Photoremovable Protecting Groups

Photoremovable Protecting Groups: History

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Photoremovable protecting groups (PPGs) (also often called photocages in the literature) are used for temporary inactivation of biologically active substrates. By photoirradiation the PPG could be cleaved off and the biological activity could be restored on-demand, with a high spatiotemporal precision. The on-site liberation of the biologically active substrate could be exploited for studying dynamic biological processes or for designing targeted pharmacological interventions in vitro or in vivo. Several chemical scaffolds have been described and tested as PPGs, operating at different wavelengths. The scope of potential substrates is very broad, spanning from small molecules to proteins. In a wider context, PPGs could be used for the design of various light-responsive materials as well, for diverse applications.

photoremovable protecting groups
photocages
photoactivation
uncaging
two-photon irradiation
drug delivery

Gaining spatiotemporal control over drug action or biological functions in a broader sense is a long sought for goal for therapeutic or experimental interventions. Thus, dynamic functions could be studied in vivo with high precision, ideally on a timescale relevant for the process studied, or in a clinical setting, deleterious side effects could be avoided or minimized. A possible approach towards this goal is to use materials/systems responding to a specific internal or external stimulus ^[1]. Chemical, physical and biological stimuli (e.g., pH, enzymes, ionic microenvironment, temperature, ultrasound, magnetic field, light) have been addressed in this respect. Of the various external stimuli, light has several potential benefits ^[2]. At appropriate wavelengths, phototoxicity could be avoided and light could be considered bioorthogonal (i.e., not interfering with biological signals or functioning). The light pulse can be precisely tuned in its duration and intensity and, with this external stimulus, extracellular regions or intracellular compartments could be selectively addressed, as necessary ^[3]. Moreover, the external activation is independent of the microenvironment vs. the case of endogenous approaches.

The operational mode of photoremovable protecting groups (PPGs, often referred to in the literature with the illustrative (photo)cage name, expressing the concept of the biological activity being trapped, although the term photolabile/photosensitive/photocleavable (protecting group) are also in use) is to temporarily inactivate the biological action of a given agent by linking a PPG to it. The action could be restored on-demand following a photoactivation step: the cleavage of the PPG via the dissociation of a covalent bond and the liberation of the parent biologically active compound (Figure 1). The activation step in the case of PPGs is typically a one-way, irreversible process ^[4]. (A reversible process, based on photoisomerisation occurs in the case of the so-called photoswitches ^[5]. The field of photoswitches—also referred to as photopharmacology—has seen a considerable expansion in the last decade with more elaborate applications emerging ^[6]^[7] that are, however, beyond the scope of the present entry). The relative simplicity of the PPG approach has its benefits, e.g., in terms of design, as the properties of an already optimized active agent could be further modified via a PPG linked to it. However, the approach has its limits as well, such as the on-site release of the PPG in stoichiometric amounts, the irreversibility of the process allowing only a one-time activation protocol, or the potential unwanted effects caused by the parent effector molecules upon diffusion from the intended site of action.

Figure 1. A simplified overview of the operation of PPGs for the release of biologically active substrates (adapted from Korzycka et al. ^[8] and Piant et al. ^[9]).

The application of PPGs in the biological context dates back to the 1970s, to the first studies of Engels and Schlaeger and Kaplan et al. with caged cAMP and ATP ^[10]^[11], following an earlier report by Barltrop and Schofield on the photorelease of glycine (Figure 2) ^[12]. Although the present paper will focus on the biological applications of PPGs, synthetic applications (although relatively less common in the literature vs. the biological ones) could also be envisaged ^[13]^[14]. A deprotection step carried out under mild conditions and not requiring an additional reagent (i.e., light acting as a traceless reagent) is of considerable interest also for designing a (more complex/multi-step) synthesis pathway.

Figure 2. First applications of PPGs for biologically active substrates: glycine ^[12], cAMP ^[10] and ATP ^[11].

This entry is adapted from the peer-reviewed paper 10.3390/encyclopedia2030082

References

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Engels, J.; Schlaeger, E.J. Synthesis, structure, and reactivity of adenosine cyclic 3′,5′-phosphate-benzyltriesters. J. Med. Chem. 1977, 20, 907–911.
Kaplan, J.H.; Forbush, I.B.; Hoffman, J.F. Rapid photolytic release of adenosine 5′-triphosphate from a protected analog: Utilization by the sodium:potassium pump of human red blood cell ghosts. Biochemistry 1978, 17, 1929–1935.
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Kessler, M.; Glatthar, R.; Giese, B.; Bochet, C.G. Sequentially Photocleavable Protecting Groups in Solid-Phase Synthesis. Org. Lett. 2003, 5, 1179–1181.

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