Molecular Recognition of Steroids and Bile Salts by Substituted Cyclodextrins: The Influence of Gonane Isomerism and Rim Functionalization on Complexation Thermodynamics

Rim functionalization is what makes cyclodextrins pharmaceutically usable, yet how the type and degree of substitution influence steroid recognition has been established almost solely for conjugated bile salts. Using isothermal titration calorimetry and 1H NMR, we determined the complexation thermodynamics of neutral androsterone, its cis-isomer etiocholanolone, and the cholate, deoxycholate, and lithocholate anions with 2-hydroxypropyl-β- and -γ-, randomly methylated β-, and sulfobutylether-β-cyclodextrins, all compared with the parent hosts measured under identical conditions. Two findings stand out. First, unlike β-cyclodextrin, its derivatives bind the steroids exclusively as 1:1 complexes regardless of gonane isomerism. Second, in sulfobutylether hosts, the degree of substitution could be used as a selectivity filter: affinity for the most polar cholate falls steeply once degree of substitution (DS) exceeds about six, while binding of the least hydroxylated lithocholate is barely affected, opposite to the loss of selectivity usually reported upon substitution. For all hosts, functionalization lowers stability and shifts binding toward the classical hydrophobic effect. The obtained results, apart from the type of substituent, identify the host substitution degree as a potential lever for choosing cyclodextrin excipients that defy bile salt competition. Moreover, the substituted β-cyclodextrins do not form sparingly soluble complexes with trans-steroids, as does the parent receptor.