TAGGING THE UNTAGGABLE: NEW OPENNING FOR BIOCONJUGATION CHEMISTRY

Bioconjugation is typically implemented through chemoselective modification of native functional groups of the target molecule. This process of derivatization often involves “click” chemistry, such as azide−alkyne cycloaddition, amines through amide linkages, and carbonyl groups through oxime ligation. Although many medicinal agents include traditional “taggable” functional groups such as heteroatom−H bonds, some compounds present the challenge of not having any apparent chemical handles.

This presentation describes the synthesis of a new difluoroalkyl ketone sulfinate reagent that enables the direct tagging of unactivated C−H bonds in untagged bioactive heteroarenes for use in bioconjugation. Tagged drug molecules bearing a carbonyl group can then be simply conjugated to a targeting moiety through the labile hydrazone linkage. The developed reagent was applied for direct incorporation of difluoroalkyl ketone handle onto substrate molecules (e.g., camptothecin-CPT, temozolomide-TMZ and Methotrexate-MTX). In vitro biological efficacy study clearly indicates that the designed ketone handle can completely maintain the original activity of a biologically relevant molecule when it is tagged with difluoropentyl ketone at the appropriate position. Bioconjugation of the "tagged" CPT drug molecules with folic acid via acid-sensitive semicarbazone linkage was evaluated. Similar In vitro antitumor effect of the CPT-bioconjugate on KB cells compared to that of the free drug was observed.

Such chemistries, i.e. tagging and bioconjugation, represent a promising strategy to grant targeting features to small "untaggable" drug molecules.