title: Aryl bis(diazeniumdiolates): potent inducers of S-glutathionylation of cellular proteins and their in vitro antiproliferative activities.
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.
authors.affiliation: Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA. dandrei@dom.edu
authors.forename: Daniela
authors.initials: D
authors.lastname: Andrei
authors.forename: Anna E
authors.initials: AE
authors.lastname: Maciag
authors.forename: Harinath
authors.initials: H
authors.lastname: Chakrapani
authors.forename: Michael L
authors.initials: ML
authors.lastname: Citro
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
mesh_terms: D001391:Azo Compounds / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000737:chemistry*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009569:Nitric Oxide / Q000737:chemistry; D020030:Nitric Oxide Donors / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry
chemical_list: D001391:Azo Compounds; D020030:Nitric Oxide Donors; D011355:Prodrugs; C452539:diazeniumdiolate; D009569:Nitric Oxide; D005978:Glutathione