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

Abstract

SummaryThe 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.

Inclusion of the Phytoalexin trans-Resveratrol in Native Cyclodextrins: A Thermal, Spectroscopic, and X-Ray Structural Study

“…Predicting whether a given guest molecule will be included within the cavity of a specific CD is challenging due to the current imperfect level of understanding of the complex nature of the molecular interactions involved in the inclusion process, and although computational methods may suggest possible modes of guest inclusion for a given host-guest pair, such modes may be unrealistic if the medium (e.g., liquid/other phase) is not take into account explicitly in the calculations. Our previous study of the reactions between RSV and a series of methylated CDs using analogous preparative methods to those described here resulted in the isolation of its inclusion complexes with permethylated α-CD (TMA), 2,6-dimethyl β-CD (DMB) and permethylated β-CD (TMB) [24]. X-ray structures of these phases revealed insertion of the sterically less bulky 4-hydroxyphenyl ring of RSV into the cavities of the respective CDs from their secondary sides and in two cases (with TMA and DMB), the phenolic group of RSV is linked to the CD host via water-mediated hydrogen bonding of the type RSV complex due to severe guest disorder.…”

“…In our study of the inclusion of RSV in methylated CDs [24], we presented comprehensive quantitative thermal and FT-IR data for the commercially available sample of RSV used in the present study. Figure 2 shows the respective TGA and DSC traces (curves a', a) as well as the FT-IR spectrum (b) of RSV.…”

“…In a previous paper, we reported the solid-state characterization by thermal analysis of inclusion complexes of trans-RSV in methylated CDs, specifically permethylated -CD, permethylated -CD and 2,6-dimethylated -CD. Isolation of the corresponding crystalline 1:1 inclusion complexes 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 [24].…”

“…The crystals displayed blade-like morphology at room temperature and on heating shrank slightly but retained their original shape until they melted at approximately 260 °C, prior to decomposing. We reported previously that RSV itself does not undergo any significant changes in solid-phase characteristics and/or physical stability upon treatment with procedures, such as kneading (KN), microwave irradiation (MW), and co-precipitation (CP) [24]. This was established prior to undertaking the screening experiments with binary mixtures of RSV and various native CDs in attempts to isolate new solid forms of the bioactive compound using the above preparative conditions.…”

Resveratrol and resveratrol-hydroxypropyl-β-cyclodextrin complex recovered the changes of creatine kinase and Na+, K+-ATPase activities found in the spleen from streptozotocin-induced diabetic rats

“…So, an alternative for increasing the bioavailability is to complex it with cyclodextrin (Cd), which is capable of forming inclusion complexes with hydrophobic substances (Teixeira et al 2013, Torres et al 2018. Besides, the bioavailability may be enhanced by increasing the solubility and stability, and dissolution rate (Trollope et al 2014, Kumar et al 2017.…”