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首页> 美国卫生研究院文献>Journal of Pharmaceutical Analysis >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
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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

机译：S-亚硝基-N-乙酰基-L-半胱氨酸乙酯（SNACET）和N-乙酰基-L-半胱氨酸乙酯（NACET）–基于半胱氨​​酸的候选药物具有独特的药理学特征可作为NOH2S和GSH的供应商进行口服作为抗氧化剂：结果和概述

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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). The 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, 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-[15N]nitroso-N-acetyl-L-cysteine ethyl ester (S15NACET) demonstrating the favorable pharmacological profile of SNACET.
机译：通式为RSNO的S-亚硝基硫醇或亚硫氰酸盐由亚硝酰基阳离子（NO + ）和硫醇盐（RS -）形式组成，后者是相应酸RSH的碱。最小的S-亚硝基硫醇是HSNO，衍生自硫化氢（HSH，H2S）。最常见的生理S-亚硝基硫醇衍生自氨基酸L-半胱氨酸（CysSH）。因此，最简单的S-亚硝基硫醇是S-亚硝基-L-半胱氨酸（CysSNO）。 CysSNO是一氧化氮（NO）的自发有效供体，可激活可溶性鸟苷基环化酶形成环状鸟苷单磷酸（cGMP）。这种激活与多种生物学作用有关，包括松弛平滑肌细胞和抑制血小板聚集。与NO一样，CysSNO是短命的物种，在人体血液中的生理浓度约为1nM。 CysSNO可由CysSH和NO的高级氧化物（包括亚硝酸（HONO）及其酸酐（N2O3））形成。 RSNO的最典型特征是S-反硝化反应，通过该反应，NO + 基团可逆地转移到另一种硫醇盐上。通过这种方式，可以形成许多RSNO，例如低分子S-亚硝基-N-乙酰基-L-半胱氨酸（SNAC）和S-亚硝基谷胱甘肽（GSNO），以及高分子量S-亚硝基溶胶血浆中存在的-L-半胱氨酸血红蛋白（HbCysSNO）和血浆中存在的S-亚硝酚-L-半胱氨酸白蛋白（AlbCysSNO）的浓度约为200 nM。以上提到的RSNO均具有NO相关的生物学活性，但必须静脉内给药。这个重要的缺点可以通过无亲脂性的RSNO克服。因此，我们从合成的N-乙酰基-L-半胱氨酸乙酯（NACET）制备了SNAC的乙酯，即S-亚硝基-N-乙酰基-L-半胱氨酸乙酯（SNACET）。 NACET和SNACET分别具有比N-乙酰基-L-半胱氨酸（NAC）和S-亚硝基-N-乙酰基-L-半胱氨酸（SNAC）更高的药理特性，包括更高的口服生物利用度。 SNACET发挥与NO相关的活性，可在泌尿生殖道和心血管系统中利用。 NACET具有很高的口服生物利用度，与GSH的游离酸 N -乙酰基-L-半胱氨酸（NAC）不同，它是GSH的强抗氧化剂和丰富的前体。在这里，我们审查SNACET和NACET的化学和药理特性，以及它们的分析化学。我们还报告了摄入 S -[ 15 N]亚硝基- N -乙酰基-L-半胱氨酸乙酯（S < sup> 15 NACET）证明了SNACET的良好药理特性。

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