Origin of Increased Reactivity in Rhenium-Mediated Cycloadditions of Tetrazines

Turlik, Aneta; Houk, K. N.; Svatunek, Dennis

doi:10.1021/acs.joc.1c01564

Cited by 12 publications

(6 citation statements)

References 46 publications

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“…However, both labeling methods (Cu-mediated 18 F-fluorinartion and direct aliphatic 18 F-labeling) have thus far only been successful for H-Tzs. Bispyridyl scaffolds could not be labeled with Cu-mediated approaches due to the chelating effect of the pyridyl nitrogen [32,35]. Aliphatic labeling was only applied on monosubstituted Tzs [34].…”

Section: Figurementioning

confidence: 99%

“…Bispyridyl Tzs are, however, very appealing subjects to be used for pretargeted experiments (Figure 2). Beside H-Tzs, these structures are the only other structural class that have been successfully applied in vivo [6,[35][36][37][38]. Bispyridyl Tzs have intrinsic high-reaction kinetics and allow for greater flexibility with respect to structural modifications compared to H-Tzs.…”

Section: Figurementioning

confidence: 99%

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Development of 18F-Labeled Bispyridyl Tetrazines for In Vivo Pretargeted PET Imaging

et al. 2022

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Pretargeted PET imaging is an emerging and fast-developing method to monitor immuno-oncology strategies. Currently, tetrazine ligation is considered the most promising bioorthogonal reaction for pretargeting in vivo. Recently, we have developed a method to 18F-label ultrareactive tetrazines by copper-mediated fluorinations. However, bispyridyl tetrazines—one of the most promising structures for in vivo pretargeted applications—were inaccessible using this strategy. We believed that our successful efforts to 18F-label H-tetrazines using low basic labeling conditions could also be used to label bispyridyl tetrazines via aliphatic nucleophilic substitution. Here, we report the first direct 18F-labeling of bispyridyl tetrazines, their optimization for in vivo use, as well as their successful application in pretargeted PET imaging. This strategy resulted in the design of [18F]45, which could be labeled in a satisfactorily radiochemical yield (RCY = 16%), molar activity (Am = 57 GBq/µmol), and high radiochemical purity (RCP > 98%). The [18F]45 displayed a target-to-background ratio comparable to previously successfully applied tracers for pretargeted imaging. This study showed that bispyridyl tetrazines can be developed into pretargeted imaging agents. These structures allow an easy chemical modification of 18F-labeled tetrazines, paving the road toward highly functionalized pretargeting tools. Moreover, bispyridyl tetrazines led to near-instant drug release of iTCO-tetrazine-based ‘click-to-release’ reactions. Consequently, 18F-labeled bispyridyl tetrazines bear the possibility to quantify such release in vivo in the future.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Development of 18F-Labeled Bispyridyl Tetrazines for In Vivo Pretargeted PET Imaging

et al. 2022

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“…Interestingly, also in the related reaction between styrene and [ReCl(CO) 3 {κ 2 N -3-(2-pyridyl)-1,2,4,5-tetrazine}] ( Scheme 1 b), the regioselectivity is driven by a kinetically favorable interaction between the terminal styrene carbon and the less hindered tetrazine carbon ( Scheme 5 c). 22 Despite the low bond polarization of the alkene, if compared to thiocyanate, the transition states are rather asynchronous and the energy difference between them is significant (4.7 kcal·mol –1 ), while the final ortho- or meta-disubstituted dihydropyridazine products are practically isoenergetic.…”

Section: Resultsmentioning

confidence: 99%

Triazine Chalcogenones from Thiocyanate or Selenocyanate Addition to Tetrazine Ligands in Ruthenium Arene Complexes

Bonaldi,

Bortoluzzi,

Zacchini

et al. 2023

Inorg. Chem.

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The chemistry of 1,2,4,5-tetrazines has attracted considerable interest both from a synthetic and applicative standpoint. Recently, regioselective reactions with alkynes and alkenes have been reported to be favored once the tetrazine ring is coordinated to Re(I), Ru(II), and Ir(III) centers. Aiming to further explore the effects of metal coordination, herein, we unveil the unexplored reactivity of tetrazines with chalcogenocyanate anions. Thus, ruthenium(II) tetrazine complexes, [RuCl{κ2 N-3-(2-pyridyl)-6-R-1,2,4,5-tetrazine}(η6-arene)]+ (arene = p-cymene, R = H, [1a]+, R = Me, [1b]+, R = 2-pyridyl, [1c]+; arene = C6Me6, R = H, [1d]+, R = Me, [1e]+; PF6 – salts), reacted quantitatively and in mild conditions with M(ECN) salts (M = Na, K, Bu4N; E = O, S, Se). The addition of thiocyanate or selenocyanate to the tetrazine ligand is regioselective and afforded, via N2 release, 1,2,4-triazine-5-chalcogenone heterocycles, the one with selenium being unprecedented. The novel ruthenium complexes [RuCl{κ2 N-(2-pyridyl)}{triazine chalcogenone}(η6-arene)] 2a–e (sulfur), 3b, 3d, and 3e (selenium) were characterized by analytical (CHNS analyses, conductivity), spectroscopic (IR, multinuclear and two-dimensional (2D) NMR), and spectrometric (electrospray ionization mass spectrometry (ESI-MS)) techniques. According to density functional theory (DFT) calculations, the nucleophilic attack of SCN– on the tetrazine ring is kinetically driven. Compound 2b is selectively and reversibly mono-protonated on the triazine ring by HCl or other strong acids, affording a single tautomer. When reactions of chalcogenocyanates were performed on the 2,2′-bipyridine (bpy) complex [RuCl(bpy)(η6-p-cymene)]+, the chloride substitution products [Ru(ECN)(bpy)(η6-p-cymene)]+ (E = O, [4]+; E = S, [5]+; E = Se, [6]+) were obtained in 82–90% yields (PF6 – salts). Combined spectroscopic data (IR, 1H/13C/77Se NMR) was revealed to be a useful tool to study the linkage isomerism of the chalcogenocyanate ligand in [4–6]+.

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“…Coordination of tetrazine to a transition metal center is found to lower the LUMO level of the tetrazine and increase its reactivity . [11a] Also, coordination of tetrazine to a metal center is known to restrict its motion and weaken its double bonds, which will contribute to a lower transition state energy and induce faster reaction rate, respectively [11b] . Furthermore, ancillary ligands on the metal center are known to play an important role in modulating the IEDDA reaction kinetics of a coordinated tetrazine [11c] .…”

Section: Resultsmentioning

confidence: 99%

Phosphorogenic Iridium(III) bis‐Tetrazine Complexes for Bioorthogonal Peptide Stapling, Bioimaging, Photocytotoxic Applications, and the Construction of Nanosized Hydrogels

et al. 2022

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The dual functionality of 1,2,4,5-tetrazine as a bioorthogonal reactive unit and a luminescence quencher has shaped tetrazine-based probes as attractive candidates for luminogenic labeling of biomolecules in living systems. In this work, three cyclometalated iridium(III) complexes featuring two tetrazine units were synthesized and characterized. Upon photoexcitation, the complexes were non-emissive but displayed up to 3900-fold emission enhancement upon the inverse electron-demand Diels-Alder (IEDDA) [4+2] cycloaddition with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) substrates. The rapid reaction kinetics (k 2 up to 1.47 × 10 4 M À 1 s À 1 ) of the complexes toward BCN substrates allowed effective peptide labeling. The complexes were also applied as live cell bioimaging reagents and photocytotoxic agents. One of the complexes was utilized in the preparation of luminescent nanosized hydrogels that exhibited interesting cargo delivery properties.

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Origin of Increased Reactivity in Rhenium-Mediated Cycloadditions of Tetrazines

Cited by 12 publications

References 46 publications

Development of 18F-Labeled Bispyridyl Tetrazines for In Vivo Pretargeted PET Imaging

Development of 18F-Labeled Bispyridyl Tetrazines for In Vivo Pretargeted PET Imaging

Triazine Chalcogenones from Thiocyanate or Selenocyanate Addition to Tetrazine Ligands in Ruthenium Arene Complexes

Phosphorogenic Iridium(III) bis‐Tetrazine Complexes for Bioorthogonal Peptide Stapling, Bioimaging, Photocytotoxic Applications, and the Construction of Nanosized Hydrogels

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