4-Aryl-1,3,2-oxathiazolylium-5-olates as pH-controlled NO-donors: the next generation of S-nitrosothiols.
S-Nitrosothiols (RSNOs) are important exogenous and endogenous sources of nitric oxide (NO) in biological systems. A series of 4-aryl-1,3,2-oxathiazolylium-5-olates derivatives with varying aryl para-substituents (-CF3, -H, -Cl, and -OCH3) were synthesized. These compounds were found to release NO under acidic condition (pH = 5). The decomposition pathway of the aryloxathiazolyliumolates proceeded via an acid-catalyzed ring-opening mechanism after which NO was released and an S-centered radical was generated. Electron paramagnetic resonance (EPR) spin trapping studies were performed to detect NO and the S-centered radical using the spin traps of iron(II) N-methyl-D-glucamine dithiocarbamate [(MGD)2-FeII] and 5,5-dimethyl-1-pyrroline N-oxide (DMPO). Also, EPR spin trapping and UV-vis spectrophotometry were used to analyze the effect of aryl para substitution on the NO-releasing property of aryloxathiazolyliumolates. The results showed that the presence of an electron-withdrawing substituent such as -CF3 enhanced the NO-releasing capability of the aryloxathiazolyliumolates, whereas an electron-donating substituent like methoxy (-OCH3) diminished it. Computational studies using density functional theory (DFT) at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level were used to rationalize the experimental observations. The aryloxathiazolyliumolates diminished susceptibility to reduction by ascorbate or gluthathione, and their capacity to cause vasodilation as compared to other S-nitrosothiols suggests potential application in biological systems.
Lu
Dongning
D
Department of Biochemistry, The Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Nadas
Janos
J
Zhang
Guisheng
G
Johnson
Wesley
W
Zweier
Jay L
JL
Cardounel
Arturo J
AJ
Villamena
Frederick A
FA
Wang
Peng George
PG
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D019295:Computational Biology; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008958:Models, Molecular; D009569:Nitric Oxide / Q000737:chemistry; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D026403:S-Nitrosothiols / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D007202:Indicators and Reagents; D020030:Nitric Oxide Donors; D010080:Oxazoles; D026403:S-Nitrosothiols; D013844:Thiazoles; D014665:Vasodilator Agents; D009569:Nitric Oxide