Synthesis of <sup>14</sup>C‐labelled DDD isomers of high specific activity

Lindholm, Anna Maria; Klasson-Wehler, Eva; Wehler, Thomas; Bergman, Åke

doi:10.1002/jlcr.2580240902

Cited by 17 publications

(3 citation statements)

References 3 publications

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“…Chemicals. 3-Methylsulfonyl-2,2´-bis(4chloro-[ 14 C]-phenyl)-1,1´-dichloroethene (MeSO 2 -[ 14 C]DDE; 13.4 mCi/mmol), unlabeled MeSO 2 -DDE, and 2-(2-chlorophenyl)-2-(4-chloro-[ 14 C]-phenyl)-1,1-dichlorethane (o,p´-[ 14 C]DDD; 11.2 mCi/mmol) were prepared as previously described (25,26). DL [4, H]leucine (40 Ci/mmol) was purchased from Amersham Life Science (Amersham, England).…”

Section: Methodsmentioning

confidence: 99%

Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture.

Lindhe

Lund²,

Bergman³

et al. 2001

Environ Health Perspect

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The persistent adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE (MeSO(2)-DDE) was originally identified in Baltic grey seals, a population suffering from adrenocortical hyperplasia. In mice, MeSO(2)-DDE induces mitochondrial degeneration and cellular necrosis in the adrenal zona fasciculata. In this study, we used precision-cut tissue slice culture to examine local CYP11B1-catalyzed irreversible binding of MeSO(2)-DDE in the murine adrenal cortex. We also examined effects on steroid hormone secretion, histology, and ultrastructure. As determined by microautoradiography, selective binding occurred in zona fasciculata of slices exposed to MeSO(2)-[(14)C]-DDE. Quantification of binding by phosphorautoradiography revealed a 3-fold reduction of binding in slices co-exposed to the CYP11B1 inhibitor metyrapone. As measured by HPLC, corticosterone and 11-deoxycorticosterone secretion to the medium increased linearly for at least 24 hr. Addition of the ACTH analog tetracosactide caused an 8-fold increase in corticosterone secretion. Addition of metyrapone reduced corticosterone secretion 4-fold. Exposure of slices to MeSO(2)-DDE (50 microM) reduced the rate of corticosterone secretion by 90% after 24 hr of incubation. As determined by electron microscopy, vacuolated mitochondria were present in zona fasciculata of slices exposed to MeSO(2)-DDE (50 microM) for 24 hr. Our findings show that all effects of MeSO(2)-DDE previously reported in vivo could be reproduced in adrenal slice culture ex vivo. This test system allows analysis of zone-specific irreversible binding and effects on steroid hormone secretion and target cell ultrastructure. We propose adrenal slice culture as a simple ex vivo test system with which to examine the adrenocorticolytic activity of xenobiotics in human and wild animal tissue.

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Section: Methodsmentioning

confidence: 99%

Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture.

Lindhe

Lund²,

Bergman³

et al. 2001

Environ Health Perspect

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“…For comparison, we also determined whether adrenal tissue from otter is capable of activating these adrenocorticolytic DDT-derivatives to metabolites that are covalently bound to adrenal protein in vitro. (Bergman and Wachtmeister, 1977;Lindholm et al, 1987). The radiochemical purities were >97% as determined by TLC on silica gel plates (hexane + ethylacetate, 4:1) and reversed phase (C18) TLC plates (methanol).…”

Section: Introductionmentioning

confidence: 99%

Adrenocorticolytic DDT-metabolites: studies in mink, Mustela vison and otter, Lutra lutra

Liu

Brandt

1993

Ecotoxicology

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Eighteen stranded Atlantic bottlenose dolphins (Tursiops truncatus) examined postmortem were sampled for histologic study. All cases were examined for ferric ion and lipofuscin. Ages were determined from tooth growth layers. Electron microscopic (EM) examination and X-ray spectroscopy (EDAX) were performed. Chemical analysis for mercury was conducted on 12 of the animals by atomic absorption spectrophotometry. Nine animals were found to have excessive lipofuscin in both liver and kidney. Four of these nine animals also exhibited active liver disease (fat globules, central necrosis, lymphocytic infiltrates) whereas, of the animals without the excessive pigment, only one animal had an active liver lesion. EM and EDAX showed electron-dense amorphous material presumably within lysosomes to be Hg with no deposits on mitochondrial or nuclear membranes noted. Age relationship to portal pigment deposition was positive. Liver mercury concentrations ranged from 0.01 to 443 micrograms/g of wet weight with all animals having liver pigment yielding values of or above 61 micrograms/g, whereas all animals lacking pigment had values of or below 50 micrograms/g. The evidence suggests that the excessive pigment accumulation is related to toxic effects of Hg and presents as increased active liver disease.

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“…Other Grignard reagents also added to tert -butylamide 23 , as shown in Table . p -Fluoro- o -tolylmagnesium bromide, p -fluorophenylmagnesium bromide, and isopropylmagnesium chloride afforded good to moderate yields of 49 − 51 , respectively, whereas o -chlorophenylmagnesium bromide unexpectedly did not react at all.…”

Section: Resultsmentioning

confidence: 95%

Efficient Synthesis of Novel NK₁ Receptor Antagonists: Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives

et al. 2006

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A new efficient synthesis of two novel classes of NK1 receptor antagonists, among them befetupitant and netupitant, starting from 6-chloronicotinic acid is described. The introduction of the o-tolyl substituent at C4 of the pyridine ring was achieved by a one-pot selective 1,4-Grignard addition/oxidation sequence to 6-chloronicotinic acid or a derivative of it. The scope of this addition/oxidation sequence was examined. It was also shown that the carboxylic function can be converted to a methyl amino group by a Hofmann rearrangement followed by reduction. Furthermore, a new high-yielding synthesis of 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionic acid based on the carbonylation of the tertiary alcohol obtained by Grignard addition of 3,5-bis(trifluoromethyl)bromobenzene to acetone was established.

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Synthesis of ¹⁴C‐labelled DDD isomers of high specific activity

Abstract: Three major DDD isomers, O,P'-DDD, m,p'-DDD and p,p'-DDD, 14C-labelled

Cited by 17 publications

References 3 publications

Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture.

Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture.

Adrenocorticolytic DDT-metabolites: studies in mink, Mustela vison and otter, Lutra lutra

Efficient Synthesis of Novel NK₁ Receptor Antagonists: Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives

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Synthesis of 14C‐labelled DDD isomers of high specific activity

Abstract: Three major DDD isomers, O,P'-DDD, m,p'-DDD and p,p'-DDD, 14C-labelled

Cited by 17 publications

References 3 publications

Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture.

Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture.

Adrenocorticolytic DDT-metabolites: studies in mink, Mustela vison and otter, Lutra lutra

Efficient Synthesis of Novel NK1 Receptor Antagonists: Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives

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Synthesis of ¹⁴C‐labelled DDD isomers of high specific activity

Efficient Synthesis of Novel NK₁ Receptor Antagonists: Selective 1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid Derivatives