Isomeric triazines exhibit unique profiles of bioorthogonal reactivity

Abstract

Isomeric triazines can be tuned to exhibit unique reaction profiles with biocompatible strained alkenes and alkynes.

The Collective Power of Genetically Encoded Protein/Peptide Tags and Bioorthogonal Chemistry in Biological Fluorescence Imaging

“…For example, 1,2,4‐triazine reacts with TCO with an adequate rate but not with NB or CYP [139] . Furthermore, 5‐ and 6‐substituted 1,2,4‐triazines (Figure 11c) and Tz have different reactivity profiles, [140] which opens up the possibility of running non‐interfering, i. e., orthogonal, cycloaddition reactions in parallel. For instance, the pair of 5‐substituted‐1,2,4‐triazine and thiacycloheptyne (TMTH in Figure 9a) could work together with the pair of Tz and CYP to achieve “orthogonal and bioorthogonal” conjugations [140] .…”

“…Furthermore, 5‐ and 6‐substituted 1,2,4‐triazines (Figure 11c) and Tz have different reactivity profiles, [140] which opens up the possibility of running non‐interfering, i. e., orthogonal, cycloaddition reactions in parallel. For instance, the pair of 5‐substituted‐1,2,4‐triazine and thiacycloheptyne (TMTH in Figure 9a) could work together with the pair of Tz and CYP to achieve “orthogonal and bioorthogonal” conjugations [140] . Another diene with bioorthogonal potential is o ‐quinone (Figure 11c), which is produced via in situ oxidation (e. g., by using NaIO 4 ) of a catechol [141] .…”

Readily Accessible Ambiphilic Cyclopentadienes for Bioorthogonal Labeling

“…3 Cyclooctynes (CO), 16 norbornenes (NB), 20 and cyclopropenes (1,3-CP) 21,22 have been paired with tetrazines when a more stable dienophile is required, but these reactions are considerably slower (Scheme 2). Bulky dienophiles, such as 3,3-disubstituted cyclopropenes (3,3-CP) 23 and 3,3,6,6-tetramethylthiacycloheptynes (TMTH), 24 react poorly with tetrazines. These bulky dienophiles react with azides and allow for tandem labeling studies with tetrazine− trans -cyclooctene reactions for multitarget imaging.…”

Iridium(iii) complexes of 1,2,4-triazines as potential bioorthogonal reagents: metal coordination facilitates luminogenic reaction with strained cyclooctynes

“…Recently, 1,2,4-triazines have been reported as potential bioorthogonal reagents offering excellent stability. [4][5][6][7][8][9][10][11] Unfortunately, 1,2,4-triazines react much slower in IEDDA reactions. Although it has been shown that the kinetics can be improved by the introduction of electronwithdrawing groups, 9,10 the rate constant is two-three orders of magnitude lower than for tetrazines.…”

“…Additional motivation for the use of isomer 1 is that 5-substituted 1,2,4-triazines are the least sterically crowded and able to react even with sterically encumbered strained alkynes such as tetramethylthiacycloheptyne (TMTH). 5 To prepare the ligand 1, we first tested the most direct route by reacting 2-pyridineglyoxal 4 with formamidrazone 24 but unfortunately, the reaction gave a mixture of two isomers 1 and 3 that we could not separate either by recrystallization, or by column chromatography. We therefore used another synthetic route, depicted in Scheme 1.…”