ArticleCommunications chemistry2024
Ortho-functionalized pyridinyl-tetrazines break the inverse correlation between click reactivity and cleavage yields in click-to-release chemistry.
Article in Communications chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 7 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed.
- Organelle-Resolved Tetrazine-trans-Cyclooctene Click Chemistry for Cargo Delivery and Release.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- Bioorthogonal Activation of Protein Function through a retro-Cope/Cope Elimination Cascade.Journal of the American Chemical Society · 2026Article
- Click-to-Release Reactions for Tertiary Amines and Pyridines.Journal of the American Chemical Society · 2026Article
- Coumarin-Based Photolabile Solid Support Facilitates Nonchromatographic Purification of RNA Oligonucleotides.The Journal of organic chemistry · 2025Article
- Precision delivery of estrogen receptor antagonists using bioorthogonal chemistry-based intelligent nanocarriers to overcome cervical cancer drug resistance.Materials today. Bio · 2025Review
- Covalent chemical probes.Communications chemistry · 2025Article
- Scission-Enhanced Molecular Imaging (SEMI).Bioconjugate chemistry · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene(TCO)-linked payloads has strong potential for widespread use in drug delivery and in particular in click-cleavable antibody-drug conjugates (ADCs). However, clinical translation is hampered by an inverse correlation between click reactivity and payload release yield, requiring high doses of less reactive tetrazines to drive in vivo TCO reactions and payload release to completion. Herein we report that the cause for the low release when using the highly reactive bis-(2-pyridinyl)-tetrazine is the stability of the initially formed 4,5-dihydropyridazine product, precluding tautomerization to the releasing 1,4-dihydropyridazine tautomer. We demonstrate that efficient tautomerization and payload elimination can be achieved by ortho-substituting bis-pyridinyl-tetrazines with hydrogen-bonding hydroxyl or amido groups, achieving a.o. release yields of 96% with 18-fold more reactive tetrazines. Applied to on-tumor activation of a click-cleavable ADC in mice, these tetrazines afforded near-quantitative ADC conversion at a ca. 10- to 20-fold lower dose than what was previously needed, resulting in a strong therapeutic response.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.