S-Nitroso-N-acetyl-L-cysteine ethyl ester (SNACET) and N-acetyl-L-cysteine ethyl ester (NACET)–Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H2S and GSH suppliers and as antioxidants: Results and overview

摘要

S-Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosylcation(NO+)and a thiolate(RS-),the base of the corresponding acids RSH.The smallest S-nitrosothiol isHSNO and derives from hydrogen sulfide(HSH,H2S).The most common physiological S-nitrosothiols arederived 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 guanylylcyclase to form cyclic guanosine monophosphate(cGMP).This activation is associated with multiplebiological 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 inhuman blood.CysSNO can be formed from CysSH and higher oxides of NO including nitrous acid(HONO)and its anhydride(N2O3).The most characteristic feature of RSNO is the S-transnitrosation reaction bywhich the NO+group is reversibly transferred to another thiolate.By this way numerous RSNO can beformed 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 erythrocytesand S-nitrosol-L-cysteine albumin(AlbCysSNO)present in plasma at concentrations of theorder of 200 nM.All above mentioned RSNO exert NO-related biological activity,but they must be administeredintravenously.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),fromsynthetic N-acetyl-L-cysteine ethyl ester(NACET).Both NACET and SNACET have improved pharmacologicalfeatures 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 theurogenital tract and in the cardiovascular system.NACET,with high oral bioavailability,is a strong antioxidantand abundant precursor of GSH,unlike its free acid N-acetyl-L-cysteine(NAC).Here,we reviewthe 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.