Family of BODIPY Photocages Cleaved by Single Photons of Visible/Near-Infrared Light

Abstract

Photocages are light-sensitive chemical protecting groups that provide external control over when, where, and how much of a biological substrate is activated in cells using targeted light irradiation. Regrettably, most popular photocages (e.g., o-nitrobenzyl groups) absorb cell-damaging ultraviolet wavelengths. A challenge with achieving longer wavelength bond-breaking photochemistry is that long-wavelength-absorbing chromophores have shorter excited-state lifetimes and diminished excited-state energies. However, here we report the synthesis of a family of BODIPY-derived photocages with tunable absorptions across the visible/near-infrared that release chemical cargo under irradiation. Derivatives with appended styryl groups feature absorptions above 700 nm, yielding photocages cleaved with the highest known wavelengths of light via a direct single-photon-release mechanism. Photorelease with red light is demonstrated in living HeLa cells, Drosophila S2 cells, and bovine GM07373 cells upon ∼5 min irradiation. No cytotoxicity is observed at 20 μM photocage concentration using the trypan blue exclusion assay. Improved B-alkylated derivatives feature improved quantum efficiencies of photorelease ∼20-fold larger, on par with the popular o-nitrobenzyl photocages (εΦ = 50-100 M cm), but absorbing red/near-IR light in the biological window instead of UV light.

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

“…Moreover, Smith and Winter recently developed π‐extended BODIPY derivatives (e.g. compound 48 in Scheme ) featuring light absorptions above 700 nm, the longest wavelengths ever reported for photocage activation with single‐photon irradiation . However, since these photocages often include hydrolytically labile ester bonds, it is not clear whether the plasma stability may limit future translational programs.…”

“… A) Examples of π‐extended photosensitive linkers, cleavable by either two‐photon (TP, as compound 47 ) or single‐photon (SP, compound 48 ) excitation with NIR wavelengths. B) ADC 49 developed by Schnermann and co‐workers, based on a NIR light‐sensitive cyanine linker, a duocarmycin (Duo) payload and a diamine‐based self‐immolative spacer (depicted in green) …”

“…compound 48 in Scheme7)f eaturing light absorptions above 700 nm, the longest wavelengths ever reportedf or photocage activationw ith single-photon irradiation. [90] However,s ince these photocages Scheme7.A) Examples of p-extended photosensitive linkers, cleavablebye ither two-photon (TP,asc ompound 47) [89] or single-photon (SP,compound 48) [90] excitationw ith NIRw avelengths. B) ADC 49 developed by Schnermann and co-workers, based on aN IR light-sensitive cyanine linker,aduocarmycin( Duo) payload and ad iamine-based self-immolative spacer (depicted in green).…”

Optical Control of Antibody Activity by Using Photocleavable Bivalent Peptide–DNA Locks

“…Several chemical approaches for increasing the hydrolytic stability of the linker are available, including the use of 2′‐MeO‐ or phosphorothioate‐modified DNA, or the use of protein nucleic acids (PNAs) or locked nucleic acids (LNAs) . Similarly, a variety of red‐light‐activatable photocleavable ligands have recently been reported that could be used to avoid the potential phototoxicity of 365 nm light and to allow deeper tissue penetration …”

S,S‐Chiral Linker Induced U Shape with a Syn‐facial Sensitizer and Photocleavable Ethene Group

“…Photoreleased molecules are of considerable interest not only in the field of photochemistry but also in site‐specific delivery applications . Current literature on sensitizer and drug photorelease has mainly focused on the use of direct UV, visible and near‐IR light to activate the release mechanisms.…”