903568-91-2Relevant academic research and scientific papers
Hybrid molecule from O2-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid: A glutathione S-transferase π-activated nitric oxide prodrug with selective anti-human hepatocellular carcinoma activity and improved stability
Fu, Junjie,Liu, Ling,Huang, Zhangjian,Lai, Yisheng,Ji, Hui,Peng, Sixun,Tian, Jide,Zhang, Yihua
, p. 4641 - 4655 (2013/07/19)
A series of hybrids from O2-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferase π (GSTπ) overexpressed in a number of cancer cells. It was discovered that the most active compound, 21, released high levels of NO selectively in HCC cells but not in the normal cells and exhibited potent antiproliferative activity in vitro as well as remarkable tumor-retarding effects in vivo. Compared with the reported GSTπ-activated prodrugs JS-K and PABA/NO, 21 exhibited remarkably improved stability in the absence of GSTπ. Importantly, the decomposition of 21 occurred in the presence of GSTπ and was much more effective than in glutathione S-transferase α. Additionally, 21 induced apoptosis in HepG2 cells by arresting the cell cycle at the G2/M phase, activating both the mitochondrion-mediated pathway and the MAPK pathway and enhancing the intracellular production of ROS.
Aryl bis(diazeniumdiolates): Potent inducers of S-glutathionylation of cellular proteins and their in vitro antiproliferative activities
Andrei, Daniela,Maciag, Anna E.,Chakrapani, Harinath,Citro, Michael L.,Keefer, Larry K.,Saavedra, Joseph E.
scheme or table, p. 7944 - 7952 (2009/12/07)
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.
The secondary amine/nitric oxide complex ion R2N[N(O)NO]- as nucleophile and leaving group in SNAr reactions
Saavedra,Srinivasan,Bonifant,Chu,Shanklin,Flippen-Anderson,Rice,Turpin,Davies,Keefer
, p. 3090 - 3098 (2007/10/03)
Ions of structure R2N[N(O)NO]- and their alkylation products have seen increasing use as nitric oxide (NO)-generating agents for biomedical research applications. Here we show that such diazeniumdiolate anions can readily displace halide from a variety of electrophilic aza- or nitroaromatic substrates to form O2-arylated derivatives of structure R2N-N(O)=N-OAr. The site of arylation and the cis arrangement of the oxygens were confirmed by X-ray crystallography. Displacement by various nucleophiles showed R2N[N(O)NO]- to be a reasonably good leaving group, with rate constants for displacement by hydroxide, methoxide, and isopropylamine that were between those of chloride and fluoride in the SNAr reactions we surveyed. The Meisenheimer intermediate could be spectrally observed. These O2-aryl diazeniumdiolates proved capable of reacting with the nucleophilic sulfur of the HIV-1 p7 nucleocapsid protein's zinc finger assembly to eject the zinc, disrupting a structural motif critical to viral replication and suggesting possible utility in the drug discovery realm.
