Communications Chemistry, Год журнала: 2024, Номер 7(1)
Опубликована: Дек. 19, 2024
Язык: Английский
Опубликована: Июнь 26, 2024
The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene(TCO)-linked payloads has strong potential for widespread use in drug delivery and particular click-cleavable ADCs, but clinical translation is hampered by an inverse correlation between click reactivity payload release yield. This requires the high doses relatively less reactive tetrazines to drive vivo TCO reactions completion achieve sufficient release. Herein we report that main cause low when using highly bis-(2-pyridinyl)-tetrazine stability initially formed 4,5-dihydropyridazine product, precluding tautomerization releasing 1,4-dihydropyridazine tautomer. We demonstrate efficient elimination can be achieved ortho-substituting bis-pyridinyl-tetrazines with hydrogen-bonding hydroxyl or amido groups, thereby achieving a.o. yields 96 % 18-fold more tetrazines. Applied on-tumor activation a ADC mice, new afforded near-quantitative conversion at ca. 10- 20-fold lower dose than what was previously needed, resulting therapeutic response.
Язык: Английский
Процитировано
1
RSC Advances, Год журнала: 2024, Номер 14(7), С. 4345 - 4351
Опубликована: Янв. 1, 2024
Tetrazines are widely employed reagents in bioorthogonal chemistry, as they react readily with strained alkenes inverse electron demand Diels-Alder reactions, allowing for selective labeling of biomacromolecules. For optimal performance, tetrazine have to alkenes, while remaining inert against nucleophiles like thiols. Balancing these conditions is a challenge, reactivity towards and governed by the same factor - energy unoccupied orbitals tetrazine. Herein, we utilize computational chemistry screen set derivatives, aiming identify structural elements responsible better ratio vs. stability nucleophiles. This advantageous trait present sulfone- sulfoxide-substituted tetrazines. In end, distortion/interaction model helped us that reason behind this enhanced profile secondary orbital interaction between alkene sulfone-/sulfoxide-substituted insight can be used design new tetrazines improved reactivity/stability profiles.
Язык: Английский
Процитировано
1
Опубликована: Май 31, 2024
The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene(TCO)-linked payloads has strong potential for widespread use in drug delivery and particular click-cleavable ADCs, but clinical translation is hampered by an inverse correlation between click reactivity payload release yield. This requires the high doses relatively less reactive tetrazines to drive vivo TCO reactions completion achieve sufficient release. Herein we report that main cause low when using highly bis-(2-pyridinyl)-tetrazine stability initially formed 4,5-dihydropyridazine product, precluding tautomerization releasing 1,4-dihydropyridazine tautomer. We demonstrate efficient elimination can be achieved ortho-substituting bis-pyridinyl-tetrazines with hydrogen-bonding hydroxyl or amido groups, thereby achieving a.o. yields 96 % 18-fold more tetrazines. Applied on-tumor activation a ADC mice, new afforded near-quantitative conversion at ca. 10- 20-fold lower dose than what was previously needed, resulting therapeutic response.
Язык: Английский
Процитировано
1
Опубликована: Авг. 16, 2023
Understanding the geometrical preferences in chemical reactions is crucial for advancing field of organic chemistry and improving synthetic strategies. One such preference, Bürgi-Dunitz angle, central to nucleophilic addition involving carbonyl groups. This study successfully employs a novel two-dimensional Distortion-Interaction/Activation-Strain Model combination with Energy Decomposition Analysis investigate origins angle reaction CN– (CH3)2C=O. We constructed 2D potential energy surface defined by distance between nucleophile carbonylic carbon atom attack followed an in-depth exploration components including strain interaction energy. Our analysis reveals that emerges from delicate balance two key factors: High energy, as result compound distorting avoid Pauli repulsion, encountered at high angles, thus setting upper bound. On other hand, shaped dominant repulsion when angles are lower. work emphasizes value refined tool, offering both quantitative qualitative insights into reactivity selectivity.
Язык: Английский
Процитировано
1
Russian Journal of General Chemistry, Год журнала: 2024, Номер 94(11), С. 2833 - 2840
Опубликована: Ноя. 1, 2024
Язык: Английский
Процитировано
0
Опубликована: Апрель 25, 2024
Bioorthogonal reactions between 1,2,4,5-tetrazines and trans-cyclooctenes have emerged as valuable chemical tools in the fields of biology material science, they hold significant potential for medical applications. The most critical attribute such is their rate. Experimental investigations into reactivity are time-consuming costly. In contrast, computational screenings can rapidly identify reactants that exhibit desired reactivity. this study, we introduce a tool automated screening assesses large pool tetrazines. This effort has produced an initial dataset 1,288 reaction barriers, which be utilized to develop machine learning models.
Язык: Английский
Процитировано
0
Organic Chemistry Frontiers, Год журнала: 2024, Номер 11(21), С. 6159 - 6165
Опубликована: Янв. 1, 2024
A regioselective synthesis of trisubstituted pyridazines from tetrazines and alkynyl sulfides is disclosed. Good transformability sulfur-substituents allowed us to synthesize various pyridazines.
Язык: Английский
Процитировано
0
Bulletin of the Korean Chemical Society, Год журнала: 2024, Номер 45(10), С. 867 - 872
Опубликована: Окт. 1, 2024
Abstract 1,2,4,5‐Tetrazines serve as versatile two‐carbon synthons, essential for synthesizing a variety of (hetero)aromatic compounds. Their specific reactivity with certain dienophiles, without interfering biochemical processes, makes them ideal bioorthogonal ligation. Despite their broad utility, current synthetic methods are costly and raise safety concerns, particularly during scale‐up. This study introduces safer more cost‐effective strategies utilizing zinc chloride or boron trifluoride diethyl etherate catalysts. These alternatives significantly reduce costs enhance safety, potentially expanding the applicability tetrazine synthesis across broader research domains.
Язык: Английский
Процитировано
0
Communications Chemistry, Год журнала: 2024, Номер 7(1)
Опубликована: Дек. 19, 2024
Язык: Английский
Процитировано
0