S-Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation (NO?) and a thiolate (RS?), the
base of the corresponding acids RSH. The smallest S-nitrosothiol is
HSNO and derives from hydrogen sulfide (HSH, H2S). The most common
physiological S-nitrosothiols are derived from the amino acid L-cysteine
(CysSH). Thus, the simplest S-nitrosothiol is S-nitroso-L-cysteine
(CysSNO). CysSNO is a spontaneous potent donor of nitric oxide (NO)
which activates soluble guanylyl cyclase to form cyclic guanosine
monophosphate (cGMP). This activation is associated with multiple
biological actions that include relaxation of smooth muscle cells and
inhibition of platelet aggregation. Like NO, CysSNO is a short-lived
species and occurs physiologically at concentrations around 1 nM in
human blood. CysSNO can be formed from CysSH and higher oxides of NO
including nitrous acid (HONO) and its anhydride (N2O3).
N-Acetyl-L-cysteine ethyl esterThe most characteristic feature of RSNO is the S-transnitrosation
reaction by which the NO? group is reversibly transferred to another
thiolate. By this way numerous RSNO can be formed such as the
low-molecular-mass S-nitroso-N-acetyl-L-cysteine (SNAC) and
S-nitroso-glutathione (GSNO), and the high-molecular-mass
S-nitrosol-L-cysteine hemoglobin (HbCysSNO) present in erythrocytes and
S-nitrosol-L-cysteine albumin (AlbCysSNO) present in plasma at
concentrations of the order of 200 nM. All above mentioned RSNO exert
NO-related biological activity, but they must be administered
intravenously.
This important drawback can be overcome by lipophilic charge-free RSNO.
Thus, we prepared the ethyl ester of SNAC, the
S-nitroso-N-acetyl-L-cysteine ethyl ester (SNACET), from synthetic
N-acetyl-L-cysteine ethyl ester (NACET). Both NACET and SNACET have
improved pharmacological features over N-acetyl-L-cysteine (NAC) and
S-nitroso-N-acetyl-L-cysteine (SNAC), respectively, including higher
oral bioavailability. SNACET exerts NO-related activities which can be
utilized in the urogenital tract and in the cardiovascular system. NACET
has high oral bioavailability, is a strong antioxidant and abundant
precursor of GSH, unlike its free acid N-acetyl-L-cysteine (NAC). Here,
we review the chemical and pharmacological properties of SNACET and
NACET as well as their analytical chemistry. We also report new results
from the ingestion of S-[¹5N]nitroso-N-acetyl-L-cysteine ethyl ester
(S¹5NACET) demonstrating the favorable pharmacological profile of
SNACET.
