Tetrazine-Triggered Bioorthogonal Cleavage of trans-Cyclooctene-Caged Phenols Using a Minimal Self-Immolative Linker Strategy

被引：6

作者：

Keppel, Patrick ^{[1
]}

Sohr, Barbara ^{[1
]}

Kuba, Walter ^{[1
]}

Goldeck, Marion ^{[1
,2
]}

Skrinjar, Philipp ^{[1
]}

Carlson, Jonathan C. T. ^{[3
,4
]}

Mikula, Hannes ^{[1
]}

机构：

[1] TU Wien, Inst Appl Synthet Chem, A-1060 Vienna, Austria

[2] Med Univ Vienna, Ctr Anat & Cell Biol, A-1090 Vienna, Austria

[3] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA

[4] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

来源：

CHEMBIOCHEM | 2022年 / 23卷 / 20期

基金：

奥地利科学基金会;

关键词：

bioorthogonal chemistry; click chemistry; cycloaddition; elimination; prodrugs; RELEASE; CHEMISTRY; PRODRUGS; CLICK; DRUG;

D O I：

10.1002/cbic.202200363

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Bond-cleavage reactions triggered by bioorthogonal tetrazine ligation have emerged as strategies to chemically control the function of (bio)molecules and achieve activation of prodrugs in living systems. While most of these approaches make use of caged amines, current methods for the release of phenols are limited by unfavorable reaction kinetics or insufficient stability of the Tz-responsive reactants. To address this issue, we have implemented a self-immolative linker that enables the connection of cleavable trans-cyclooctenes (TCO) and phenols via carbamate linkages. Based on detailed investigation of the reaction mechanism with several Tz, revealing up to 96 % elimination after 2 hours, we have developed a TCO-caged prodrug with 750-fold reduced cytotoxicity compared to the parent drug and achieved in situ activation upon Tz/TCO click-to-release.

引用

页数：7