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

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Abstract

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; 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 Gibbs energy and enthalpy for this binding reaction, and the results were compared with those of rimantadine with native β-CD.

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Acknowledgements

M.K.G. has an equity interest in, and is a cofounder and scientific advisor of, VeraChem LLC. NMR spectra were collected at the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences NMR Facility.

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  1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0736, USA

    K. Kellett, S. A. Kantonen, B. M. Duggan & M. K. Gilson

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Kellett, K., Kantonen, S.A., Duggan, B.M. et al. Toward Expanded Diversity of Host–Guest Interactions via Synthesis and Characterization of Cyclodextrin Derivatives. J Solution Chem 47, 1597–1608 (2018). https://doi.org/10.1007/s10953-018-0769-1

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