Enhanced water solubility, stability, and in vitro antitumor activity of ferulic acid by chemical conjugation  with amino-β-cyclodextrins

To improve the water solubility, stability and bioactivity of ferulic acid (FA), a series of conjugates (FA-NH-CD, FA-EDA-CD, and FA-HDA-CD) were synthesized by bonding FA with different amino-β-cyclodextrins (amino-β-CD, ACDs) through amidation reactions. The structures of the conjugates were characterized by nuclear magnetic resonance, high-resolution mass spectra, scanning electron microscope, and X-ray diffraction, and FA was successfully linked with the ACDs in 1:1 molar ratios. The study of self-assembling behaviors of the conjugates indicated that FA-NH-CD with short and rigid alkyl chains displayed an intermolecular assembly mode in which the appended FA was accommodated into the cavities of other ACDs, while FA-EDA-CD and FA-HDA-CD with flexible alkyl chains could form self-inclusion structures. The solubility of FA-EDA-CD and FA-HDA-CD was remarkably enhanced, which also supported the formation of self-inclusion complexes. Moreover, all the conjugates exhibited improved stability and in vitro cytotoxicity against HepG2 cells compared with the parent FA, suggesting that conjugation with ACDs offered a promising way in the exploitation and utilization of insoluble natural products such as FA.