Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions
The recently developed compound, tetramethylthiocycloheptyne sulfoximine (TMTHSI), has shown to be a promising strained alkyne for strain-promoted azide–alkyne cycloaddition (SPAAC), metal-free click chemistry. This research explores the properties of TMTHSI-based compounds via three aspects: (1) la...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/8/1155 |
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| author | Matt Timmers Andi Kipper Raphael Frey Stef Notermans Maksym Voievudskyi Claire Wilson Nina Hentzen Michael Ringle Clara Bovino Bernhard Stump Cristianne J. F. Rijcken Tina Vermonden Ingrid Dijkgraaf Rob Liskamp |
| author_facet | Matt Timmers Andi Kipper Raphael Frey Stef Notermans Maksym Voievudskyi Claire Wilson Nina Hentzen Michael Ringle Clara Bovino Bernhard Stump Cristianne J. F. Rijcken Tina Vermonden Ingrid Dijkgraaf Rob Liskamp |
| author_sort | Matt Timmers |
| collection | DOAJ |
| description | The recently developed compound, tetramethylthiocycloheptyne sulfoximine (TMTHSI), has shown to be a promising strained alkyne for strain-promoted azide–alkyne cycloaddition (SPAAC), metal-free click chemistry. This research explores the properties of TMTHSI-based compounds via three aspects: (1) large-scale production, (2) unique stability in acidic conditions and its subsequent use in peptide synthesis, and (3) the functionalization of antibodies. Here, it is shown that (1) scale-up is achieved on a scale of up to 100 g. (2) TMTHSI is remarkably stable against TFA allowing for the site-specific functionalization of peptides on resin. Finally, (3) the functionalization of an antibody with a model payload is very efficient, with antibody conjugation demonstrating more beneficial features such as a high yield and limited hydrophobicity as compared to other alkyne reagent conjugates. These results illustrate the high potential of TMTHSI for diverse bioconjugation applications, with production already being GMP-compatible and a highly efficient conversion resulting in attractive costs of goods. |
| first_indexed | 2024-03-10T23:39:46Z |
| format | Article |
| id | doaj.art-9da70c47b33e40b898bbaddea38432fe |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T23:39:46Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-9da70c47b33e40b898bbaddea38432fe2023-11-19T02:34:53ZengMDPI AGPharmaceuticals1424-82472023-08-01168115510.3390/ph16081155Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition ReactionsMatt Timmers0Andi Kipper1Raphael Frey2Stef Notermans3Maksym Voievudskyi4Claire Wilson5Nina Hentzen6Michael Ringle7Clara Bovino8Bernhard Stump9Cristianne J. F. Rijcken10Tina Vermonden11Ingrid Dijkgraaf12Rob Liskamp13Cristal Therapeutics, 6229 EV Maastricht, The NetherlandsTBD Pharmatech, 50410 Tartu, EstoniaLonza AG, Bioconjugates Development, Rottenstr., 3930 Visp, SwitzerlandDepartment of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The NetherlandsTBD Pharmatech, 50410 Tartu, EstoniaSchool of Chemistry, University of Glasgow, Glasgow G12 8QQ, UKLonza AG, Bioconjugates Development, Rottenstr., 3930 Visp, SwitzerlandLonza AG, Bioconjugates Development, Rottenstr., 3930 Visp, SwitzerlandLonza AG, Bioconjugates Development, Rottenstr., 3930 Visp, SwitzerlandLonza AG, Bioconjugates Development, Rottenstr., 3930 Visp, SwitzerlandCristal Therapeutics, 6229 EV Maastricht, The NetherlandsDepartment of Pharmaceutics, Utrecht Institute for Pharmaceutic Sciences, Utrecht University, 3584 CG Utrecht, The NetherlandsDepartment of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The NetherlandsCristal Therapeutics, 6229 EV Maastricht, The NetherlandsThe recently developed compound, tetramethylthiocycloheptyne sulfoximine (TMTHSI), has shown to be a promising strained alkyne for strain-promoted azide–alkyne cycloaddition (SPAAC), metal-free click chemistry. This research explores the properties of TMTHSI-based compounds via three aspects: (1) large-scale production, (2) unique stability in acidic conditions and its subsequent use in peptide synthesis, and (3) the functionalization of antibodies. Here, it is shown that (1) scale-up is achieved on a scale of up to 100 g. (2) TMTHSI is remarkably stable against TFA allowing for the site-specific functionalization of peptides on resin. Finally, (3) the functionalization of an antibody with a model payload is very efficient, with antibody conjugation demonstrating more beneficial features such as a high yield and limited hydrophobicity as compared to other alkyne reagent conjugates. These results illustrate the high potential of TMTHSI for diverse bioconjugation applications, with production already being GMP-compatible and a highly efficient conversion resulting in attractive costs of goods.https://www.mdpi.com/1424-8247/16/8/1155SPAACclick chemistrystabilitybio-orthogonal chemistrybioconjugation |
| spellingShingle | Matt Timmers Andi Kipper Raphael Frey Stef Notermans Maksym Voievudskyi Claire Wilson Nina Hentzen Michael Ringle Clara Bovino Bernhard Stump Cristianne J. F. Rijcken Tina Vermonden Ingrid Dijkgraaf Rob Liskamp Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions Pharmaceuticals SPAAC click chemistry stability bio-orthogonal chemistry bioconjugation |
| title | Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions |
| title_full | Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions |
| title_fullStr | Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions |
| title_full_unstemmed | Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions |
| title_short | Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions |
| title_sort | exploring the chemical properties and medicinal applications of tetramethylthiocycloheptyne sulfoximine used in strain promoted azide alkyne cycloaddition reactions |
| topic | SPAAC click chemistry stability bio-orthogonal chemistry bioconjugation |
| url | https://www.mdpi.com/1424-8247/16/8/1155 |
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