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-m ethyl)-beta-cyclodextrin (DM-beta-CyD), and the resulting heptakis(2,6-di-O -methyl-3-Oacetyl)-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 S-position were substituted by acetyl groups. Thus, it has the degr ee of substitution (DS) of 7, whereas DMA4-beta-CyD with the lower substitu tion (DS 3.8) was a mixture of components with different DS. The aqueous so lubility of DMA-beta-CyD was higher than those of beta-CyD, DM-beta-CyD, an d heptakis(2,3,6-tri-Omeihyl)-beta-CyD (TM-beta-CyD). The hydrophobicity of the whole molecule, assessed from measurements of surface tension, increas ed 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, a nd there was only slight liberation of acetic acid in rabbit plasma and car boxylesterase (EC 3.1.1.1) at 37 degrees C. DMA-beta-CyD had an inclusion a bility 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-b eta-CyD with DS 7. The results suggest that the water-soluble CyD derivativ e with superior bioadaptability and inclusion ability can be prepared by pr operly designing substituents at the 3-position and by optimally controllin g their degree of substitution.