Fast pKa determination for lead optimisation. Application of chemical shift imaging and chemical gradients into analysis of APIs Krzysztof Baj 1 , Alexandra Hindle 2 , Stephen P. Marsden 2 , James Brammer 1 , Nichola Davies 3 , Sylvain Demanze 3 , Matthew Wallace 4 , Jonathan A. Iggo 1 1 University of Liverpool, UK , 2 University of Leeds, UK , 3 Oncology R&D, AstraZeneca, UK , 4 University of East Anglia, UK H Chemical Shift Imaging 1 with a chemical gradient (CSI-CG) provides an efficient, one-shot method for the determination of pKa. 2 This Poster will describe its application to measurements in DMSO-d6 for the purpose of understanding basicity patterns in homologous series of bridged anilines followed by density-functional theory(DFT) geometry optimisation, Figure 1. 3,4 Several pulse sequences for water suppression have been evaluated, and automation routines developed to allow the use of sample changers for high throughput of data acquisition in an industrial setting. 5 Water signals are suppressed using excitation sculpting, while pre-saturation can be used to suppress a second solvent peak if required, Figure 2. That allowed method extension to mixed solvents with zero organic solvent extrapolation and obtaining pKa aq for poorly water-soluble analytes using little material. Employing 19 F would streamline the data processing of particularly complex analytes with very crowded 1 H spectra. This requires the simultaneous acquisition of both 1 H and 19 F images, i.e. a multi-receiver instrument not available to the group. We have, therefore, adopted an alternative approach in which an HFH sandwich is acquired. The pH in each slice of the 19 F-CSI is obtained by interpolation from two 1 H-CSI experiments. Finally, we explore adapting the one-shot method to study pH and solvent-dependent conformational changes. The project's ultimate goal is to provide a tool for measuring multiple structural properties in a function of any variable if the gradient of the latter is obtainable in an NMR tube.
Figure1. Reduced electrostatic potential on bridged anilines free electron pair in homologous series follows the drop in measured pKa value using CSI-CG.
Figure 2. Pulse sequence for double solvent suppression 1 H Chemical Shift Imaging. References 1. P. Trigo-Mourino, C. Merle, M. R. Koos, B. Luy and R. R. Gil, Chemistry, 2013, 19, 7013-7019.M. Wallace, D. J. Adams and J. A. Iggo, Anal. Chem., 2018, 90, 4160-4166. 2. A. D. Bochevarov, E. Harder, T. F. Hughes, J. R.Greenwood, D. A. Braden, D. M. Philipp, D. Rinaldo, M. D. 3. Halls, J. Zhang and R. A. Friesner, Int. J. Quantum Chem. 2013, 113, 2110-2142; Schrödinger Release 2023-1: Maestro, Schrödinger, LLC, New York, NY, 2021. 4. Hindle, A., Baj, K., Iggo, J., Cox, D., Pask, C., Nelson, A., Marsden, S., 2023. Modular Synthesis of Bicyclic Twisted Amides and Anilines. https://doi.org/10.26434/chemrxiv-2023-g1b0dG. Schenck, K. Baj, J. A. Iggo and M. Wallace, Anal. Chem., 2022, DOI: 10.1021/acs.analchem.2c00200.
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