Cocaine detoxification by combinatorially substituted beta-cyclodextrin libraries.
Per-6-substituted- and A,C,E(F)-tri-6-substituted-6-deoxy-beta-cyclodextrin (beta-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 beta-CD library I producing complete hydrolysis in 24h. 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 beta-CD libraries and A,C,E(F)-tri-6-substituted-6-deoxy-beta-CD libraries (I and XV) showed three common side chains (3, 4, and 5), suggesting that active side chains in the tri-substituted beta-CD library might be predicted from evaluation of the more easily prepared per-6-substituted-6-deoxy-beta-CD series.
Yu
Jiaxin
J
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612, USA.
Zhao
Yongzhong
Y
Holterman
Mark
M
Venton
Duane L
DL
D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D020650:Combinatorial Chemistry Techniques; D003505:Cyclodextrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006868:Hydrolysis / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D003042:Cocaine; C031215:betadex