Entropy-Driven Inclusion of Natural Protoberberine Alkaloids in Sulfobutylether-beta-Cyclodextrin

The understanding of the relationship between molecular structure and the thermodynamics of host-guest binding is essential for the rational design of the applications of inclusion complexes. To obtain insight into the factors governing the driving force of complex formation in aqueous solutions, the encapsulation of five pharmaceutically important protoberberine alkaloids was studied in sulfobutylether-beta-cyclodextrin having on average 6.4 degrees of substitution (SBE6.4 beta CD). Spectrophotometric, fluorescence spectroscopic, and isothermal calorimetric measurements showed 1:1 complexation in dilute solutions. From 1.92 x 10(4) M-1, about an eight-fold decrease of the association constant was observed in the series of berberine approximate to coptisine >> palmatine > epiberberine > dehydrocorydaline. The embedment of these alkaloids in the SBE6.4 beta CD cavity was entropy-controlled with mildly negative enthalpy contributions. These findings suggest that the stabilization of the examined complexes arises primarily from the hydrophobic interaction between the constituents. The more than three orders of magnitude smaller association constants of protoberberine alkaloids with SBE6.4 beta CD than with cucurbit[7]uril, a host having similar cavity size, originates from the much smaller exothermicity of the confinement in the former macrocycle.

Automated summary

The study on the encapsulation of protoberberine alkaloids in SBE6.4 beta CD revealed 1:1 complexation in dilute solutions, with thermodynamics primarily controlled by entropy.