Programmable wide-range pH gradients for NMR titrations: application to antibody–drug conjugate linker group modifications
We generate pH gradients spanning more than six units in standard NMR tubes and determine all the p<i>K</i><sub>a</sub> 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 p<i>K</i><sub>a</sub> values of a family of vinylpyridines employed as antibody drug conjugate linkers. Our analysis reveals a strong correlation between the experimental aqueous p<i>K</i><sub>a</sub> and the rate of conjugate addition of thiol nucleophiles to the vinyl group, representing a powerful predictive method.
Authors
- Jonathan A. Iggo (ORCID: https://orcid.org/0000-0001-8070-1226)
- Thomas E. Storr
- G. R. Stephenson (ORCID: https://orcid.org/0000-0003-1487-9178)
- Krzysztof Baj (ORCID: https://orcid.org/0000-0001-9195-4974)
- Patrick L. Higgs (ORCID: https://orcid.org/0000-0003-3481-1496)
- Jody Sharpe
- Matthew Wallace (ORCID: https://orcid.org/0000-0002-5751-1827)
- Christopher J. Richards (ORCID: https://orcid.org/0000-0001-7899-4082)
- Jenny Thirlway
- Michael Ngwube
Institutions
- University of East Anglia (GB)
- University of Liverpool (GB)
- Norwich Research Park (GB)
Publication Details
- Journal
- The Analyst
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d5an00406c
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- AstraZeneca
- UK Research and Innovation
- Royal Commission for the Exhibition of 1851
- University of East Anglia
- Medical Research Council