Cyclooctyne click triggers Cope elimination to unmask Michael acceptor warheads and release payloads
- Michael acceptors are masked with a hydroxylamine; a bioorthogonal reaction with a cyclooctyne triggers Cope elimination, regenerating the electrophile under mild conditions.
- The approach covers several warhead types, including unsaturated carbonyl, cyano, sulfonyl, phosphonate and maleimide, with tunable activation rates.
- Functionalized cyclooctynes can release an imaging or functional payload at the same time, giving a signal that reports activation.
- Applied to covalent inhibitors, it gave controlled activation in cells.
💡 Points
Could a masked warhead finally fix the off-target reactivity of acrylamide-class leads? Caging the Michael acceptor as a hydroxylamine and uncaging it by cyclooctyne click is a neat way to turn on covalency only where you dose the trigger. From the abstract alone I would want the rate constants, whether the hydroxylamine-bearing prodrug keeps target affinity, and how the cyclooctyne's size and lipophilicity compare with a conventional warhead.