Bis- and mono-cyclopropenone fused dibenzocyclooctadiynes
Sutton, Dewey Andrew
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We have synthesized the first fully conjugated bis-cyclopropenone (photo-DIBOD), a derivative of dibenzo[a,e]annulene. 350-420 nm irradiation of these robust compounds results in the efficient formation of dibenzo[a,e]cyclooctadiyne (DIBOD), an unstable, but useful reagent for strain-promoted alkyne azide cycloaddition (SPAAC). Photochemical release of DIBOD allows for full spatial and temporal control of ligations therefrom. We have demonstrated the utility of this platform by derivatizing a model protein, bovine serum abumin (BSA) with a variety of functional moieties. Additionally, we have synthesized a mono-cyclopropenone caged dibenzocyclooctadiyne (MC-DIBOD). An order of magnitude difference in photo-reactivity between bis- (photo-DIBOD) and mono-cyclopropenone - caged dibenzocyclooctadiynes (MC-DIBOD,) allows for selective mono-decarbonylation of photo-DIBOD. Alternatively, MC-DIBOD is prepared by selective mono-cyclopropanation of dibenzo[a,e]cyclooctadiyne. MC-DIBOD permits efficient sequential SPAAC cross-linking of azide-derivatized substrates. Cycloaddition of MC-DIBOD converts an azide moiety into a photo-caged form of triazole-fused dibenzo[a,e]cyclooctyne. While azide reactivity MC-DIBOD and dibenzo[a,e] cyclooctadiyne (DIBOD) is similar to other cyclooctynes, fusion of a triazole to the dibenzocyclooctyne system results in three orders of magnitude enhancement in SPAAC rates. In methanol, this triazole reacts with butyl azide at an astonishing rate constant of 34 M-1s-1, thus representing the most reactive cyclooctyne analog reported so far. MC-DIBOD was utilized in the preparation of mixed bis-triazoles and derivatization of a protein (BSA) with fluorescent dye and polyethylene glycol. We have also worked towards the development of a targeted, cleavable photoaffinity label for immunoglobulin G’s (IgG). Such a molecule can reversibly bind to the Z domain of Staphylococcal protein A (Z protein), allowing for targeted labelling of IgG’s. Subsequent cleavage of Z protein would provide homogeneous antibody-drug conjugates without the immunogenicity associated with Z protein.