Bioorthogonal release of sulfonamides and mutually orthogonal liberation of two drugs

Abstract

Sulfonamide derivatives have been used in pharmaceutics for decades. Here we report a new approach to release sulfonamides efficiently using a bioorthogonal reaction of sulfonyl sydnonimines and dibenzoazacyclooctyne (DIBAC). The second-order rate constant of the cycloaddition reaction can be up to 0.62 M−1 s−1, and the reactants are highly stable under physiological conditions. Most significantly, we also discovered the mutual orthogonality between the sydnonimine–DIBAC and benzonorbornadiene–tetrazine cycloaddition pairs, which can be used for selective and simultaneous liberation of sulfonamide and primary amine drugs.

Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

“…There is considerable interest in developing reaction schemes that allow for the release of two molecules simultaneously in vivo. 24,39 We rationalized that combining the TzMe-release chemistry with our previously disclosed 3-isocyanopropyl (ICPr) chemistry, 37 would liberate two independent payloads. Dual release was rst tested in vitro.…”

“…Running two bioorthogonal release reactions in parallel is one possibility to achieve such dual-release as has been demonstrated by combining the reaction of tetrazines and benzonorbornadienes with that between sulfonyl sydnonimines and dibenzoazacyclooctyne. 39 A second example involved the reaction between vinyl ethers and tetrazines, which released alcohols but was limited to generating pyridazine and had slow reaction kinetics. 24 A single pair of reactants that releases two molecules in a single fast reaction would bring such approaches to the next level.…”

Dissociative Bioorthogonal Reactions

“…[77] Ar elated sydnone design enabled the controlled release of sulfonamides. [78] For the sydnones releasing ureas, the rate of the reactionw ith dibenzocyclooctyne was 3.15 m À1 s À1 in PBS/DMSO (4:1) at 25 8C; additional strain increasedt he reactionr ate further,a lbeit at the risk of decreasing the stability of the alkyne. Furthermore, halogen substituents on the sydnones tructure have been shown to accelerate the cycloaddition with cyclooctynes.…”

Stable, Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles

“…Indeed, 3 c near‐quantitatively removed ICPr groups from a ratiometric 4‐hydroxy‐1,8‐naphthalimide fluorophore (Supporting Information, Figure S13). Given that 3 c reacts preferentially with isonitriles relative to other dienophiles (Table ), it could be used to control the release of two different molecules by separate chemical stimuli . We further tested whether the optimized tetrazines are compatible with in vivo use by implanting a bead modified with 3 a (Tz‐PS) into the yolk sac of zebrafish embryos and monitoring the release of an ICPr‐caged resorufin fluorophore (Figure A, for in vitro release, see the Supporting Information, Figure S15).…”