Reactions of the nitroso analogue of chloramphenicol with reduced glutathione

Eyer, Peter; Schneller, Maximilian

doi:10.1016/0006-2952(83)90621-4

Cited by 34 publications

(46 citation statements)

References 23 publications

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“…Thiols are known to react with aromatic nitroso agents to give unstable thionitroxide radicals [ARN(O•)SR] 50 and, as mentioned earlier, form semimercaptals. 44,51,52 Thiols, including glutathione, also react with one electron reduction products of nitroaromatic drugs 53 but in some cases the thiol acts as a reducing agents only after alternative formation of the nitro radical anion. 48 …”

Section: Resultsmentioning

confidence: 99%

Thiolates Chemically Induce Redox Activation of BTZ043 and Related Potent Nitroaromatic Anti-Tuberculosis Agents

et al. 2013

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The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitro aromatic compounds, including 1, 3-Benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl-β-D-ribose 2′ oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitro aromatic compounds synthesized by us and the others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide and hydride induce non-enzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron deficient aromatic carbon present in these compounds. Furthermore we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypotheses for the mechanism of action of nitro aromatic anti-TB agents in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1.

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Section: Resultsmentioning

confidence: 99%

Thiolates Chemically Induce Redox Activation of BTZ043 and Related Potent Nitroaromatic Anti-Tuberculosis Agents

et al. 2013

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“…Reduction of the carbonyl moiety and hydrolysis of the acetamido group produced the desired bases 19-22 as an oily mixture. Using procedures described above, ( 5 )-2-dichloroacetamido-~-hydroxy-4-methylmercaptopropiophenone (35) was reduced with sodium borohydride to give a mixture of 23-26; yield 64%, melting range 102-115 "C. A portion of the reduction product was hydrolyzed to obtain a mixture of the bases (kl-threo-and (~)-erythro-2-amino-l-(p-methylmercaptophenyl)-1,3-propanediol (27)(28)(29)(30) in an overall yield of 60%; melting range 98-113°C. Oxidation of another portion of the reduction product with peracetic acid following a published procedure" produced a mixture of (*)-three-and (-t)-erythro-l-pmethanesulfonylphenyl-2-dichloroacetamido-1,3-propanediol (1 1-14) in 63% yield; melting range 159-171 "C. Hydrolysis of this mixture, as usual, afforded a mixture of the bases (*)-three-and (?…”

Section: Methodsmentioning

confidence: 99%

Reversed-Phase Liquid Chromatographic Separation of Enantiomeric and Diastereomeric Bases Related to Chloramphenicol and Thiamphenicol

Gál

Meyer-Lehnert

1988

Journal of Pharmaceutical Sciences

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“…The inhibition seen with NAC and NO-CAP may involve direct interaction of the SH group with the p-NO moiety. Aromatic nitroso groups are known to react with glutathione to yield reduction products of the nitroso group [17]. In the presence of sulfhydryl such as NAC, NO-CAP could be inactivated by conversion to the corresponding amine.…”

Section: Discussionmentioning

confidence: 99%

DNA Damage Induced by Chloramphenicol and Nitroso-Chloramphenicol: Protection by N-Acetylcysteine

Aa¹,

Lo²,

Gk³

1986

Respiration

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We have previously demonstrated that nitroso-chloramphenicol (NO-CAP) in small concentrations causes the hydrolysis of isolated double stranded DNA in vitro and this action is blocked by sulfhydryl groups. The present study was designed to assess damage to isolated DNA as well as intact cells DNA and examine the protective effect of N-acetylcysteine (NAC). Using alkaline sucrose gradient sedimentation and the alkali elution technique of Kohn we were able to demonstrate DNA damage in Raji cells as well as phytohemagglutinin stimulated human lymphocytes after exposure to NO-CAP. Damage could be totally blocked by NAC. In preliminary studies we also observed that NAC protects bone marrow cells from the growth-inhibitory effects of chloramphenicol and thiamphenicol

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Reactions of the nitroso analogue of chloramphenicol with reduced glutathione

Cited by 34 publications

References 23 publications

Thiolates Chemically Induce Redox Activation of BTZ043 and Related Potent Nitroaromatic Anti-Tuberculosis Agents

Thiolates Chemically Induce Redox Activation of BTZ043 and Related Potent Nitroaromatic Anti-Tuberculosis Agents

Reversed-Phase Liquid Chromatographic Separation of Enantiomeric and Diastereomeric Bases Related to Chloramphenicol and Thiamphenicol

DNA Damage Induced by Chloramphenicol and Nitroso-Chloramphenicol: Protection by N-Acetylcysteine

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