Photoremovable Protecting Groups: Across the Light Spectrum to Near-Infrared Absorbing Photocages

Abstract

We discuss the past decade of progress in the field of photoremovable protecting groups that allowed the development of photocages activatable by near-IR light and highlight the individual conceptual advancements that lead to general guidelines to design new such photoremovable protecting groups. We emphasize the importance of understanding the individual photochemical reaction mechanisms that was necessary to achieve this progress and provide an outlook of the subsequent steps to facilitate a swift translation of this research into clinical praxis. Since this issue of CHIMIA is dedicated to the late Prof. Thomas Bally, we decided to provide a personal perspective on the field to which he contributed himself. We tried to write this review with the general readership of CHIMIA in mind in a hope to pay a tribute to the extraordinary dedication and clarity with which Thomas Bally used to explain abstract chemical concepts to his students or colleagues. We are uncertain whether we matched such challenge but we believe that he would have liked such approach very much.

Computational Design, Synthesis, and Photochemistry of Cy7‐PPG, an Efficient NIR‐Activated Photolabile Protecting Group for Therapeutic Applications**

“…the phototoxic sensitization of triplet oxygen to singlet oxygen from T 1 , or ion pair recombination) are analogously shown in red. Strategies toward efficient NIR‐PPGs should therefore strive to minimize the sum of all these unproductive photochemical processes [12] . After PL heterolysis, successful interception of the PPG cation commonly takes place by the solvent.…”

“…Cy7‐PPG is also soluble in aqueous media at pharmacological concentrations. Furthermore our redesign of Cy7 into Cy7‐PPG has ablated two photochemical pathways that are seen as less‐than‐desirable in PPGs: i) fluorescence, which competes with payload heterolysis; and ii) oxygen sensitization, a process that results in PPG phototoxicity [12] . Cy7‐PPG is thus a NIR‐photocage system whose release mechanism is entirely uncoupled from singlet oxygen phototoxicity.…”

“…Beyond its absorbance, the ideal PPG must uncage efficiently (i.e. the product of its molar extinction coefficient and its uncaging quantum yield, ϵ×Φ het >100 M −1 cm −1 ), [12] and be both soluble and non‐toxic to the tissue (Figure 1c). For uncaging to occur without phototoxicity and to allow for PL release in a wide range of biological targets, including hypoxic tissues such as solid tumors, or even bacterial biofilms, the PL release mechanism should be independent of the presence of oxygen [19, 20] …”

“…However, these red‐shifting strategies employed are not without their downsides. Red‐shifting PPGs typically involves extending the conjugation of their chromophore, which results in: i) loss of PPG solubility in water due to increased lipophilicity; and ii) decreased uncaging quantum yield (Φ het ) [10–12, 22–24] . Beyond being an inherently uphill battle, red‐shifting strategies suffer from a multi‐parameter “hydra paradox” since improvement towards one ideal property often leads to diminished progress towards another ideal property [12] …”

A Strategy for Engineering High Photolysis Efficiency of Photocleavable Protecting Groups Through Cation Stabilization

“…[14,[17][18][19]26,27] However, in most cases, high ε at long irradiation wavelengths was achieved at the expense of photochemical QY, negatively affecting the overall efficiency of these PPGs. [20] Few exceptions to this trend often rely on the introduction of extended π-systems with strongly electron-donating moieties into the PPG structure, yet these strategies come at a great synthetic step cost and the flat, extended π-systems suffer from low aqueous solubility, restricting their use in photopharmacology. [28,29] Here, we present a rational strategy for increasing PPG efficiency, hinging on detailed investigation into the important factors that determine PPG QYs.…”