Aryl Bis(diazeniumdiolates): Potent Inducers of S-Glutathionylation of Cellular Proteins and Their in Vitro Antiproliferative Activities
- Daniela Andrei
- ,
- Anna E. Maciag
- ,
- Harinath Chakrapani
- ,
- Michael L. Citro
- ,
- Larry K. Keefer
- , and
- Joseph E. Saavedra
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Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702, and Basic Research Program, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702
* To whom correspondence should be addressed. For D.A.: phone, 708-524-6540; fax, 708-524-6055; e-mail, [email protected]. For L.K.K.: phone, 301-846-1467; fax, 301-846-5946; e-mail, [email protected]
†Laboratory of Comparative Carcinogenesis, National Cancer Institute.
‡Present address: Chemistry Department, Dominican University, 7900 W. Division Street, River Forest, IL 60305.
§These authors contributed equally to this work.
⊥SAIC-Frederick.
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 O2-{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.
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