Inclusion complexes of purine nucleosides with cyclodextrins. I. Complexation and stabilization of a dideoxypurine nucleoside with 2-hydroxypropyl-β-cyclodextrin

Abstract

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) markedly inhibits the acid-catalyzed hydrolysis of 2',3'-dideoxyadenosine (DDA), a compound under development for the treatment of HIV infections. The kinetic data conform to a model which assumes 1:1 complex formation between HP-β-CD and both the neutral and protonated forms of DDA. UV difference spectra were generated as a function of both HP-β-CD concentration and temperature to obtain independent estimates of formation constants and enthalpies and entropies for the binding of the neutral species of DDA to HP-β-CD. The acid lability of DDA at the low pH necessary to form the protonated species precluded the use of difference spectra to obtain complexation data for the protonated species. Binding constants for the protonated species were therefore obtained by combining apparent pKa values as a function of HP-β-CD concentration and temperature with the spectral data. Binding constants for the neutral species ranged from 28 M-1 at 50° C to 56 M-1 at 4° C and were at least 3-times larger than those of the protonated species over this temperature range. A negligible difference in the enthalpy of complexation was observed between the protonated and neutral forms of DDA, while the entropy of formation appeared to favor the neutral complex. Although hydrolysis is 100% suppressed in both the protonated and neutral complexes, due to the small binding constants, the maximum stabilization attainable in a 0.1 M solution of HP-gb-CD at 25° C was approx. 5-fold at pH 5 and 2-fold at pH 2. Possible inclusion geometries are considered in an attempt to account for the kinetic data. © 1990.