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Toward Expanded Diversity of Host-Guest Interactions via Synthesis and Characterization of Cyclodextrin Derivatives

preprint
submitted on 11.01.2018 and posted on 12.01.2018 by Kathryn Kellett, Samuel A. Kantonen, Brendan M. Duggan, Michael K. Gilson
Researchers developing software to predict the binding constants of small molecules for proteins have, in recent years, turned to host-guest systems as simple, computationally tractable model systems to test and improve these computational methods. However, taking full advantage of this strategy requires aqueous host-guest systems that probe a greater diversity of chemical interactions. Here, we advance the development of an experimental platform to generate such systems by building on the cyclodextrin (CD) class of hosts. The secondary face derivative mono-3-carboxypropionamido-β-cyclodextrin (CP-β-CD) was synthesized in a one-pot strategy with 87% yield, and proved to have much greater aqueous solubility than native β-CD. The complexation of anionic CP-β-CD with the cationic drug rimantadine hydrochloride was explored using one and two-dimensional nuclear magnetic resonance (NMR); NOESY analysis showed secondary face binding of the ammonium moiety of the guest, based on cross-correlations between the amic acid functionality and the side-chain of rimantadine. Isothermal titration calorimetry was furthermore used to determine the standard free energy and enthalpy for this binding reaction, and the results were compared with those of rimantadine with native β-CD.

History

Topic

  • Thermodynamics (Physical Chem.)
  • Physical and Chemical Properties

Email Address of Submitting Author

kkellett@ucsd.edu

Email Address(es) for Other Author(s)

mgilson@ucsd.edu, skantone@ucsd.edu, bmduggan@ucsd.edu

Institution

University of California San Diego

Country

United States of America

ORCID For Submitting Author

0000-0001-9618-944X

Declaration of Conflict of Interest

M.K.G. has an equity interest in, and is a cofounder and scientific advisor of VeraChem LLC.

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