Heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-cyclodextrin: A water-soluble cyclodextrin derivative with low hemolytic activity.
Acetyl groups were introduced to the hydroxyl groups of heptakis(2, 6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), and the resulting heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-CyD (DMA-beta-CyD) was evaluated for the inclusion property and hemolytic activity. It was confirmed by means of NMR and mass spectroscopies that in the DMA-beta-CyD molecule, all seven hydroxyl groups at the 3-position were substituted by acetyl groups. Thus, it has the degree of substitution (DS) of 7, whereas DMA4-beta-CyD with the lower substitution (DS 3.8) was a mixture of components with different DS. The aqueous solubility of DMA-beta-CyD was higher than those of beta-CyD, DM-beta-CyD, and heptakis(2,3,6-tri-O-methyl)-beta-CyD (TM-beta-CyD). The hydrophobicity of the whole molecule, assessed from measurements of surface tension, increased in the order of DM-beta-CyD < DMA-beta-CyD < TM-beta-CyD. The half-life of DMA-beta-CyD for hydrolysis in pH 9.5 and 60 degrees C was about 19 h, and there was only slight liberation of acetic acid in rabbit plasma and carboxylesterase (EC 3.1.1.1) at 37 degrees C. DMA-beta-CyD had an inclusion ability similar to that of TM-beta-CyD for p-hydroxybenzoic acid esters with different alkyl chain lengths and an antiinflammatory drug, flurbiprofen, although it was inferior to that of DM-beta-CyD. The hemolytic activity and rabbit muscular irritation of DMA-beta-CyDs were much weaker than those of DM-beta-CyD: no hemolysis was observed even in the presence of 0.1 M DMA-beta-CyD with DS 7. The results suggest that the water-soluble CyD derivative with superior bioadaptability and inclusion ability can be prepared by properly designing substituents at the 3-position and by optimally controlling their degree of substitution.
Hirayama
F
F
Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Mieda
S
S
Miyamoto
Y
Y
Arima
H
H
Uekama
K
K
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002784:Cholesterol / Q000097:blood; D003505:Cyclodextrins / Q000138:chemical synthesis / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects; D005079:Excipients / Q000138:chemical synthesis / Q000633:toxicity*; D006461:Hemolysis / Q000187:drug effects*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007509:Irritants / Q000633:toxicity; D009135:Muscular Diseases / Q000139:chemically induced / Q000473:pathology; D011817:Rabbits; D012995:Solubility; D013050:Spectrometry, Fluorescence; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D005079:Excipients; D007509:Irritants; D047392:beta-Cyclodextrins; C401801:heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-cyclodextrin; D002784:Cholesterol