Water-Soluble BODIPY Photocages with Tunable Cellular Localization

Abstract

Photoactivation of bioactive molecules allows manipulation of cellular processes with high spatiotemporal precision. The recent emergence of visible-light excitable photoprotecting groups has the potential to further expand the established utility of the photoactivation strategy in biological applications by offering higher tissue penetration, diminished phototoxicity, and compatibility with other light-dependent techniques. Nevertheless, a critical barrier to such applications remains the significant hydrophobicity of most visible-light excitable photocaging groups. Here, we find that applying the conventional 2,6-sulfonation to meso-methyl BODIPY photocages is incompatible with their photoreaction due to an increase in the excited state barrier for photorelease. We present a simple, remote sulfonation solution to BODIPY photocages that imparts water solubility and provides control over cellular permeability while retaining their favorable spectroscopic and photoreaction properties. Peripherally disulfonated BODIPY photocages are cell impermeable, making them useful for modulation of cell-surface receptors, while monosulfonated BODIPY retains the ability to cross the cellular membrane and can modulate intracellular targets. This new approach is generalizable for controlling BODIPY localization and was validated by sensitization of mammalian cells and neurons by visible-light photoactivation of signaling molecules.

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

“… 809 Stronger EWGs such as aldehydes or sulfonates in the 2,6-positions substantially raised the barrier to C–O bond heterolysis on the triplet surface of 144 and thus impeded photorelease. 811 For example, the calculated C–O bond (heterolytic) dissociation energies for derivatives of 144 bearing 2,6-disulfonate, -dihydrogen, and -diethyl substituents were 18.9, 15.7, and 13.5 kcal mol –1 , respectively, with photouncaging quantum yields of 0, 0.6 × 10 –4 and 3.9 × 10 –4 , respectively. 811 The absence of the 1,7-methyl groups reduced Φ r by a factor of ∼1.5, probably due to a reduced electron density in the BODIPY core and thus a reduced capacity to stabilize the putative cationic diradical intermediate.…”

“… 803 Weinstain and co-workers introduced a protecting-group-free, late-stage functionalization of meso -methyl BODIPYs that enabled their targeting to specific cellular organelles 805 and the development of water-soluble derivatives. 811 Other notable applications include the selective photorelease of the protonophore 2,4-dinitrophenol in mitochondria and the protein synthesis inhibitor puromycin in the endoplasmic reticulum, 805 as well as the light-dependent delivery of cytotoxic molecules including chlorambucil and a cathepsin B inhibitor (CA-074 816 ) to cells. 804 , 806 In both of the latter cases, the observed cytotoxicity was partly due to photosensitized 1 O 2 generation by the BODIPY PPG.…”

Thiocoumarin Caged Nucleotides: Synthetic Access and Their Photophysical Properties

“…The quest for the development of red-shifted photocages is important to provide better compatibility with biological systems [ 45 , 46 , 47 , 48 ] both in terms of toxicity and penetration depth of the incident light in tissues. The possibility of low-intensity light irradiation, combined with visible light activation and rapid uncaging render thio-DEACM an alternative to the widely used DEACM, when caging of phosphates is required.…”

In the Search for Photocages Cleavable with Visible Light: An Overview of Recent Advances and Chemical Strategies

“…In a more recent example by Miller, Weinstain and coworkers, the cellular permeability of photocages, and consequently their biological activity, was shown to be tunable via the number of incorporated remote sulfonate groups [51] . Using small molecule drugs with a range polarities, their non‐sulfonated derivatives had a range of permeabilities but mostly accumulated intracellularly, while the di‐sulfonated ones were completely cell impermeable.…”