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Bioactive Conformers of Chiral Quinuclidinium Esters

(&plusmn ; )-, (R)- and (S)- esters of quinuclidin-3-ol and acetic, pivalic, butyric and benzoic acid were synthesized as well as their racemic and chiral, quaternary N-benzyl derivatives. Butyrylcholinesterase (BChE) was identified, among other tested esterases, as a catalyst of choice in hydrolysis reactions of prepared quaternary esters. Kinetic studies revealed that (R)-enantiomers of tested esters are much better substrates than (S)-enantiomers. On the other hand, (S)-enantiomers showed higher affinity toward BChE (3-60 micro M). In order to explain experimental data concerning reactivity of enantiomers, quantum chemical calculations (ONIOM scheme, B3LYP/3-21G:PM3) of the stable species in the acylation step were performed. It was shown that enantiomeric preference of BChE, as well as rates of hydrolysis, are governed in large part by steric limitations and electrostatic interactions in the choline subsite. Optimal positioning of the enantiomers in the active site resulted in a different twisted structures of quinuclidinium skeleton (Figure 1) and obvious steric hindrance for (S)-esters, explaining why they were a poor substrates for the enzyme.

butyrylcholinesterase; esters of quinuclidin-3-ol; hydrolysis kinetics; molecular modeling

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