Physical properties and biological activities of hesperetin and naringenin in complex with methylated ß-cyclodextrin.

The aim of this work is to improve physical properties and biological activities of the two flavanones hesperetin and naringenin by complexation with ß-cyclodextrin (ß-CD) and its methylated derivatives (2,6-di-O-methyl-ß-cyclodextrin, DM-ß-CD and randomly methylated-ß-CD, RAMEB). The free energies of inclusion complexes between hesperetin with cyclodextrins (ß-CD and DM-ß-CD) were theoretically investigated by molecular dynamics simulation. The free energy values obtained suggested a more stable inclusion complex with DM-ß-CD. The vdW force is the main guest-host interaction when hesperetin binds with CDs. The phase solubility diagram showed the formation of a soluble complex of AL type, with higher increase in solubility and stability when hesperetin and naringenin were complexed with RAMEB. Solid complexes were prepared by freeze-drying, and the data from differential scanning calorimetry (DSC) confirmed the formation of inclusion complexes. The data obtained by the dissolution method showed that complexation with RAMEB resulted in a better release of both flavanones to aqueous solution. The flavanones-ß-CD/DM-ß-CD complexes demonstrated a similar or a slight increase in anti-inflammatory activity and cytotoxicity towards three different cancer cell lines. The overall results suggested that solubilities and bioactivities of both flavanones were increased by complexation with methylated ß-CDs.

Enhanced stability of a naringenin/2,6-dimethyl ß-cyclodextrin inclusion complex: molecular dynamics and free energy calculations based on MM- and QM-PBSA/GBSA.

The structure, dynamic behavior and binding affinity of the inclusion complexes between naringenin and the two cyclodextrins (CDs), ß-CD and its 2,6-dimethyl derivative (DM-ß-CD), were theoretically studied by multiple molecular dynamics simulations and free energy calculations. Naringenin most likely prefers to bind with CDs through the phenyl ring. Although a lower hydrogen bond formation of naringenin with the 3-hydroxyl group of DM-ß-CD (relative to ß-CD) was observed, the higher cavity could encapsulate almost the whole naringenin molecule. In contrast for the naringenin/ß-CD complex, the phenyl ring feasibly passed through the primary rim resulting in the chromone ring binding inside instead. MM-PBSA/GBSA and QM-PBSA/GBSA binding free energies strongly suggested a greater stability of the naringenin/DM-ß-CD inclusion complex. Van der Waals force played an important role as the key guest-host interaction for the complexation between naringenin and each cyclodextrin.