Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Finkelstein, Martin B.; Vamvakas, Spyridon; Bittner, Detlef; Anders, M. W.

doi:10.1021/tx00038a007

Cited by 21 publications

(11 citation statements)

References 41 publications

(65 reference statements)

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“…Independent experimental studies on the cysteine S-conjugate precursors to the 2,2-dihalo-DFETs have provided clear evidence for a thionoacyl fluoride pathway in the β-lyase-mediated bioactivation of TFE (14-17, 20, 21). Experimental studies are also in agreement in support of an alternate metabolic pathway for bioactivation of the brominated 2,2-dihalo-DFECs, although different pathways have been proposed to account for characteristic metabolites and mutagenicity, involving either a thiirane intermediate (13,15,16,22) or a novel degradation pathway via an R-thiolactone from the initial formation of a thionoacyl fluoride intermediate (20,21). In agreement with experiment, the present computational results consistently predict that the TFE-derived, 2,2-difluoro-DFET prefers a thionoacyl fluoride pathway.…”

Section: Discussionsupporting

confidence: 59%

Theoretical Evaluation of Two Plausible Routes for Bioactivation of S-(1,1-Difluoro-2,2-dihaloethyl)-l-cysteine Conjugates: Thiirane vs Thionoacyl Fluoride Pathway

Shim

Richard

1997

Chem. Res. Toxicol.

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The selective nephrotoxicity of halogenated alkenes has been attributed to a glutathione (GSH) S-conjugate pathway involving enzymatic hydrolysis to the cysteine S-conjugate and beta-lyase bioactivation to thiolates, which are presumed to give rise to the ultimate mutagenic or cytotoxic reactive species. Studies have shown that the brominated S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteine conjugates are mutagenic in the Ames test, whereas the nonbrominated analogues are nonmutagenic. While careful experimentation has contributed much to current understanding, the ultimate reactive species responsible for the differing mutagenic effects remain unknown. Computational methods were applied to the investigation of two proposed metabolic pathways leading from the thiolate to either a thiirane or thionoacyl fluoride intermediate, both electrophilic species presumed capable of binding to proteins or DNA. Studied were six F-, Cl-, and Br-substituted 2,2-dihalo-1,1-difluoroethane-1-thiolates (2,2-dihalo-DFETs). Pathway preference was determined for each thiolate by comparison of reaction energy profiles and activation energies. At all but the lowest level of ab initio theory, a thionoacyl fluoride pathway was predicted for 2,2-difluoro-DFET, while a thiirane pathway was energetically preferred for the brominated 2,2-dihalo-DFETs. These results offer a clear mechanism-based rationale for distinguishing 2,2-difluoro-DFET from the brominated 2,2-dihalo-DFETs, while the results are less clear for the 2,2-dichloro and 2-chloro-2-fluoro-DFETs, which at the highest level of ab initio treatment had a relatively small energy preference (2.4 kcal/mol) for the thiirane pathway. The predicted clear preference for a thiirane pathway for the brominated 2,2-dihalo-DFETs is not consistent with a recently proposed pathway involving alpha-thiolactone formation through a thionoacyl fluoride intermediate [Finkelstein, M. B., et al. (1995) J. Am. Chem. Soc. 117, 9590-9591], but is supported by results of a recent study providing experimental evidence for thiirane formation from the brominated 2,2-dihalo-DFETs [Finkelstein, M. B., et al. (1996) Chem. Res. Toxicol. 9, 227-231].

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Section: Discussionsupporting

confidence: 59%

Theoretical Evaluation of Two Plausible Routes for Bioactivation of S-(1,1-Difluoro-2,2-dihaloethyl)-l-cysteine Conjugates: Thiirane vs Thionoacyl Fluoride Pathway

Shim

Richard

1997

Chem. Res. Toxicol.

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“…Within the dataset used, we found 12 compounds that contain bromine (many with multiple bromine atoms), 11 of which are mutagenic, and thus the number of bromine atoms represents a simple mutagenicity filter based on these data. This finding is consistent with experimental findings that bromine-containing chemical structures are more mutagenic than analogues within which chlorine is substituted for bromine (Finkelstein 1994).…”

Section: Mutagenicitysupporting

confidence: 91%

A Randomized Exhaustive Propositionalization Approach for Molecule Classification

Samorani

Laguna

DeLisle

et al. 2011

INFORMS Journal on Computing

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Drug discovery is the process of designing compounds that have desirable properties, such as activity and non-toxicity. Molecule classification techniques are used along this process to predict the properties of the compounds in order to expedite their testing. Ideally, the classification rules found should be accurate and reveal novel chemical properties, but current molecule representation techniques lead to less than adequate accuracy and knowledge discovery. This work extends the propositionalization approach recently proposed for multi-relational data mining in two ways: it generates expressive attributes exhaustively and it uses randomization to sample a limited set of complex ("deep") attributes. Our experimental tests show that the procedure is able to generate meaningful and interpretable attributes from molecular structural data, and that these features are effective for classification purposes.

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“…The product gave white crystals: mp 97-99 °C [lit. mp 100 °C (30)]; 1 (33), respectively, with pentafluorophenyl acetate in DMF, as described above. The acetylated products were purified by silica gel column chromatography.…”

Section: N-acetyl-l-2-aminopentanoic Acid N-acetyl-o-methyl-mentioning

confidence: 99%

Acylase I-Catalyzed Deacetylation of N-Acetyl-l-cysteine and S-Alkyl-N-acetyl-l-cysteines

Uttamsingh

Keller

Anders

1998

Chem. Res. Toxicol.

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The aminoacylase that catalyzes the hydrolysis of N-acetyl-L-cysteine (NAC) was identified as acylase I after purification by column chromatography and electrophoretic analysis. Rat kidney cytosol was fractionated by ammonium sulfate precipitation, and the proteins were separated by ion-exchange column chromatography, gel-filtration column chromatography, and hydrophobic interaction column chromatography. Acylase activity with NAC and N-acetyl-L-methionine (NAM), a known substrate for acylase I, as substrates coeluted during all chromatographic steps. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the protein was purified to near homogeneity and had a subunit Mr of 43 000, which is identical with the Mr of acylase I from porcine kidney and bovine liver. n-Butylmalonic acid was a slow-binding inhibitor of acylase I and inhibited the deacetylation of NAC with a Ki of 192 +/- 27 microM. These results show that acylase I catalyzes the deacetylation of NAC. The acylase I-catalyzed deacetylation of a range of S-alkyl-N-acetyl-L-cysteines, their carbon and oxygen analogues, and the selenium analogue of NAM was also studied with porcine kidney acylase I. The specific activity of the acylase I-catalyzed deacetylation of these substrates was related to their calculated molar volumes and log P values. The S-alkyl-N-acetyl-L-cysteines with short (C0-C3) and unbranched S-alkyl substituents were good acylase I substrates, whereas the S-alkyl-N-acetyl-L-cysteines with long (>C3) and branched S-alkyl substituents were poLr acylase I substrates. The carbon and oxygen analogues of S-methyl-N-acetyl-L-cysteine and the carbon analogue of S-ethyl-N-acetyl-L-cysteine were poor acylase I substrates, whereas the selenium analogue of NAM was a good acylase I substrate.

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Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Cited by 21 publications

References 41 publications

Theoretical Evaluation of Two Plausible Routes for Bioactivation of S-(1,1-Difluoro-2,2-dihaloethyl)-l-cysteine Conjugates: Thiirane vs Thionoacyl Fluoride Pathway

Theoretical Evaluation of Two Plausible Routes for Bioactivation of S-(1,1-Difluoro-2,2-dihaloethyl)-l-cysteine Conjugates: Thiirane vs Thionoacyl Fluoride Pathway

A Randomized Exhaustive Propositionalization Approach for Molecule Classification

Acylase I-Catalyzed Deacetylation of N-Acetyl-l-cysteine and S-Alkyl-N-acetyl-l-cysteines

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