7-oxanorbornadiene-2,3-dicarboxylates (ONDs) are easily prepared by Diels-Alder cycloaddition from furans and electron-deficient alkynes, often in a single high-yielding step. These linkers have recently been reported as potent and selective Michael acceptors toward thiol nucleophiles and have been used to label thiol-containing biomolecules. A unique feature of the resulting thiol conjugates is the tunable degradation by a retro-Diels-Alder reaction, the rate of which varies with the OND substitution pattern with half-lives ranging from hours to days under simulated physiological conditions. We have engaged this reactivity to directly label serum albumins in vitro with OND reagents bearing molecular cargos for exploration as drug carriers. The preparation and properties of albumin-OND-cargo conjugates and in vivo evaluation of payload release will be described.

Oxanorbornadiene derivatives as thiol-reactive degradable linkages for the release of molecular cargo

243rd National Meeting (2012)

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