Further developments in research on the chemistry and pharmacology of synthetic quinuclidine derivatives

Mashkovsky, M. D.; Yakhontov, L. N.; Kaminka, M. É.; Mikhlina, E. E.

doi:10.1007/978-3-0348-7115-0_1

Cited by 8 publications

(10 citation statements)

References 12 publications

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“…[1] They have also been shown to be potential antidotes against poisoning by organophosphorus compounds such as pesticides, insecticides and chemical warfare agents. [2] Since quinuclidin-3-ol contains an asymmetric carbon atom, preparation of its esters leads to racemates.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Hydrolysis of Quaternary Quinuclidinium Benzoates Catalyzed by Butyrylcholinesterase

et al. 2002

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Four chiral, quaternary, N-methyl and N-benzyl derivatives of (R)-and (S)-quinuclidin-3-yl benzoates were synthesized and studied as substrates of horse serum butyrylcholinesterase (BChE). The k cat for the substrates decreased in the order (R)-N-methyl Ͼ (R)-N-benzyl (2.3-fold slower) ϾϾ (S)-Nmethyl (70.5-fold slower reaction), while for the (S)-N-benzyl ester inhibition of the enzyme was observed. The kinetics of inhibition (K a = 3.3 µM) indicated that binding to the catalytic site of BChE occurred. From the ratio of the k cat /K M values of both enantiomers an enantiomeric excess of 95% was calculated for N-methyl derivatives. Thus, BChE is suitable as a biocatalyst for the resolution of racemic quaternary quinu-

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Section: Introductionmentioning

confidence: 99%

Stereoselective Hydrolysis of Quaternary Quinuclidinium Benzoates Catalyzed by Butyrylcholinesterase

et al. 2002

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“…7,8 In our previous work, 9,10 chiral esters of quinuclidin-3-ol and benzoylcholine were subjected to enzymatic hydrolysis in the presence of BChE 11,12 and the kinetics of BChE-catalyzed hydrolyses were determined. The hydrolysis of quaternary quinuclidine esters proved to be highly enantioselective.…”

Section: Introductionmentioning

confidence: 99%

Binding Modes of Quinuclidinium Esters to Butyrylcholinesterase

Primožič¹,

Hrenar²,

Tomić³

2012

Croat. Chem. Acta

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Abstract. The orientations of chiral quinuclidin-3-ol esters and benzoylcholine in the active site of horse butyrylcholinesterase have been investigated by flexible ligand docking. Change of the esters' acyl moiety as well as the substituent at the quinuclidinium nitrogen atom affected the activity and stereoselectivity of the biotransformations. Analysis of interactions in the active site revealed the most important binding patterns for enantiomers, which define their reactivity. Calculated Gibbs energies of binding obtained by molecular docking simulations were well correlated to the experimentally determined binding affinities of the investigated chiral esters. (doi: 10.5562/cca2060)

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“…Structural complementarity of choline and quinuclidin-3-ol pointed to racemic quinuclidine derivatives as candidates for kinetic resolution catalyzed by this enzyme [ 7 , 8 , 9 ]. Compounds which contain quinuclidin-3-ol moiety are valuable intermediates for the synthesis of optically active pharmaceuticals [ 10 ], thus, efficient synthesis of chiral quinuclidin-3-ols is necessary for the preparation of biologically active compounds. In our previous work, various chiral quaternary esters of quinuclidin-3-ol were subjected to hydrolysis in the presence of BChE [ 11 ], and it was shown that hydrolysis is highly stereoselective.…”

Section: Introductionmentioning

confidence: 99%

Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase

et al. 2012

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Since the optically active quinuclidin-3-ol is an important intermediate in the preparation of physiologically or pharmacologically active compounds, a new biocatalytic method for the production of chiral quinuclidin-3-ols was examined. Butyrylcholinesterase (BChE; EC 3.1.1.8) was chosen as a biocatalyst in a preparative kinetic resolution of enantiomers. A series of racemic, (R)- and (S)-esters of quinuclidin-3-ol and acetic, benzoic, phthalic and isonicotinic acids were synthesized, as well as their racemic quaternary N-benzyl, meta- and para-N-bromo and N-methylbenzyl derivatives. After the resolution, all N-benzyl protected groups were successfully removed by catalytic transfer hydrogenation with ammonium formate (10% Pd-C). Hydrolyses studies with BChE confirmed that (R)-enantiomers of the prepared esters are much better substrates for the enzyme than (S)-enantiomers. Introduction of bromine atom or methyl group in the meta or para position of the benzyl moiety resulted in a considerable improvement of the stereoselectivity compared to the non-substituted compounds. Optically pure quinuclidin-3-ols were prepared in high yields and enantiopurity by the usage of various N-benzyl protected groups and BChE as a biocatalyst.

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Further developments in research on the chemistry and pharmacology of synthetic quinuclidine derivatives

Cited by 8 publications

References 12 publications

Stereoselective Hydrolysis of Quaternary Quinuclidinium Benzoates Catalyzed by Butyrylcholinesterase

Stereoselective Hydrolysis of Quaternary Quinuclidinium Benzoates Catalyzed by Butyrylcholinesterase

Binding Modes of Quinuclidinium Esters to Butyrylcholinesterase

Preparation of Novel meta- and para-Substituted N-Benzyl Protected Quinuclidine Esters and Their Resolution with Butyrylcholinesterase

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