S-Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation(NOt) and a thiolate(RSà), the base of the corresponding acids RSH. The smallest S-nitrosothiol is HSNO an...S-Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation(NOt) and a thiolate(RSà), the base of the corresponding acids RSH. The smallest S-nitrosothiol is HSNO and derives from hydrogen sulfide(HSH, H_2S). The most common physiological S-nitrosothiols are derived from the amino acid L-cysteine(Cys SH). Thus, the simplest S-nitrosothiol is S-nitroso-L-cysteine(Cys SNO). Cys SNO is a spontaneous potent donor of nitric oxide(NO) which activates soluble guanylyl cyclase to form cyclic guanosine monophosphate(c GMP). This activation is associated with multiple biological actions that include relaxation of smooth muscle cells and inhibition of platelet aggregation.Like NO, Cys SNO is a short-lived species and occurs physiologically at concentrations around 1 n M in human blood. Cys SNO can be formed from Cys SH and higher oxides of NO including nitrous acid(HONO)and its anhydride(N_2O_3). The most characteristic feature of RSNO is the S-transnitrosation reaction by which the NOtgroup 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(Hb Cys SNO) present in erythrocytes and S-nitrosol-L-cysteine albumin(Alb Cys SNO) present in plasma at concentrations of the order of 200 n M. 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, with 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-[^(15) N]nitroso-N-acetyl-L-cysteine ethyl ester(S^(15) NACET) demonstrating the favorable pharmacological profile of SNACET.展开更多
文摘S-Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation(NOt) and a thiolate(RSà), the base of the corresponding acids RSH. The smallest S-nitrosothiol is HSNO and derives from hydrogen sulfide(HSH, H_2S). The most common physiological S-nitrosothiols are derived from the amino acid L-cysteine(Cys SH). Thus, the simplest S-nitrosothiol is S-nitroso-L-cysteine(Cys SNO). Cys SNO is a spontaneous potent donor of nitric oxide(NO) which activates soluble guanylyl cyclase to form cyclic guanosine monophosphate(c GMP). This activation is associated with multiple biological actions that include relaxation of smooth muscle cells and inhibition of platelet aggregation.Like NO, Cys SNO is a short-lived species and occurs physiologically at concentrations around 1 n M in human blood. Cys SNO can be formed from Cys SH and higher oxides of NO including nitrous acid(HONO)and its anhydride(N_2O_3). The most characteristic feature of RSNO is the S-transnitrosation reaction by which the NOtgroup 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(Hb Cys SNO) present in erythrocytes and S-nitrosol-L-cysteine albumin(Alb Cys SNO) present in plasma at concentrations of the order of 200 n M. 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, with 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-[^(15) N]nitroso-N-acetyl-L-cysteine ethyl ester(S^(15) NACET) demonstrating the favorable pharmacological profile of SNACET.
