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Synthesis

Attaching ‘unlinkable’ drugs to antibodies

Quaternary ammonium group connects drugs to antibodies for targeted delivery

by Celia Henry Arnaud
October 24, 2016 | APPEARED IN VOLUME 94, ISSUE 42

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A disulfide-containing linker forms a quaternary ammonium complex with the anticancer drug tubulysin, which can then be linked to an antibody.
A disulfide-containing linker forms a quaternary ammonium complex with the anticancer drug tubulysin, which can then be linked to an antibody.

Attaching a small-molecule drug to a targeting agent such as an antibody can improve the delivery of the drug. A common way to achieve that with antibodies is using a linker that connects to the drug through an amide or carbamate functional group. But tertiary and heteroaryl amines common to many drug molecules lack a place for such a connection, leading researchers to deem them “unlinkable.” A team led by Thomas H. Pillow of Genentech has now devised a strategy to attach and release such drugs through a p-aminobenzyl quaternary ammonium salt (Nat. Chem. 2016, DOI: 10.1038/nchem.2635). The team treated an alcohol-containing linker with methanesulfonyl chloride or thionyl chloride to yield a benzyl chloride that can form quaternary ammonium salts with a variety of tertiary amines. The quaternary ammonium connection was applied to dipeptide linkers, which permits enzymatic cleavage by proteases, and to disulfide-containing linkers, which allows drugs to be released by intracellular reduction of the disulfide followed by a cyclization and elimination reaction. By using these linkers, the researchers were able to conjugate a variety of drugs to antibodies, including the anticancer agents tubulysin and vinblastine and the antibacterial agents rifabutin and clindamycin.

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