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Bioorg Med Chem. 2011 Jun 15;19(12):3855-63. doi: 10.1016/j.bmc.2011.04.038. Epub 2011 Apr 22.

Biological activity of water-soluble inclusion complexes of 1'-acetoxychavicol acetate with cyclodextrins.

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Department of Applied Chemistry and Bioengineering, Graduate School of Engineering, Osaka City University, Sugimoto 3-3-138, Osaka 558-8585, Japan.


1'-Acetoxychavicol acetate (ACA), isolated from the rhizomes and the seeds of the Zingiberaceae plant, has a variety of biological activities such as antitumor, antiallergic and repellent effects. However, ACA seems to have some disadvantages which may limit for future possible clinical applications, for example, its poor water solubility. Furthermore, ACA is not stable in aqueous solutions and undergoes hydrolysis and/or isomerization. To improve the solubility and stability of ACA in water, we prepared the inclusion complexes with various β-cyclodextrins (β-CDs).In aqueous solution, the association constants of ACA with various CDs were estimated at 662±95 (β-CD), 336±70 (methyl-β-CD, Meβ-CD), and 322±44M(-1) (hydroxypropyl-β-CD, HPβ-CD), respectively, by a spectrofluorometric displacement method based on competition between a guest and a fluorescent probe for CDs. It was revealed that almost all ACAs existed as a free molecule in the CD-containing aqueous solution. However, in the case of preparing the inclusion complexes of CDs with ACA by a solid phase 'high-speed vibration milling' technique, the average inclusion rates of the obtained water-soluble complexes were calculated as 88±13% (β-CD), 70±1% (Meβ-CD), and 63±2% (HPβ-CD), respectively, by (1)H NMR analysis. To characterize the structures of the CD·ACA complexes, 2,3,6-trimethyl-β-CD (TMeβ-CD)·ACA complex was prepared as a model compound (inclusion rate: 40%). As a result of 2D ROESY experiments, it was considered that the aromatic ring of ACA is located in the narrow side of the hydrophobic cavity of the TMeβ-CD and both 1'- and 4-acetoxy groups of ACA positioned in the vicinity of the secondary and primary methoxy groups of TMeβ-CD, respectively. Furthermore, we examined the apoptogenic activity of CD·ACA complexes to evaluate whether or not the bioactivities of ACA were affected by their inclusion. Although the cytotoxicity of all CD·ACA complexes in human epithelial carcinoma HeLa cells and murine adenocarcinoma colon26 cells were diminished as compared with the ACA alone, only HPβ-CD·ACA maintained high levels of activity. In addition, HPβ-CD·ACA, and Meβ-CD·ACA showed suppressive effect for the transcription factor NF-κB activation on LPS-activated murine macrophage RAW264.7 cells and the former was more active complex. Furthermore, HPβ-CD·ACA inhibited the in vivo tumor growth of tumor-bearing mice, although the activity was slightly weak compared with that of free ACA. These results indicate that HPβ-CD is the best host molecule for ACA to form a water-soluble complex with the similar biological activity of free ACA.

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