Aryl bis(diazeniumdiolates): potent inducers of S-glutathionylation of cellular proteins and their in vitro antiproliferative activities.
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.
Andrei
Daniela
D
Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA. dandrei@dom.edu
Maciag
Anna E
AE
Chakrapani
Harinath
H
Citro
Michael L
ML
Keefer
Larry K
LK
Saavedra
Joseph E
JE
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
D001391:Azo Compounds; D020030:Nitric Oxide Donors; D011355:Prodrugs; C452539:diazeniumdiolate; D009569:Nitric Oxide; D005978:Glutathione