Synthesis of fenthion sulfoxide and fenoxon sulfoxide enantiomers: effect of sulfur chirality on acetylcholinesterase activity.

Synthesis of fenthion sulfoxide and fenoxon sulfoxide enantiomers: effect of sulfur chirality on acetylcholinesterase activity. Research Abstract Details 

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Synthesis of fenthion sulfoxide and fenoxon sulfoxide enantiomers: effect of sulfur chirality on acetylcholinesterase activity. Abstract Text:

Rama Sarma V S Gadepalli,John M Rimoldi,Frank R Fronczek,Mae Nillos,Jay Gan,Xin Deng,Gabriela Rodriguez-Fuentes,Daniel Schlenk,

Earlier reports have demonstrated that recombinant flavin-containing monooxygenase 1 (FMO1) catalyzes the oxidation of the organophosphate pesticide fenthion to (+)-fenthion sulfoxide in a stereoselective fashion. In order to elucidate the absolute configuration of the sulfoxide metabolite produced, we established an efficient synthesis of both enantiomers of fenthion sulfoxide, which were transformed into chiral fenoxon sulfoxides using a two-step protocol. The use of chiral oxidants, namely, N-(phenylsulfonyl)(3,3-dichlorocamphoryl) oxaziridines, afforded enantioenriched fenthion sulfoxides with high ee (>82%) from the parent sulfide. Single recrystallizations afforded chiral fenthion sulfoxides with >99% ee, measured by chiral HPLC analysis. The absolute configuration of the (+)-sulfoxide generated from fenthion metabolism by FMO1 was determined to be (R)-(+)-fenthion sulfoxide, confirmed by X-ray crystallographic analysis of the (S)-(-)-antipode. Inhibition of human recombinant (hrAChE) and electric eel (eeAChE) acetylcholinesterase were assayed with fenthion, fenoxon, and the racemates and enantiomers of fenthion sulfoxide and fenoxon sulfoxide. Results revealed stereoselective inhibition with (R)-(+)-fenoxon sulfoxide when compared with that of (S)-(-)-fenoxon sulfoxide (IC50 of 6.9 and 6.5 microM vs 230 and 111 microM in hrAChE and eeAChE, respectively). Fenthion sulfoxide (R or S enantiomers) did not present anti-AChE properties. Although the stereoselective sulfoxidation of fenthion to (R)-(+)-fenthion sulfoxide by FMO represents a detoxification pathway, the results of this study support the notion that subsequent oxidative desulfuration of (R)-(+)-fenthion sulfoxide (in vivo) may represent a critical bioactivation pathway, resulting in the production of (R)-(+)-fenoxon sulfoxide, a potent AChE inhibitor.

Synthesis of fenthion sulfoxide and fenoxon sulfoxide enantiomers: effect of sulfur chirality on acetylcholinesterase activity. Publishing Authors By Initials

RS Gadepalli,JM Rimoldi,FR Fronczek,M Nillos,J Gan,X Deng,G Rodriguez-Fuentes,D Schlenk,

For similar sulfoxides research abstracts see: sulfoxides research

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Synthesis of fenthion sulfoxide and fenoxon sulfoxide enantiomers: effect of sulfur chirality on acetylcholinesterase activity. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Chemical research in toxicology

VOLUME: 20

Page Numbers: 257-62

Journal Abbreviation: Chem. Res. Toxicol.

ISSN: 0893-228X

DAY: 25

MONTH: 01

YEAR: 2007

Synthesis of fenthion sulfoxide and fenoxon sulfoxide enantiomers: effect of sulfur chirality on acetylcholinesterase activity. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8807448

Synthesis of fenthion sulfoxide and fenoxon sulfoxide enantiomers: effect of sulfur chirality on acetylcholinesterase activity. Keywords Mesh Terms:

KEYWORDS: Sulfoxides

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Synthesis of fenthion sulfoxide and fenoxon sulfoxide enantiomers: effect of sulfur chirality on acetylcholinesterase activity. Information

Substance Name: Acetylcholinesterase

Registry Number: EC 3.1.1.7

Grant and Affiliation Information for Synthesis of fenthion sulfoxide and fenoxon sulfoxide enantiomers: effect of sulfur chirality on acetylcholinesterase activity.

AFFILIATION: Department of Medicinal Chemistry and Environmental Toxicology Research Program, University of Mississippi, Mississippi 38677, USA.

Country: United States

AGENCY: United States NCRR

GRANT: C06 RR-14503-01

ACRONYM: RR

MEDLINETA: Chem Res Toxicol

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