Cocaine detoxification by combinatorially substituted β-Cyclodextrin libraries Original Research Article

Per-6-substituted- and A,C,E(F)-tri-6-substituted-6-deoxy-β-cyclodextrin (β-CD) libraries were generated using solution-phase combinatorial chemistry techniques starting from the corresponding iodo precursors and different combinations of individual amine nucleophiles. Using a high throughput electrospray mass spectrometry (ESMS) screen to monitor the hydrolysis of cocaine, certain libraries showed the ability to specifically hydrolyze the methyl ester of cocaine, with the most active per-6-substituted β-CD library I producing complete hydrolysis in 24 h. The cocaine hydrolytic activity in this series showed structure–activity relationships which appeared to involve specific interaction between the amine side chains and the cocaine molecule. Comparison of the composition of the most active per-6-substiuted β-CD libraries and A,C,E(F)-tri-6-substituted-6-deoxy-β-CD libraries (I and XV) showed three common side chains (3, 4, and 5), suggesting that active side chains in the tri-substituted β-CD library might be predicted from evaluation of the more easily prepared per-6-substituted-6-deoxy-β-CD series.