FIGURE

Fig. 8

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ZDB-FIG-260407-37

Publication

Chojnacki et al., 2026 - Click-to-Release Reactions for Tertiary Amines and Pyridines

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Fig. 8

Synthesis and activation of prodrugs through click-to-release reactions. (a) Synthesis of ICPr-mepivacaine. Direct reaction of mepivacaine with 3-isocyanopropyl tosylate failed, indicating the limited reactivity of this reagent for highly sterically encumbered tertiary amines. ICPr-mepivacaine was instead synthesized from N-desmethyl mepivacaine by incorporation of the ICPr group followed by methylation. (b) Tetrazine-induced cleavage efficiently liberated mepivacaine from the ICPr-protected precursor (Figure S24 in the Supporting Information). (c) Caging of drugs with TzMe groups and corresponding release studies. Camptothecin was unreactive to TzMeBr, and the reaction of TzMe-bupivacaine with tBuNC stalled at an intermediate (Figures S25–S29 in the Supporting Information).a For TzMe-Fentanylinact, part of the structure was excluded to avoid regulatory and toxicity concerns. The structure of fentanyl and its TzMe precursor is shown in Figure 10. b Yield for quaternization step; yield for chlorination step was 19%. c Observed yield corresponds to a lower limit because mechlorethamine spontaneously cyclizes.

Expression Data

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Antibody Labeling

Phenotype Data

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Acknowledgments

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