Solubility enhancement of pinostrobin by complexationwith β-cyclodextrin and its derivatives

Abstract

Pinostrobin (PNS) is one of the important flavonoids and can be abundantly found in the rhizomes of fingerroot Boesenbergia rotrunda and galangal Alpinia galangal and A. officinarum. Similar to other flavonoids, PNS has an extremely low water solubility that limits its use in pharmaceutical applications. Beta-cyclodextrin (βCD) and its derivatives, heptakis (2,6-di-O-methyl)-βCD (2,6-DMβCD) and 2-hydroxypropyl-βCD (HPβCD), can enhance the stability and solubility of low-soluble guest molecules. In the present work, computational and experimental studies were applied to investigate the dynamics and stability of PNS inclusion complexes with βCD and its derivatives, 2,6-DMβCD and HPβCD. From molecular dynamics (MD) study, PNS was able to form complexes with all βCDs by either the chromone (C-PNS) or phenyl (P-PNS) ring dipping towards the cavity. According to calculated binding free energies, the stability of the different PNS/βCDs complexes was in the order of 2,6-DMβCD > HPβCD > βCD in good agreement with the experimental stability constants. The AL-type diagram exhibited the formed inclusion complexes with the 1:1 molar ratio. The inclusion complexes were successfully prepared by freeze-drying method and characterized by DSC and 2D-ROESY NMR techniques. Steered MD and 2D-ROESY results revealed the both binding modes of PNS favorably occupied inside the cavity of βCD derivatives, whilst C-PNS likely preferred to interact with the parental βCD. All PNS/βCDs complexes had a higher dissolution rate than the free PNS. Both PNS and its complexes significantly exerted a lowering effect on the IL-6 secretion in LPS-stimulated macrophages and showed a moderate cytotoxic effect against HeLa and MCF-7 cancer cell lines in vitro.