Bioorthogonal prodrug activation driven by a strain-promoted 1,3-dipolar cycloaddition.

نویسندگان

  • Siddharth S Matikonda
  • Douglas L Orsi
  • Verena Staudacher
  • Imogen A Jenkins
  • Franziska Fiedler
  • Jiayi Chen
  • Allan B Gamble
چکیده

Due to the formation of hydrolysis-susceptible adducts, the 1,3-dipolar cycloaddition between an azide and strained trans-cyclooctene (TCO) has been disregarded in the field of bioorthogonal chemistry. We report a method which uses the instability of the adducts to our advantage in a prodrug activation strategy. The reaction of trans-cyclooctenol (TCO-OH) with a model prodrug resulted in a rapid 1,3-dipolar cycloaddition with second-order rates of 0.017 M-1 s-1 and 0.027 M-1 s-1 for the equatorial and axial isomers, respectively, resulting in release of the active compound. 1H NMR studies showed that activation proceeded via a triazoline and imine, both of which are rapidly hydrolyzed to release the model drug. Cytotoxicity of a doxorubicin prodrug was restored in vitro upon activation with TCO-OH, while with cis-cyclooctenol (CCO-OH) no activation was observed. The data also demonstrates the potential of this reaction in organic synthesis as a mild orthogonal protecting group strategy for amino and hydroxyl groups.

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عنوان ژورنال:
  • Chemical science

دوره 6 2  شماره 

صفحات  -

تاریخ انتشار 2015