Inclusion of Hydroxycinnamic Acids in Methylated Cyclodextrins: Host-Guest Interactions and Effects on Guest Thermal Stability

Lee E. Hunt,Susan A. Bourne,Mino R. Caira

doi:10.3390/biom11010045

Abstract

There is ongoing interest in exploiting the antioxidant activity and other medicinal properties of natural monophenolic/polyphenolic compounds, but their generally low aqueous solubility limits their applications. Numerous studies have been undertaken to solubilize such compounds via supramolecular derivatization with co-crystal formation with biocompatible coformer molecules and cyclodextrin (CD) complexation being two successful approaches. In this study, eight new crystalline products obtained by complexation between methylated cyclodextrins and the bioactive phenolic acids (ferulic, hydroferulic, caffeic, and p-coumaric acids) were investigated using thermal analysis (hot stage microscopy, thermogravimetry, differential scanning calorimetry) and X-ray diffraction. All of the complexes crystallized as ternary systems containing the host CD, a phenolic acid guest, and water. On heating each complex, the primary thermal events were dehydration and liberation of the respective phenolic acid component, the mass loss for the latter step enabling determination of the host-guest stoichiometry. Systematic examination of the X-ray crystal structures of the eight complexes enabled their classification according to the extent of inclusion of each guest molecule within the cavity of its respective CD molecule. This revealed three CD inclusion compounds with full guest encapsulation, three with partial guest inclusion, and two that belong to the rare class of ‘non-inclusion’ compounds.

Highlights

The present study is a sequel to our earlier investigation [1] of the feasibility of using cyclodextrins (CDs, toroidal macrocyclic oligosaccharides with a hydrophobic central cavity and peripheral hydroxyl groups that render these molecules water soluble) to form inclusion complexes with the naturally occurring triphenolic compound trans-resveratrol (5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol), widely known as a potent antioxidant with inter alia anti-carcinogenic and cardioprotective properties [2,3,4]
Of the six bioactive phenolic acids selected as potential guest compounds for inclusion in the methylated cyclodextrins three CD hosts permethylated α-CD (TMA), TMB, and DMB, only ferulic acid (FA), caffeic acid (CAF), p-coumaric acid (PCA), and HFA yielded complexes via the common procedure employed for their synthesis
These complexes were identified as TMB·HFA, TMB·PCA, TMA·PCA, DMB·HFA, DMB·PCA, and TMA·FA with 1:1 host-guest stoichiometries, and DMB·FA and DMB·CAF with 2:1 host-guest stoichiometries

Summary

Introduction

The present study is a sequel to our earlier investigation [1] of the feasibility of using cyclodextrins (CDs, toroidal macrocyclic oligosaccharides with a hydrophobic central cavity and peripheral hydroxyl groups that render these molecules water soluble) to form inclusion complexes with the naturally occurring triphenolic compound trans-resveratrol (5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol), widely known as a potent antioxidant with inter alia anti-carcinogenic and cardioprotective properties [2,3,4]. As there have been no previous reports providing structural information for solid CD complexes of RSV in the literature, it was of interest to attempt to crystallize the target CD·RSV complexes and use X-ray diffraction to establish the nature of host-guest interactions and the detailed mode of inclusion of the RSV molecule in the CD cavity. The study revealed that crystalline inclusion complexes of RSV readily formed with the three CD hosts permethylated α-CD (TMA), permethylated β-CD (TMB), and 2,6-dimethylated β-CD (DMB) via the co-precipitation method. The unique modes of RSV inclusion within the cavities of these host molecules were established for the first time by X-ray diffraction.

Objectives

Methods

Results

Conclusion