Bioorthogonal chemistry can be defined as a toolbox of reactions that proceed rapidly and selectively in biological environments without reacting with other potential functional groups naturally present among the myriad of biomolecules. Bioorthogonal chemistry not only provides new strategies to control the function of biomolecules in biological environments and in vivo, but it also has a great potential in drug delivery applications with a precision on a molecular-scale level. As a result, bioorthogonal bond-cleavage reactions have gained much attention over the past years. Among all bioorthogonal reactions developed to date, the so called “tetrazine ligation” has become the most widely used one and it is describable as an inverse electron demand Diels-Alder (IEDDA) reaction of 1,2,4,5-tetrazines (Tz) with various dienophiles. The tetrazine-ligation product, obtained by reaction with trans-cyclooctenes modified with a carbamate moiety (release-TCOs, rTCOs), is known to undergo a spontaneous decarboxylative 1,4-elimination of a caged amine upon ligation, and this permitted the design of new diagnostic and therapeutic strategies. In this diploma thesis, the aim is the design of a new class of “molecular scissors” to address current structural limitations in tetrazine/trans-cyclooctene click-to-release chemistry, such as the lack of functional groups on Tz which would allow a further and straightforward modification of these high promising tools. Specifically, a class of sulfonamide-modified tetrazines (saph-Tz) was successfully developed and it surprisingly enabled complete bioorthogonal bond-cleavage, despite the aryl-substituent on the Tz. To conclude, click kinetics and release efficiency of this new class of Tz were characterized. Additionally, the cytotoxicity of a prodrug and its bioorthogonal activation by reaction with a saph-Tz were investigated.

Bioorthogonal chemistry can be defined as a toolbox of reactions that proceed rapidly and selectively in biological environments without reacting with other potential functional groups naturally present among the myriad of biomolecules. Bioorthogonal chemistry not only provides new strategies to control the function of biomolecules in biological environments and in vivo, but it also has a great potential in drug delivery applications with a precision on a molecular-scale level. As a result, bioorthogonal bond-cleavage reactions have gained much attention over the past years. Among all bioorthogonal reactions developed to date, the so called “tetrazine ligation” has become the most widely used one and it is describable as an inverse electron demand Diels-Alder (IEDDA) reaction of 1,2,4,5-tetrazines (Tz) with various dienophiles. The tetrazine-ligation product, obtained by reaction with trans-cyclooctenes modified with a carbamate moiety (release-TCOs, rTCOs), is known to undergo a spontaneous decarboxylative 1,4-elimination of a caged amine upon ligation, and this permitted the design of new diagnostic and therapeutic strategies. In this diploma thesis, the aim is the design of a new class of “molecular scissors” to address current structural limitations in tetrazine/trans-cyclooctene click-to-release chemistry, such as the lack of functional groups on Tz which would allow a further and straightforward modification of these high promising tools. Specifically, a class of sulfonamide-modified tetrazines (saph-Tz) was successfully developed and it surprisingly enabled complete bioorthogonal bond-cleavage, despite the aryl-substituent on the Tz. To conclude, click kinetics and release efficiency of this new class of Tz were characterized. Additionally, the cytotoxicity of a prodrug and its bioorthogonal activation by reaction with a saph-Tz were investigated.

Sulfonamide-modified tetrazines as bioorthogonal tools for click-to-release reactions.

YAGHI, FATIMA
2021/2022

Abstract

Bioorthogonal chemistry can be defined as a toolbox of reactions that proceed rapidly and selectively in biological environments without reacting with other potential functional groups naturally present among the myriad of biomolecules. Bioorthogonal chemistry not only provides new strategies to control the function of biomolecules in biological environments and in vivo, but it also has a great potential in drug delivery applications with a precision on a molecular-scale level. As a result, bioorthogonal bond-cleavage reactions have gained much attention over the past years. Among all bioorthogonal reactions developed to date, the so called “tetrazine ligation” has become the most widely used one and it is describable as an inverse electron demand Diels-Alder (IEDDA) reaction of 1,2,4,5-tetrazines (Tz) with various dienophiles. The tetrazine-ligation product, obtained by reaction with trans-cyclooctenes modified with a carbamate moiety (release-TCOs, rTCOs), is known to undergo a spontaneous decarboxylative 1,4-elimination of a caged amine upon ligation, and this permitted the design of new diagnostic and therapeutic strategies. In this diploma thesis, the aim is the design of a new class of “molecular scissors” to address current structural limitations in tetrazine/trans-cyclooctene click-to-release chemistry, such as the lack of functional groups on Tz which would allow a further and straightforward modification of these high promising tools. Specifically, a class of sulfonamide-modified tetrazines (saph-Tz) was successfully developed and it surprisingly enabled complete bioorthogonal bond-cleavage, despite the aryl-substituent on the Tz. To conclude, click kinetics and release efficiency of this new class of Tz were characterized. Additionally, the cytotoxicity of a prodrug and its bioorthogonal activation by reaction with a saph-Tz were investigated.
2021
Sulfonamide-modified tetrazines as bioorthogonal tools for click-to-release reactions.
Bioorthogonal chemistry can be defined as a toolbox of reactions that proceed rapidly and selectively in biological environments without reacting with other potential functional groups naturally present among the myriad of biomolecules. Bioorthogonal chemistry not only provides new strategies to control the function of biomolecules in biological environments and in vivo, but it also has a great potential in drug delivery applications with a precision on a molecular-scale level. As a result, bioorthogonal bond-cleavage reactions have gained much attention over the past years. Among all bioorthogonal reactions developed to date, the so called “tetrazine ligation” has become the most widely used one and it is describable as an inverse electron demand Diels-Alder (IEDDA) reaction of 1,2,4,5-tetrazines (Tz) with various dienophiles. The tetrazine-ligation product, obtained by reaction with trans-cyclooctenes modified with a carbamate moiety (release-TCOs, rTCOs), is known to undergo a spontaneous decarboxylative 1,4-elimination of a caged amine upon ligation, and this permitted the design of new diagnostic and therapeutic strategies. In this diploma thesis, the aim is the design of a new class of “molecular scissors” to address current structural limitations in tetrazine/trans-cyclooctene click-to-release chemistry, such as the lack of functional groups on Tz which would allow a further and straightforward modification of these high promising tools. Specifically, a class of sulfonamide-modified tetrazines (saph-Tz) was successfully developed and it surprisingly enabled complete bioorthogonal bond-cleavage, despite the aryl-substituent on the Tz. To conclude, click kinetics and release efficiency of this new class of Tz were characterized. Additionally, the cytotoxicity of a prodrug and its bioorthogonal activation by reaction with a saph-Tz were investigated.
Click chemistry
Cycloaddition
Elimination
Prodrugs
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12608/37130