧化物和硼试剂具有快速反应动力学（: ∼10 M s）和完全裂解（在几分钟内超过 90%）。独特的是，一种创新的基于 1,6-消除的自毁性连接子被-氧化物掩蔽，该连接子可以被硼试剂生物正交地去掩蔽，从而在活细胞中释放含氨基和羟基的有效载荷。该策略被用于制备喜树碱衍生物 SN-38 的生物正交前药，结果导致对 A549 细胞的细胞毒性降低了 10 倍，水溶解度提高了 300 倍，并且在点击反应时可以“按需”激活。这种新的生物正交前药策略与现有策略相比具有显著的优势，在未来可能会在药物输送中得到广泛应用。
