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The term click chemistry, coined by Karl Barry Sharpless, refers to a variety of reactions that are considered simple and regiospecific and provide high yields. Other linkers used in chemical biology can be generated through the reaction commonly referred to as click chemistry ( Figure 2c).

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This entire moiety is then bound to an antibody through generation of a disulfide bond between the free thiol linked to the small molecule and a cysteine residue on the antibody. A linker containing a free thiol is conjugated to the small molecule of interest at a location that does not affect its activity. (19) This method increases the uptake of the cytotoxic drug by cancer cells and not by the healthy ones. Anticancer drugs, including doxorubicin ( 1), methotrexate, and mitomycin C, have been linked to antibodies and, after internalization, the disulfide linker is cleaved and the cytotoxic agent released. (18) The disulfide linker has been extensively used in the conjugation of small molecules to antibodies. Once the disulfide-linked drug enters the cytosol, the disulfide can be reduced, releasing the drug moiety. Cells have a high level of free −SH moieties in their cytosol. Since the disulfide linker bond can be reversed under physiological conditions, it has been integrated into drug delivery approaches and in prodrug scaffolds. The Dawson group developed a bisaryl hydrazone linker also highlighting the mild conditions that can be exploited to release captured proteins from a hydrazone-linked molecule. Captured proteins do not have to be exposed to SDS or 8 M guanidine to release them for mass spectrometry experiments. (10) Their study highlights a more efficient capture and release of the targeted protein pool as compared to standard protocols due to the mild conditions for the hydrazone release. (9) Several different types have been developed, including an acyl hydrazone from the Kohn laboratory. (6) While the hydrazone moiety has been widely used in diversity-oriented synthesis (7) and as an additional handle in peptide synthesis, (8) more recently it has been exploited as a reversible linker for proteomics experiments.

(5) The hydrazone moiety is stable at physiological pH and cleaves at an acidic pH, but additional conditions that do not require acids have been developed. The hydrazone moiety can typically be easily installed because of its compatibility with peptide synthesis. A commonly used linker type is hydrazone, Figure 2a.

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