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

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 activat...

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Detalles Bibliográficos
Autores principales: Matikonda, Siddharth S., Orsi, Douglas L., Staudacher, Verena, Jenkins, Imogen A., Fiedler, Franziska, Chen, Jiayi, Gamble, Allan B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811098/
https://www.ncbi.nlm.nih.gov/pubmed/29560207
http://dx.doi.org/10.1039/c4sc02574a
Descripción
Sumario: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. (1)H 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.