Abstract:Modified trans-cyclooctenes (TCO) are capable of highly efficient molecular manipulations in biological environments, driven by the bioorthogonal reaction with tetrazines (Tz). The development of click-cleavable TCO has fueled the field of in vivo chemistry and enabled the design of therapeutic strategies that have already started to enter the clinic. A key element for most of these approaches is the implementation of a cleavable TCO linker. So far, only one member of this class has been developed, a compound … Show more
Computational organic chemistry has become a valuable tool in the field of bioorthogonal chemistry, offering insights and aiding in the progression of this branch of chemistry. In this review, I present an overview of computational work in this field, including an exploration of both the primary computational analysis methods used and their application in the main areas of bioorthogonal chemistry: (3 + 2) and [4 + 2] cycloadditions. In the context of (3 + 2) cycloadditions, detailed studies of electronic effects have informed the evolution of cycloalkyne/1,3-dipole cycloadditions. Through computational techniques, researchers have found ways to adjust the electronic structure via hyperconjugation to enhance reactions without compromising stability. For [4 + 2] cycloadditions, methods such as distortion/interaction analysis and energy decomposition analysis have been beneficial, leading to the development of bioorthogonal reactants with improved reactivity and the creation of orthogonal reaction pairs. To conclude, I touch upon the emerging fields of cheminformatics and machine learning, which promise to play a role in future reaction discovery and optimization.
Computational organic chemistry has become a valuable tool in the field of bioorthogonal chemistry, offering insights and aiding in the progression of this branch of chemistry. In this review, I present an overview of computational work in this field, including an exploration of both the primary computational analysis methods used and their application in the main areas of bioorthogonal chemistry: (3 + 2) and [4 + 2] cycloadditions. In the context of (3 + 2) cycloadditions, detailed studies of electronic effects have informed the evolution of cycloalkyne/1,3-dipole cycloadditions. Through computational techniques, researchers have found ways to adjust the electronic structure via hyperconjugation to enhance reactions without compromising stability. For [4 + 2] cycloadditions, methods such as distortion/interaction analysis and energy decomposition analysis have been beneficial, leading to the development of bioorthogonal reactants with improved reactivity and the creation of orthogonal reaction pairs. To conclude, I touch upon the emerging fields of cheminformatics and machine learning, which promise to play a role in future reaction discovery and optimization.
“…We hypothesized that this stereoselective and efficient method could also be used to prepare cleavable sTCO linkers using a syn ‐positioned carboxylic acid substituent on the fused cyclopropane of a bicyclo[6.1.0]non‐2‐ene, forming a five‐ and ten‐, and a seven‐ and eight‐membered bicyclic lactone ring starting from cycloocta‐1,3‐diene and cycloocta‐1,5‐diene, respectively (Schemes 2 and 4). During the completion of this manuscript, Mikula [15] and Rutjes [16] recently published elegant alternative approaches to stereoselective preparation of cleavable d‐TCO and sTCO linkers.…”
An increase in the click‐to‐release reaction rate between cleavable trans‐cyclooctenes (TCO) and tetrazines would be beneficial for drug delivery applications. In this work, we have developed a short and stereoselective synthesis route towards highly reactive sTCOs that serve as cleavable linkers, affording quantitative tetrazine‐triggered payload release. In addition, the fivefold more reactive sTCO exhibited the same in vivo stability as current TCO linkers when used as antibody linkers in circulation in mice.
“…A higher click reaction rate will allow a lower dose of the activator, facilitating clinical translation. Recently, the groups of Mikula, Rutjes and our group reported approaches to increase reaction kinetics of systems using the less reactive tetrazines by increasing the ring strain of the TCO linker through cis-fusion of a 3-or 5-membered ring [23][24][25] . However, further reactivity increases using this approach would likely impact TCO stability and thereby the application scope 26 .…”
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 ADCs, but clinical translation is hampered by an inverse correlation between click reactivity and payload release yield. This requires the use of high doses of relatively less reactive tetrazines to drive in vivo TCO reactions to completion and achieve sufficient payload release. Herein we report that the main 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, thereby 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, the new 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.
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