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ToolsWallace, Matthew, Sharpe, James M., Baj, Krzysztof, Ngwube, Michael, Thirlway, Jenny, Kerigan Higgs, Patrick L., Stephenson, G. Richard, Iggo, Jonathan A., Storr, Thomas E. and Richards, Christopher J. (2025) Programmable wide-range pH gradients for NMR titrations: Application to antibody–drug conjugate linker group modifications. Analyst, 150 (13). pp. 2872-2879. ISSN 0003-2654
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Abstract
We generate pH gradients spanning more than six units in standard NMR tubes and determine all the pKa values of polyprotic compounds in single 20 minutes chemical shift imaging (CSI) NMR experiments. The modest demands of our method in terms of sample quantity and preparation time allow it be performed as part of the routine characterisation and optimisation of organic molecules during synthesis campaigns. As proof of concept, we measure the pKa values of a family of vinylpyridines employed as antibody drug conjugate linkers. Our analysis reveals a strong correlation between the experimental aqueous pKa and the rate of conjugate addition of thiol nucleophiles to the vinyl group, representing a powerful predictive method.
| Item Type: | Article |
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| Additional Information: | Data availability: Additional data supporting this article (experimental procedures, synthetic details, stacked NMR plots) are available in the ESI. A spreadsheet for prediction of pH gradients and processing of CSI data is also provided as ESI. Raw CSI data files will be openly available at: https://research-portal.uea.ac.uk/en/datasets/. Acknowledgements: MW thanks UKRI for a Future Leaders Fellowship (MR/T044020/1) and the Royal Commission for the Exhibition of 1851 for a Research Fellowship. Iksuda Therapeutics Ltd and the MRC are acknowledged for funding (JS). KB thanks AstraZeneca (Grant 10045297) and the University of Liverpool for financial support. We are grateful for use of the University of East Anglia (UEA) Faculty of Science NMR facility. We thank Schrödinger for a trial licence of their Small Molecule Drug Discovery Suite. We thank Mestrelab Research S.L. for technical advice and the gift of a software license for Mnova 14.2. |
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology Faculty of Science > School of Chemistry (former - to 2024) |
| UEA Research Groups: | Faculty of Science > Research Groups > Pharmaceutical Materials and Soft Matter Faculty of Science > Research Groups > Chemistry of Materials and Catalysis |
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| Depositing User: | LivePure Connector |
| Date Deposited: | 10 Jun 2025 13:30 |
| Last Modified: | 07 Jul 2025 03:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/99433 |
| DOI: | 10.1039/D5AN00406C |
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