Bioorthogonal Prodrug Activation Driven by a Strain-promoted 1,3-dipolar Cycloaddition

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2018 Mar 22

PMID 29560207

Citations 35

Authors

Siddharth S Matikonda

Douglas L Orsi

Verena Staudacher

Imogen A Jenkins

Franziska Fiedler

Jiayi Chen

Allan B Gamble

Affiliations

Soon will be listed here.

Abstract

Due to the formation of hydrolysis-susceptible adducts, the 1,3-dipolar cycloaddition between an azide and strained -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 -cyclooctenol (TCO-OH) with a model prodrug resulted in a rapid 1,3-dipolar cycloaddition with second-order rates of 0.017 M s and 0.027 M s for the equatorial and axial isomers, respectively, resulting in release of the active compound. H NMR studies showed that activation proceeded a triazoline and imine, both of which are rapidly hydrolyzed to release the model drug. Cytotoxicity of a doxorubicin prodrug was restored upon activation with TCO-OH, while with -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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