Development of optically pure pyrethroid-like fluorescent substrates for carboxylesterases

Huazhang Huang, Jeanette E. Stok, Donald W. Stoutamire, Shirley J. Gee, Bruce D. Hammock

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Pyrethroids are now the world's most extensively used insecticides. One of the common metabolic routes of pyrethroid insecticides in living systems is hydrolysis by carboxylesterases, and this hydrolysis may be stereospecific since most pyrethroid insecticides have chiral centers. In previous studies, pyrethroid-like fluorescent substrates have been shown to be hydrolyzed in a fashion similar to actual pyrethroids. It is important to synthesize the stereoisomers of pyrethroid-like fluorescent substrates to study the stereointeraction between carboxylesterases and these substrates. In this study, an effective synthetic method for preparing optically enriched (R)- and (S)-α-2-hydroxy-2-(6-methoxy-2-naphthyl)acetonitrile was developed. With this alcohol, an efficient synthetic route for preparation of optically pure cypermethrin and fenvalerate analogues was provided. Identification of these stereoisomers was determined based on GC, HPLC, 1H NMR, and X-ray crystallography. In addition, stereointeraction between carboxylesterases and chiral fluorescent substrates indicated that (i) stereospecificity of recombinant mouse liver carboxylesterases (NCBI accession nos. BAC36707 and NM_133960) varied significantly (up to 300-fold difference) with different stereoisomers of cypermethrin and fenvalerate analogues; (ii) on the basis of Vmax, the sensitivity of this analytical method, using a single stereoisomer of cypermethrin analogues instead of a mixture of eight stereosiomers, could be enhanced by 4-6 times for detection of these carboxylesterases; and (iii) possible usage of these carboxylesterases for chiral synthesis is discussed.

Original languageEnglish (US)
Pages (from-to)516-527
Number of pages12
JournalChemical Research in Toxicology
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2005

Fingerprint

Carboxylic Ester Hydrolases
Pyrethrins
Stereoisomerism
fenvalerate
Substrates
Insecticides
Hydrolysis
X ray crystallography
X Ray Crystallography
Liver
High Pressure Liquid Chromatography
Alcohols
Nuclear magnetic resonance

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Development of optically pure pyrethroid-like fluorescent substrates for carboxylesterases. / Huang, Huazhang; Stok, Jeanette E.; Stoutamire, Donald W.; Gee, Shirley J.; Hammock, Bruce D.

In: Chemical Research in Toxicology, Vol. 18, No. 3, 01.03.2005, p. 516-527.

Research output: Contribution to journalArticle

Huang, Huazhang ; Stok, Jeanette E. ; Stoutamire, Donald W. ; Gee, Shirley J. ; Hammock, Bruce D. / Development of optically pure pyrethroid-like fluorescent substrates for carboxylesterases. In: Chemical Research in Toxicology. 2005 ; Vol. 18, No. 3. pp. 516-527.
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