当前位置: X-MOL 学术J. Med. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
On-Demand Activation of a Bioorthogonal Prodrug of SN-38 with Fast Reaction Kinetics and High Releasing Efficiency In Vivo
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-12-29 , DOI: 10.1021/acs.jmedchem.1c01493
Zhou Zhou 1 , Shun Feng 1 , Jujun Zhou 1 , Xingyue Ji 1 , Ya-Qiu Long 1
Affiliation  

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 (k2: ∼103 M–1 s–1) and complete cleavage (>90% within minutes) using the bioorthogonal reaction pair of N-oxide and boron reagent. Distinctively, an innovative 1,6-elimination-based self-immolative linker is masked by N-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 in vitro and in vivo. This novel bioorthogonal prodrug strategy presents significant advances over the existing ones and may find wide applications in drug delivery in the future.

中文翻译:

SN-38生物正交前药的按需激活,具有快速反应动力学和体内高释放效率

尽管已经开发了无数的生物正交前药,但其中很少有同时具有快速反应动力学和完全裂解的特性。在此,我们报告了一种新的生物正交前药策略,该策略使用N-氧化物和硼试剂的生物正交反应对,具有快速反应动力学 ( k 2 : ∼10 3 M –1 s –1 ) 和完全裂解(在几分钟内>90%). 独特的是,一种创新的基于 1,6-消除的自我牺牲连接器被N掩盖-氧化物,可以通过硼试剂进行生物正交去掩蔽,以在活细胞中释放含氨基和羟基的有效载荷。这种策略被应用于制备喜树碱衍生物 SN-38 的生物正交前药,导致对 A549 细胞的细胞毒性减弱 10 倍,水溶性提高 300 倍,并且在点击反应时“按需”激活。体外体内。这种新颖的生物正交前药策略比现有策略取得了重大进展,未来可能会在药物递送中得到广泛应用。
更新日期:2022-01-13
down
wechat
bug