Table of Contents
The concept of bioorthogonal chemistry was first introduced by Bertozzi and his coworkers which elucidated on the efficiency of a chemical reaction catalyzed by numerous functional groups present in bio systems including oxidants, reductants, electrophiles and nucleophiles amidst having a very minimal impact on the surrounding systems (Hang et al. 2003; Bertozzi 2010). Bioorthogonal chemistry has offered a very valuable connection between chemical biology and organic chemistry that enables biologists in devising tools to understand living systems in new light.
Over the years, numerous strategies have been employed to conjugate the active compound with photolabile groups that serve as protecting groups. Such a conjugation with the protecting groups will result in the active compound to get converted into its latent state by a process known as caging. The photolabile groups can be cleaved under biological conditions to restore their functionality (uncaging) at a selective site based on the application. Despite the fact that these light-sensitive reactions are bioorthogonally driven, their activation and efficiency is highly dependent on the nature of the light source (Meggers and Vo 2015). Consequently, if one aims to bring out such uncaging reactions in places that are not easily accessible by light, strategies other than photochemistry needs to be considered.
Role of Transition Metal Catalysts (TMCs)
TMCs offer a very promising role in bringing about bioorthogonal transformations in living systems that has paved way for their applications in drug delivery, imaging and many other applications (Streu and Meggers 2006; Vçlker and Meggers 2017; Meggers and Vo 2015). Despite their prominent role, the direct use of TMCs is challenged due to limitations in its nature of biocompatibility and low solubility.
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Numerous studies have been done to encapsulate TMCs in nanometric scaffolds like nanoparticles or polymeric assemblies to enhance the biocompatibility and the solubility of these TMCs all the while providing a protective setting for the metal complexes (X. Zhang, R. Huang, S. Gopalakrishnan 2018)
Several studies have been done over the years to identify transition metal complexes that can bring about efficient uncaging reaction within cells.
Palladium-based Complexes
Bradley et. al. pioneered in reporting the first intracellular reactions catalyzed by functionalized polystyrene microspheres with Pd0 nanoparticles that were able to enter the living cells and perform bioorthogonal conversions (Unciti-broceta et al. 2012). In a similar study, Chen et. al. identified organopalladium complexes that are air-stable and the absence of any bulky groups allows them to easily enter the cells (Li et al. 2014). In their study, they demonstrated how palladium metal catalysts can cleave a propargyl group protected lysine derivative to release active lysine. Independently non-toxic propargyl group protected uracil and Pd0 microspheres were shown to exhibit anti-proliferative property that was comparable to the active drug used for treatment of pancreatic cancer cells (Weiss et al. 2014).
Ruthenium-based Complexes
Some of the earliest works ruthenium (Ru) as a catalyst came from Streu and Meggers, who reported the ability of the Ru-complexes to be able to cleave allylcarbamate protected amines inside the cells (Streu and Meggers 2006). However, the lower efficiency and TON of catalysis alongside the use of a toxic additive like thiophenol made this approach less suited for further application. Sanchez et. al. studied on the ability of Ru-complexes to carry out bioorthogonal uncaging to control DNA binding (Penas and Eugenio 2014). Recently, Castro et. al. reported on the photocatalytic activation of Ru-based complexes in the presence of FAD and flavoproteins by the generation of singlet oxygen species (SOG) and NADH oxidase (NOX) (Castro et al. 2018).
Although these catalysts show potent activity, one of the greatest challenges in maintaining their catalytic nature is the presence of minimal quantities of thiols that can deactivate the catalysts under highly protic environments.
Iron-based Complexes
Sasmal et. al reported the use of a robust catalyst containing Fe-porphyrin to reduce organic azides to amines (Sasmal et al. 2012). Upon screening of a number of Fe-porphyrin derived complexes, they concluded that Fe-(tetraphenyl porphyrin) chloride, [Fe(TPP)]Cl, was able to easily catalyze the reduction to amines with the same efficiency even in the presence of thiols and highly protic solvents and in biological conditions. Meanwhile, Rotello and his coworkers employed these Fe-based metal complexes to encapsulate them into nanometric scaffolds and contrive nanozymes to perform catalysis similar to naturally occurring enzymes.
