期刊
CHEMICAL SCIENCE
卷 6, 期 2, 页码 1212-1218出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c4sc02574a
关键词
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资金
- University of Otago Research Grant (UORG)
- Health Research Council (HRC) of New Zealand
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. H-1 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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