Nitroreductase activity of animal tissues and of normal and neoplastic human tissues

Green, Morris N.; Josimovich, John B.; Tsou, K. C.; Seligman, Arnold M.

doi:10.1002/1097-0142(195601/02)9:1<176::aid-cncr2820090118>3.0.co;2-s

Cited by 10 publications

(6 citation statements)

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“…There is a significant body of data indicating that nitrobenzene substrates can be reduced by nitroreductase enzymes 61−64 that are present in numerous human tissues. 65 Based on these findings and the sequential reduction mechanism of aromatic nitro compounds proposed by Biaglow et al, 66 we infer that the carbamyl-linked trinitrobenzene end-caps of the polyrotaxanes may be reduced to sterically smaller amine substituents that enable the cyclodextrins to slip off the polymer axles. Enzymatic end-cap cleavage is another potential mode of HP-β-CD release; 67 however, enzyme-mediated prodrug activation has not been reported for NPC cells to our knowledge.…”

Section: ■ Results and Discussionsupporting

confidence: 58%

“…Given the stability of the compounds at pH 5.5, we believe that the TNB group is nevertheless cleaved from the polyrotaxane by either an enzymatic or reduction reaction occurring within the LE/LY compartment. There is a significant body of data indicating that nitrobenzene substrates can be reduced by nitroreductase enzymes − that are present in numerous human tissues . Based on these findings and the sequential reduction mechanism of aromatic nitro compounds proposed by Biaglow et al, we infer that the carbamyl-linked trinitrobenzene end-caps of the polyrotaxanes may be reduced to sterically smaller amine substituents that enable the cyclodextrins to slip off the polymer axles.…”

Section: Resultsmentioning

confidence: 56%

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Synthesis of 2-Hydroxypropyl-β-cyclodextrin/Pluronic-Based Polyrotaxanes via Heterogeneous Reaction as Potential Niemann-Pick Type C Therapeutics

et al. 2013

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Five polyrotaxanes were synthesized by threading 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) onto a variety of α,ω-ditriethylenediamino-N-carbamoyl-poly-(ethylene oxide)-block-poly(propylene oxide)-block-poly-(ethylene oxide) (Pluronic) triblock copolymers using a two-pot strategy under heterogeneous, nonaqueous conditions. The threaded HP-β-CD units were retained on the pseudopolyrotaxane precursors by end-capping the branched diamine termini with sodium 2,4,6-trinitrobenzene sulfonate. Inclusion of the Pluronic copolymers within the HP-β-CD cavities was more favorable in nonpolar solvents, such as diethyl ether and n-hexane, both of which gave better coverage ratios than polar solvents. 1H NMR and MALDI-TOF were used to estimate the average molecular weights of the purified polyrotaxane products. A globular morphology of aggregated polyrotaxanes was observed by tapping-mode AFM imaging of dried samples. Treatment of Niemann-Pick C (NPC) type 2-deficient fibroblasts with the polyrotaxane derivatives produced substantial reductions in sterol accumulation, as seen by diminished filipin staining in these cells, suggesting that Pluronic-based polyrotaxanes may be promising vehicles for delivery of HP-β-CD to cells with abnormal cholesterol accumulation.

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Section: ■ Results and Discussionsupporting

confidence: 58%

Section: Resultsmentioning

confidence: 56%

Synthesis of 2-Hydroxypropyl-β-cyclodextrin/Pluronic-Based Polyrotaxanes via Heterogeneous Reaction as Potential Niemann-Pick Type C Therapeutics

et al. 2013

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“…Eine ältere Studie belegt auch eine Aktivität der Nitroreduktasen in der menschlichen Brustdrüse. Sie beträgt 1/8 der Aktivität der humanen Leber (Green et al 1956).…”

Section: Kanzerogenitätunclassified

Nitrobenzol [MAK Value Documentation in German language, 2017]

Hartwig

Arand²

2017

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated carcinogenicity of nitrobenzene [ 98‐95‐3 ], considering all endpoints. Available publications and unpublished study reports are described in detail. The genotoxic potential of nitrobenzene is low and might be a result of reactive oxygen species. Long‐term studies with exposure by inhalation resulted in a significant increase in liver and kidney adenomas in rats, and lung and mammary adenomas in mice. In severely toxic concentrations a nonsignificant increase in carcinomas was observed, probably resulting from a chronic toxic mechanism, supported by secondary genotoxic or DNA‐damaging effects at high doses. In view of other aromatic amines and the known mechanisms of action via phenylhydroxylamine, nitrobenzene is considered to be carcinogenic. Because of the non‐linear dose‐response relationship of the tumour incidences and as genotoxic effects play a minor part, nitrobenzene is classified in Carcinogen Category 4. Eye and skin irritation from nitrobenzene is low. The critical effect is the bronchialisation in the lungs of mice in a long‐term inhalation study. However, the incidence of bronchialisation at the lowest tested concentration of 5 ml/m 3 is too high to calculate a NAEC. One long‐term inhalation study in Sprague‐Dawley rats resulted in a NOAEC of 1 ml/m 3 , another one in F344 rats showed minimal extramedullary haematopoesis in the spleen of males at the lowest tested concentration of 1 ml/m 3 . Using this concentration as point of departure, a MAK value of 0.1 ml/m 3 is calculated, which is far below the LOAEC of the critical effect in the mouse lung. As the MAK value is derived from a systemic effect, nitrobenzene is assigned to Peak Limitation Category II. Because of the initial half‐life of 5 hours, the excursion factor of 4 is set. Skin contact may contribute significantly to systemic toxicity; therefore, the “H” notation is retained. Damage to the embryo or foetus is unlikely when the MAK value is observed and thus, the substance is classified in Pregnancy Risk Group C. Sensitization is not expected from the limited data.

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“…The nitroaromatic groups undergo bioactivation via nitroreduction to form various nitrogen-containing substituents [ 27 ]. This occurs largely in the GI tract, where nitroreductases are produced by gut microbiota [ 32 , 33 ]. The resultant nitrogen-containing compounds may then be absorbed by the GI tract and react with the DNA via nucleophilic substitution resulting in the formation of 8-hydroxydeoxyguanosine (8-OH-dG), or cause DNA damage such as cleavage at pyrimidines [ 29 , 33 , 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

“…This occurs largely in the GI tract, where nitroreductases are produced by gut microbiota [ 32 , 33 ]. The resultant nitrogen-containing compounds may then be absorbed by the GI tract and react with the DNA via nucleophilic substitution resulting in the formation of 8-hydroxydeoxyguanosine (8-OH-dG), or cause DNA damage such as cleavage at pyrimidines [ 29 , 33 , 34 , 35 ]. It remains to be determined if the aniline 4′-NO 2 group on niclosamide may likewise trigger cellular DNA damage and confer nonspecific cytotoxicity in cells.…”

Section: Introductionmentioning

confidence: 99%

Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy

Ngai

Elfar

Yeo

et al. 2021

IJMS

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Niclosamide is an oral anthelmintic drug, approved for use against tapeworm infections. Recent studies suggest however that niclosamide may have broader clinical applications in cancers, spurring increased interest in the functions and mechanisms of niclosamide. Previously, we reported that niclosamide targets a metabolic vulnerability in p53-deficient tumours, providing a basis for patient stratification and personalised treatment strategies. In the present study, we functionally characterised the contribution of the aniline 4′-NO2 group on niclosamide to its cellular activities. We demonstrated that niclosamide induces genome-wide DNA damage that is mechanistically uncoupled from its antitumour effects mediated through mitochondrial uncoupling. Elimination of the nitro group in ND-Nic analogue significantly reduced γH2AX signals and DNA breaks while preserving its antitumour mechanism mediated through a calcium signalling pathway and arachidonic acid metabolism. Lipidomics profiling further revealed that ND-Nic-treated cells retained a metabolite profile characteristic of niclosamide-treated cells. Notably, quantitative scoring of drug sensitivity suggests that elimination of its nitro group enhanced the target selectivity of niclosamide against p53 deficiency. Importantly, the results also raise concern that niclosamide may impose a pleiotropic genotoxic effect, which limits its clinical efficacy and warrants further investigation into alternative drug analogues that may ameliorate any potential unwanted side effects.

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Nitroreductase activity of animal tissues and of normal and neoplastic human tissues

Cited by 10 publications

References 8 publications

Synthesis of 2-Hydroxypropyl-β-cyclodextrin/Pluronic-Based Polyrotaxanes via Heterogeneous Reaction as Potential Niemann-Pick Type C Therapeutics

Synthesis of 2-Hydroxypropyl-β-cyclodextrin/Pluronic-Based Polyrotaxanes via Heterogeneous Reaction as Potential Niemann-Pick Type C Therapeutics

Nitrobenzol [MAK Value Documentation in German language, 2017]

Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy

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