Structure Activity Relationship for Meso-Substituted BODIPY Photocages and Tuning Water Solubility and Cell Permeability

Photocaging is an efficient, non-invasive and precise method to control the biological activity of small- and macro-molecules in biological environment with high spatio-temporal resolution. However, most caging groups available that operate by one-photon are excited with highly energetic UV light. This results in potential tissue damage, limits tissue penetration and restricts the wavelength-window available for activation of multiple cues.

Recently, we¹ and others², introduced a novel photocage, excitable in the visible light range, based on the boron-dipyrromethene (BODIPY) core. In order for BODIPY cages to become more practical and functional for biological applications, two main issues need to be addressed; improving the photoreaction efficiency and fine-tuning the structure’s biological properties. To address the first issue, we’ve initiated a collaboration with the Klan and Winter labs. By systematically investigating the structure-activity relationship (SAR) in >30 BODIPY derivatives, we identified two structural motifs, namely 2,6-dihalogenation and boron alkylation, which enabled improvement of the photoreaction’s efficiency by over two orders over magnitude, reaching 70% efficiency under aerated conditions³.

To address the second issue, we’ve synthesized BODIPY cages bearing one or two 2-mercaptoethane sulfonate (mesna) units. Thus, we were able to markedly improve their water solubility and generate derivatives that either penetrate cells or are retained outside. The effectiveness of cell-impermeable BODIPY cages is now being investigated by applying them to cage neurotransmitters and evaluating them in cultured neurons.

References:

1) Rubinstein, N.; Liu, P.; Miller, E. W.; Weinstain, R. Chem. Commun. 2015, 51, 6369-6372.

2) Goswami, P. P.; Syed, A.; Beck, C. L.; Albright, T. R.; Mahoney, K. M.; Unash, R.; Smith, E. A.; Winter, A. H. J. Am. Chem. Soc. 2015, 137, 3783-3786.

3) Slanina, T.; Shrestha, P.; Palao, E.; Kand, D.; Peterson, A.; Dutton, A.; Rubinstein, N.; Weinstain, R.; Winter, A.; Klán, P. J. Am. Chem. Soc. 2017,139, 15168–15175.