1. Academic Validation
  2. On-Demand Activation of a Bioorthogonal Prodrug of SN-38 with Fast Reaction Kinetics and High Releasing Efficiency In Vivo

On-Demand Activation of a Bioorthogonal Prodrug of SN-38 with Fast Reaction Kinetics and High Releasing Efficiency In Vivo

  • J Med Chem. 2022 Jan 13;65(1):333-342. doi: 10.1021/acs.jmedchem.1c01493.
Zhou Zhou 1 Shun Feng 1 Jujun Zhou 1 Xingyue Ji 1 Ya-Qiu Long 1
Affiliations

Affiliation

  • 1 Laboratory of Medicinal Chemical Biology, Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou 215123, China.
Abstract

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.

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