Acyloxy nitroso compounds as nitroxyl (HNO) donors: kinetics, reactions with thiols, and vasodilation properties.
Acyloxy nitroso compounds hydrolyze to nitroxyl (HNO), a nitrogen monoxide with distinct chemistry and biology. Ultraviolet-visible spectroscopy and mass spectrometry show hydrolysis rate depends on pH and ester group structure with the observed rate being trifluoroacetate (3) > acetate (1) > pivalate (2). Under all conditions, 3 rapidly hydrolyzes to HNO. A combination of spectroscopic, kinetic, and product studies show that addition of thiols increases the decomposition rate of 1 and 2, leading to hydrolysis and HNO. Under conditions that favor thiolates, the thiolate directly reacts with the nitroso group, yielding oximes without HNO formation. Biologically, 3 behaves like Angeli's salt, demonstrating thiol-sensitive nitric oxide-mediated soluble guanylate cyclase-dependent vasorelaxation, suggesting HNO-mediated vasorelaxation. The slow HNO-donor 1 demonstrates weak thiol-insensitive vasorelaxation, indicating HNO release kinetics determine HNO bioavailability and activity. These results show that acyloxy nitroso compounds represent new HNO donors capable of vasorelaxation depending on HNO release kinetics.
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States.
Mai E
ME
Shoman
Jenna F
JF
DuMond
T S
TS
Isbell
J H
JH
Crawford
Angela
A
Brandon
Jaideep
J
Honovar
Dario A
DA
Vitturi
C R
CR
White
R P
RP
Patel
S Bruce
SB
King
D000818:Animals; D001011:Aorta / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009589:Nitrogen Oxides / Q000737:chemistry* / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014665:Vasodilator Agents / Q000737:chemistry* / Q000494:pharmacology*
D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D013438:Sulfhydryl Compounds; D014665:Vasodilator Agents; C039900:nitroxyl
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