Bioorthogonal Removal of 3-Isocyanopropyl Groups Enables the Controlled Release of Fluorophores and Drugs in Vivo

J Am Chem Soc. 2018 Jul 11;140(27):8410-8414. doi: 10.1021/jacs.8b05093. Epub 2018 Jun 27.


Dissociative bioorthogonal reactions allow for chemically controlling the release of bioactive agents and reporter probes. Here we describe 3-isocyanopropyl substituents as masking groups that can be effectively removed in biological systems. 3-Isocyanopropyl derivatives react with tetrazines to afford 3-oxopropyl groups that eliminate diverse functionalities. The study shows that the reaction is rapid and can liberate phenols and amines near-quantitatively under physiological conditions. The reaction is compatible with living organisms as demonstrated by the release of a resorufin fluorophore and a mexiletine drug in zebrafish embryos implanted with tetrazine-modified beads. The combined benefits of synthetic ease, rapid kinetics, diversity of leaving groups, high release yields, and structural compactness, make 3-isocyanopropyl derivatives attractive chemical caging moieties for uses in chemical biology and drug delivery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / administration & dosage*
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Delayed-Action Preparations / chemistry*
  • Drug Liberation
  • Fluorescent Dyes / administration & dosage*
  • Fluorescent Dyes / pharmacokinetics
  • Isocyanates / chemistry
  • Mexiletine / administration & dosage*
  • Mexiletine / pharmacokinetics
  • Oxazines / administration & dosage*
  • Oxazines / pharmacokinetics
  • Zebrafish / embryology


  • Anti-Arrhythmia Agents
  • Delayed-Action Preparations
  • Fluorescent Dyes
  • Isocyanates
  • Oxazines
  • Mexiletine
  • resorufin