Synthesis of six specifically deuterated analogs of 1,2‐dibromo‐3‐chloropropane

Omichinski, James G.; Nelson, Sidney D.

doi:10.1002/jlcr.2580250305

Cited by 12 publications

(4 citation statements)

References 8 publications

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“…When required, the iV-[ (benzyloxy)carbonyl] functionality was effectively removed from DHPG, CHPG, and HPBG by hydrolysis in 5 N HC1 for 2 h at ambient temperature. [l,l,2,3,3-2H5]-2,3-Dibromochloropropane (D6-DBCP) was prepared as previously described (38); the isotopic composition was determined to be 16% 2H4 and 84% 2HS based on the M -Br ions at m/z 155-165 observed upon electron impact mass spectrometric analysis.…”

Section: Methodsmentioning

confidence: 99%

Screening strategy for the detection of derivatized glutathione conjugates by tandem mass spectrometry

1990

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Section: Methodsmentioning

confidence: 99%

Screening strategy for the detection of derivatized glutathione conjugates by tandem mass spectrometry

1990

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“…DBCP was prepared by bromination of allyl chloride and purified by vacuum distillation and was found to be >99% pure by gas chromatographic analysis. Specifically deuterated analogues of DBCP were prepared by chlorination of the corresponding specifically deuterated dibromopropanols (18). Deuterium incorporation into C^-DBCP and C3D2-DBCP was greater than 95 atom % as determined by analysis of the (M -Br)+ species (at m/z 155-162) generated by electron impact mass spectrometry; the deuterated analogues were >98% chemically pure by gas chromatographic analysis.…”

Section: Methodsmentioning

confidence: 99%

Metabolic activation of 1,2-dibromo-3-chloropropane to mutagenic metabolites: detection and mechanism of formation of (Z)- and (E)-2-chloro-3-(bromomethyl) oxirane

Pearson

Omichinski

Myers

et al. 1990

Chem. Res. Toxicol.

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1,2-Dibromo-3-chloropropane (DBCP), a haloalkane nematocide and soil fumigant, is metabolically activated to chemically reactive species that are direct-acting mutagens in a Salmonella typhimurium TA 100 test system. Studies in vitro with rat liver microsomes indicated that oxidation at carbon 3 resulted in the formation of an unstable gem-chlorohydrin that rearranged with elimination of hydrogen bromide to form (Z)-2-chloro-3-(bromomethyl)oxirane [(Z)-CBPO] and (E)-2-chloro-3-(bromomethyl)oxirane [(E)-CBPO]. Gas chromatography-mass spectrometry (GC-MS) with positive ion chemical ionization (CI) was employed to identify (Z)-CBPO and (E)-CBPO by comparison of characteristic fragment ions in their CI mass spectra with those observed for authentic standards. Quantitative GC-MS methodology was exploited to quantitate the rate of formation of (Z)-CBPO and (E)-CBPO from DBCP and analogues of DBCP specifically deuterated at carbon 1 and carbon 3. The rate of formation of Z- and E-isomers of CBPO was 31 and 33 pmol/(min.mg of protein), respectively, from DBCP; substitution with deuterium at carbon 1 increased the rate of epoxide formation by 50%, whereas CBPO formation could not be detected from a substrate labeled with deuterium at carbon 3. Both epoxides were directly acting mutagens to S. typhimurium TA 100. (Z)-CBPO caused approximately twice as many his+ revertants/nmol compared to (E)-CBPO. Oxidation at carbon 2 of DBCP resulted in the formation of a bifunctional alkylating agent, 1-bromo-3-chloroacetone, presumably via the intermediacy of an unstable gem-bromohydrin.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…[ 1, 1) were prepared by chlorination of the respectively deuterated 2,3-dibromopropanols with N-chlorosuccinimide and triphenylphosphine as described elsewhere (24). [l,l,2,3,3-2H5]-l,2-Dibromo-3-chloropropane (D5-DBCP) was prepared by bromination of [1,1,2,3,3-2Hs]allyl alcohol according to a literature procedure (24) to afford [l,l,2,3,3-2H5]-2,3-dibromopropanol. [l,l,2,3,3-2Hs]-2,3-Dibromopropanol was then treated with IV-chlorosuccinimide and triphenylphosphine to afford D5-DBCP (24).…”

Section: Methodsmentioning

confidence: 99%

“…[l,l,2,3,3-2H5]-l,2-Dibromo-3-chloropropane (D5-DBCP) was prepared by bromination of [1,1,2,3,3-2Hs]allyl alcohol according to a literature procedure (24) to afford [l,l,2,3,3-2H5]-2,3-dibromopropanol. [l,l,2,3,3-2Hs]-2,3-Dibromopropanol was then treated with IV-chlorosuccinimide and triphenylphosphine to afford D5-DBCP (24). Deuterium incorporation was greater than 97 atom %, as determined by analysis of the MH+ species of the corresponding deuterated 2,3dibromopropanols by GC-MS (methane chemical ionization); the deuterated analogs ofDBCP were >98% chemically pure by gas chromatographic analysis.…”

Section: Methodsmentioning

confidence: 99%

Identification of N-Acetylcysteine Conjugates of 1,2-Dibromo-3-chloropropane: Evidence for Cytochrome P450 and Glutathione Mediated Bioactivation Pathways

Weber¹,

Steenwyk²,

Nelson³

et al. 1995

Chem. Res. Toxicol.

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The haloalkane 1,2-dibromo-3-chloropropane (DBCP) is a carcinogen, mutagen, nephrotoxin, and testicular toxin. The identification of N-acetylcysteine conjugates of DBCP provides information on GSH mediated and cytochrome P450 mediated bioactivation pathways in the expression of DBCP-induced toxicities. N-Acetylcysteine conjugates excreted in the urine of male Sprague-Dawley rats administered DBCP, C1D2-DBCP, C2D1-DBCP, C3D2-DBCP, or D5-DBCP (80 mg/kg) were purified by reverse-phase HPLC as their methyl ester derivatives and characterized by fast atom bombardment tandem mass spectrometry. These metabolites were also converted to tert-butyldimethylsilyl ether derivatives and analyzed by gas chromatography-mass spectrometry (GC-MS) to facilitate the identification of N-acetyl-S-(2,3-dihydroxypropyl)cysteine (Ia), an apparent regioisomer of Ia, 2-(S-(N-acetylcysteinyl))-1,3-propanediol (Ib), N-acetyl-S-(3-hydroxypropyl)cysteine (IIa), and N-acetyl-S-(3-chloro-2-hydroxypropyl)-cysteine (III). Metabolites Ia, Ib, and III displayed quantitative retention of deuterium, an observation consistent with the formation of episulfonium ion intermediate(s) in their biogenesis. Mercapturate IIa retained three atoms of deuterium from D5-DBCP, and two atoms of deuterium from the dideuterio analogs (C1D2-DBCP and C3D2-DBCP), thus invoking P450 mediated formation of 2-bromoacrolein (2-BA) as an intermediate in the biogenesis of IIa. A mechanism is proposed in which conjugate addition of GSH to 2-BA, subsequent episulfonium ion formation, and addition of GSH afford 1,2-(diglutathion-S-yl)propanal. Glutathione mediated reduction is invoked to afford S-(3-hydroxypropyl)GSH which would be excreted in the urine as IIa. The quantitative retention of deuterium from C1D2-DBCP or C3D2-DBCP was indicative of isotopically sensitive branching of P450 metabolism at either C1 or C3 to afford 2-BA. C2D1-DBCP showed a 30% retention of 1 deuterium atom in IIa; the loss of the deuterium is consistent with 2-BA formation, whereas the retention of one deuterium atom is indicative of the formation of metabolite IIa through GSH conjugation of either 2,3-dibromopropanal or 2-bromo-3-chloropropanal. These data indicate that IIa is a marker metabolite for the potent direct-acting mutagen, 2-BA, or its metabolic precursors 2,3-dibromopropanal or 2-bromo-3-chloropropanal. Therefore, evidence has been presented for bioactivation of DBCP by glutathione and cytochrome P450 mediated mechanisms.

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Synthesis of six specifically deuterated analogs of 1,2‐dibromo‐3‐chloropropane

Cited by 12 publications

References 8 publications

Screening strategy for the detection of derivatized glutathione conjugates by tandem mass spectrometry

Screening strategy for the detection of derivatized glutathione conjugates by tandem mass spectrometry

Metabolic activation of 1,2-dibromo-3-chloropropane to mutagenic metabolites: detection and mechanism of formation of (Z)- and (E)-2-chloro-3-(bromomethyl) oxirane

Identification of N-Acetylcysteine Conjugates of 1,2-Dibromo-3-chloropropane: Evidence for Cytochrome P450 and Glutathione Mediated Bioactivation Pathways

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