IEDDA: An Attractive Bioorthogonal Reaction for Biomedical Applications

The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide–alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature. However, due to their incomplete biocompatibility and slow kinetics, the inverse-electron demand Diels-Alder (IEDDA) reaction was advanced in 2008 by Blackman et al. as an optimal bioorthogonal reaction. The IEDDA is the fastest bioorthogonal reaction known so far. Its biocompatibility and ideal kinetics are very appealing for pretargeting applications. The use of a trans-cyclooctene (TCO) and a tetrazine (Tz) in the reaction encouraged researchers to study them deeply. It was found that both reagents are sensitive to acidic or basic conditions. Furthermore, TCO is photosensitive and can be isomerized to its cis-conformation via a radical catalyzed reaction. Unfortunately, the cis-conformer is significantly less reactive toward tetrazine than the trans-conformation. Therefore, extensive research has been carried out to optimize both click reagents and to employ the IEDDA bioorthogonal reaction in biomedical applications.     

First Synthesis of 3-Glycopyranosyl-1,2,4-Triazines and Some Cycloadditions Thereof

C-glycopyranosyl derivatives of six-membered heterocycles are scarcely represented in the chemical literature and the title 3-glycopyranosyl-1,2,4-triazines are completely unknown. In this paper, the first synthesis of this compound class is accomplished by the cyclocondensation of C-glycosyl formamidrazones and 1,2-dicarbonyl derivatives. In addition, the synthesis of C-glycopyranosyl 1,2,4-triazin-5(4H)-ones was also carried out by the transformation of the above formamidrazones with α-keto-carboxylic esters. Inverse electron demand Diels–Alder reactions of 3-glycopyranosyl-1,2,4-triazines with a bicyclononyne derivative yielded the corresponding annulated 2-glycopyranosyl pyridines.     

Direct synthesis of tetrazine functionalities on polymer backbones

Tetrazine mediated inverse Electron Demand Diels–Alder Reaction (IEDDA) is an important modification technique due to its high selectivity and super‐fast kinetics. Incorporation of tetrazine moieties on polymer chains requires multistep synthetic pathways and a post‐polymerization step leading to functional polymeric materials. Such approaches involve separate syntheses of polymer and the molecule which will be employed in modification. Herein, we introduce a straightforward synthetic approach for direct synthesis of tetrazine groups on polymers as side chains. As model systems, tetrazine functional poly(N‐isopropylacrylamide)‐and poly(ethylene glycol)‐based polymers from corresponding precursor polymers with nitrile moieties as pendant groups are prepared and IEDDA Click Reaction is achieved with trans‐cyclooctene derivatives. The click reaction is monitored by both NMR and UV–vis spectroscopies. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 673–680     

Mussel-inspired chemistry in producing mechanically robust and bioactive hydrogels as skin dressings

The development of hydrogels as skin dressings demonstrates a great potential in real life applications. To achieve this, the hydrogel has to conquer its natural poor mechanical strength, and to prolong its lifetime, antifatigue and self-healing properties originating from dynamic interactions are also required. As skin dressings, the hydrogel needs to maintain its ductility while pursuing the above mentioned properties. In this work, poly(ethylene glycol) diacrylate is used to produce skin dressings by reinforcing poly(ethylene glycol) diacrylate/alginate double network hydrogels with a crosslinker from mussel-inspired chemistry, which is 3,4-dihydroxy-l-phenylalanine. This crosslinking methodology significantly improved mechanical strength of the hydrogel, with 11,200% increase in compressive failure strength; it endowed the hydrogel with outstanding antifatigue and training strengthening properties that makes its mechanical strength increasing in a 50 cycles compressive test; the hydrogel showed excellent self-healing properties that in rheological characterization; it also displayed enhanced storage modulus after withstanding a shear strain up to 1100%; meanwhile, the hydrogel exhibited extreme ductility with an elastic modulus of only 10.90–16.53 kPa. 3,4-dihydroxy-l-phenylalanine also renders the hydrogel its inherent antioxidant activity, conductivity, and bioadhesiveness. Together with the highly transparent appearance, the hydrogels possess a great potential and practibility in the fields of skin dressings.