Aryl bis(diazeniumdiolates): potent inducers of S-glutathionylation of cellular proteins and their in vitro antiproliferative activities.

doi:10.1021/jm800831y

Paper

Aryl bis(diazeniumdiolates): potent inducers of S-glutathionylation of cellular proteins and their in vitro antiproliferative activities.

Published Dec 25, 2008 · Daniela Andrei, A. Maciąg, Harinath Chakrapani

Journal of medicinal chemistry

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21

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1

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Abstract

A number of bis(diazeniumdiolates) that we designed to release up to 4 mol of nitric oxide (NO) and that are structural analogues of the NO prodrug and anticancer lead compound O(2)-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2- diolate (PABA/NO) were synthesized and studied. A majority of these compounds yielded higher levels of NO, were better inhibitors of proliferation of a number of cancer cell lines, and more rapidly induced substantially increased levels of S-glutathionylation of cellular proteins in comparison with PABA/NO. In most cases, the antiproliferative activity and extents of S-glutathionylation correlated well with levels of intracellular NO release. We report bis(diazeniumdiolates) to be a class of S-glutathionylating agents with potent antiproliferative and S-glutathionylating activity.

In Vitro Study

Study Snapshot

Bis(diazeniumdiolates) are potent antiproliferative and S-glutathionylating agents with improved anticancer activity compared to PABA/NO.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Aryl bis(diazeniumdiolates): potent inducers of S-glutathionylation of cellular proteins and their in vitro antiproliferative activities.

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References

Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compound.

Glutathione-activated nitric oxide prodrugs show potential as effective anti-leukemic agents due to their ability to release nearly quantitative amounts of nitric oxide and their superior cytotoxic effects against human leukemia cells.

Synthesis and in vitro anti-leukemic activity of structural analogues of JS-K, an anti-cancer lead compound.

Two structural analogues of JS-K show potent inhibitory activity and a potentially favorable toxicological profile, with no effect on nitric oxide release rate.

Molecular mechanisms and potential clinical significance of S-glutathionylation.

Protein S-glutathionylation plays a role in protein redox regulation, storage of glutathione, and protection against oxidation, with potential implications in cataractogenesis, Alzheimer's disease, and aging human lenses.

Nitric oxide prodrugs: diazeniumdiolate anions of hindered secondary amines.

Nitric oxide prodrugs derived from hindered secondary amines have a longer half-life in aqueous buffer due to alpha-methyl groups around the nitrogen-bearing diazeniumdiolate group.

S-glutathionylation in protein redox regulation.

Protein S-glutathionylation plays a potential role in redox regulation of signaling and metabolic pathways in cells, with potential implications for cellular response pathways.

Citations