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Determining the Crystal Structures of Peptide Analogs of Boronic Acid in the Absence of Single Crystals: Intricate Motifs of Ixazomib Citrate Revealed by XRPD Guided by ss-NMR

  • Michal Hušák
    Michal Hušák
    Department of Solid State Chemistry, University of Chemistry and Technology, Technicka 5, 166 28 Prague 6, Czech Republic
  • Alexandr Jegorov
    Alexandr Jegorov
    Teva Pharmaceuticals CR, s.r.o., Branisovska 31, 370 05 Ceske Budejovice, Czech Republic
  • Jan Rohlíček
    Jan Rohlíček
    Department of Structural Analysis, Institute of Physics of the Czech Academy of Sciences, Na Slovance 2, Praha 8, 182 21, Czech Republic
  • Andrew Fitch
    Andrew Fitch
    ESRF, The European Synchrotron, CS40220, F-38043 Grenoble Cedex 9, France
    More by Andrew Fitch
  • Jiří Czernek
    Jiří Czernek
    Department of NMR Spectroscopy, Institute of Macromolecular Chemistry CAS, Heyrovsky sq. 2, 162 06 Prague 6, Czech Republic
  • Libor Kobera
    Libor Kobera
    Department of NMR Spectroscopy, Institute of Macromolecular Chemistry CAS, Heyrovsky sq. 2, 162 06 Prague 6, Czech Republic
    More by Libor Kobera
  • , and 
  • Jiří Brus*
    Jiří Brus
    Department of NMR Spectroscopy, Institute of Macromolecular Chemistry CAS, Heyrovsky sq. 2, 162 06 Prague 6, Czech Republic
    *E-mail: [email protected]. Website:
    More by Jiří Brus
Cite this: Cryst. Growth Des. 2018, 18, 6, 3616–3625
Publication Date (Web):April 30, 2018
Copyright © 2018 American Chemical Society

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    Abstract Image

    Uncertainties in the structure determination of peptide analogs of boronic acid, exacerbated by the many coordination modes of boron, represent an obstacle in understanding their role in living organisms and thus also in developing the next generation of anticancer drugs. For that reason, we present here a general experimental-computational strategy allowing structure determination of complex boronic acid derivatives with extensive conformational variability. We demonstrate successful solution of the crystal structures of two nonsolvated polymorphs of ixazomib citrate directly from synchrotron powder diffraction data, which is challenging because the two molecules in the asymmetric unit cell that exhibit 32 degrees of conformational freedom push the limits of current solution procedures. We used a novel two-step Rietveld refinement based on DFT-D restraints to improve information quality derived from powder diffraction data to be comparable with that of single-crystal solutions. NMR crystallography was applied to verify the crystal structures, and the high potential value of using 11B NMR parameters toward the solution of unknown structures was demonstrated. Evolution of 11B–11B double-quantum coherences allows probing of interatomic distances up to 7 Å. Overall, we present an integrated approach that applies several techniques in conjunction to provide otherwise unavailable structural information.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.8b00402.

    • Full-size diffractograms; computational methods; details of calculations of the total energy in vacuo; details of DFT calculations of isotropic chemical shifts; HETCOR spectra peak-assignments aided with DFT calculations; solid-state NMR spectroscopy (PDF)

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    CCDC 18225101822511 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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