Inclusion of trans-resveratrol in methylated cyclodextrins: synthesis and solid-state structures.

Lee Trollope,Mino R Caira,Susan A Bourne,Dyanne L Cruickshank,Milena Sorrenti,Terence Noonan,Laura Catenacci

doi:10.3762/bjoc.10.331

Abstract

The phytoalexin trans-resveratrol, 5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol, is a well-known, potent antioxidant having a variety of possible biomedical applications. However, its adverse physicochemical properties (low stability, poor aqueous solubility) limit such applications and its inclusion in cyclodextrins (CDs) has potential for addressing these shortcomings. Here, various methods of the attempted synthesis of inclusion complexes between trans-resveratrol and three methylated cyclodextrins (permethylated α-CD, permethylated β-CD and 2,6-dimethylated β-CD) are described. Isolation of the corresponding crystalline 1:1 inclusion compounds enabled their full structure determination by X-ray analysis for the first time, revealing a variety of guest inclusion modes and unique supramolecular crystal packing motifs. The three crystalline inclusion complexes were also fully characterized by thermal analysis (hot stage microscopy, thermogravimetric analysis and differential scanning calorimetry). To complement the solid-state data, phase-solubility studies were conducted using a series of CDs (native and variously derivatised) to establish their effect on the aqueous solubility of trans-resveratrol and to estimate association constants for complex formation.

Highlights

The naturally occurring phytoalexin trans-resveratrol (5-[(1E)2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol; trans-3,5,4′trihydroxystilbene, RSV) (1, Figure 1), is a triphenolic species which is known to have potent antioxidant activity and a wide range of pharmacological activities [1,2]
It was ascertained that the kneading treatment (KN) and exposure to irradiation with microwave radiation (MW) had no significant effect on RSV. (Further experimental data on this aspect and all other methods employed in this study are provided in Supporting Information File 1)
For the MW product, no RSV was evident in the powder X-ray diffraction (PXRD) pattern and solid-state interaction between the inclusion complex between permethylated β-CD (TMB) and RSV was further confirmed from the Fourier-transform Infrared (FTIR) spectrum, which showed several peaks displaced to slightly higher wavenumbers

Summary

Introduction

The naturally occurring phytoalexin trans-resveratrol (5-[(1E)2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol; trans-3,5,4′trihydroxystilbene, RSV) (1, Figure 1), is a triphenolic species which is known to have potent antioxidant activity and a wide range of pharmacological activities [1,2]. Since a primary application of CDs is enhancement of the solubility of poorly soluble guest molecules [6], phase solubility studies [11] were conducted, and the results, including estimates of complex formation constants, are reported here.

Results

Conclusion