Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions

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

doi:10.3390/ph16081155

Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	1155
Journal	Pharmaceuticals
Volume	16
Issue number	8
DOIs	https://doi.org/10.3390/ph16081155
Publication status	Published - Aug 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Funding

Cristal Therapeutics funded large-scale synthesis at TBD Pharmatech. TMTHSI stability and peptide work was part of an academic collaboration between Cristal Therapeutics and Maastricht University. Part of this work on the antibody functionalization using TMTHSI derivatives, including the synthesis of TMTSHI–FITC, was funded and executed by Lonza AG.

Funders	Funder number
Cristal Therapeutics and Maastricht University

Keywords

bio-orthogonal chemistry
bioconjugation
click chemistry
SPAAC
stability

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Cite this

Timmers, M., Kipper, A., Frey, R., Notermans, S., Voievudskyi, M., Wilson, C., Hentzen, N., Ringle, M., Bovino, C., Stump, B., Rijcken, C. J. F., Vermonden, T., Dijkgraaf, I., & Liskamp, R. (2023). Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions. Pharmaceuticals, 16(8), Article 1155. https://doi.org/10.3390/ph16081155

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title = "Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions",

abstract = "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.",

keywords = "bio-orthogonal chemistry, bioconjugation, click chemistry, SPAAC, stability",

author = "Matt Timmers and Andi Kipper and Raphael Frey and Stef Notermans and Maksym Voievudskyi and Claire Wilson and Nina Hentzen and Michael Ringle and Clara Bovino and Bernhard Stump and Rijcken, \{Cristianne J.F.\} and Tina Vermonden and Ingrid Dijkgraaf and Rob Liskamp",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = aug,

doi = "10.3390/ph16081155",

language = "English",

volume = "16",

journal = "Pharmaceuticals",

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Timmers, M, Kipper, A, Frey, R, Notermans, S, Voievudskyi, M, Wilson, C, Hentzen, N, Ringle, M, Bovino, C, Stump, B, Rijcken, CJF, Vermonden, T, Dijkgraaf, I & Liskamp, R 2023, 'Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions', Pharmaceuticals, vol. 16, no. 8, 1155. https://doi.org/10.3390/ph16081155

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T1 - Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions

AU - Timmers, Matt

AU - Kipper, Andi

AU - Frey, Raphael

AU - Notermans, Stef

AU - Voievudskyi, Maksym

AU - Wilson, Claire

AU - Hentzen, Nina

AU - Ringle, Michael

AU - Bovino, Clara

AU - Stump, Bernhard

AU - Rijcken, Cristianne J.F.

AU - Vermonden, Tina

AU - Dijkgraaf, Ingrid

AU - Liskamp, Rob

PY - 2023/8

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N2 - 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.

AB - 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.

KW - bio-orthogonal chemistry

KW - bioconjugation

KW - click chemistry

KW - SPAAC

KW - stability

UR - https://www.scopus.com/pages/publications/85168916297

U2 - 10.3390/ph16081155

DO - 10.3390/ph16081155

M3 - Article

AN - SCOPUS:85168916297

SN - 1424-8247

VL - 16

JO - Pharmaceuticals

JF - Pharmaceuticals

IS - 8

M1 - 1155

ER -

Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions

Abstract

Bibliographical note

Funding

Keywords

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