Solid-phase synthesis of peptides with azopyridine side-chains for Mn(i)–CO binding and red-light responsive CO release

Abstract

Photoactivatable carbon monoxide-releasing molecules (photoCORMs) have provided a unique opportunity for the manipulation of the highly toxic but physiologically relevant CO gas. Here we describe an operationally simple and efficient one-pot solid-phase synthesis strategy for peptides with azopyridine (azpy) side-chains enabled by the on-resin Mills reaction. Upon conjugation with the Mn–CO moiety, a series of linear or cyclic red-light activatable peptide-based photoCORMs were obtained. While not affecting the intrinsic nature of the peptides, the fac-[Mn(azpy)(CO)₃Br] moiety on the peptide bioconjugates can be safely internalized and intracellular CO release is achieved upon red-light irradiation. Importantly, the targeted/localized CO release enabled by this novel type of peptide-based photoCORM exhibited enhanced cell cytotoxicity. As such, we believe that the strategy disclosed herein could serve as a generally applicable method in the synthesis of peptide bioconjugates with the fac-[Mn(azpy)(CO)₃Br] moiety for temporal and spatial controlled CO release with red light, which should help in elucidating the physiological role of CO and mediate its safe administration.