7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid | 153881-25-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid
• 英文别名: (3R)-7-(2-aminoethyl)-5-hydroxy-3,4-dihydro-2H-1,4-benzothiazine-3-carboxylic acid
• CAS: 153881-25-5
• 化学式: C₁₁H₁₄N₂O₃S
• 分子量: 254.31
• InChiKey: HZALHIJVRHAZKE-ZETCQYMHSA-N

物化性质

• 沸点：
  525.2±50.0 °C(Predicted)
• 密度：
  1.421±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  121
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  谷胱甘肽 、 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid 以 phosphate buffer 为溶剂， 生成 6-S-glutathionyl-7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid 、 8-S-glutathionyl-7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid 、 6,8-di-S-glutathionyl-7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid
  参考文献：
  名称：

  Influence of glutathione on the oxidation chemistry of 5-S-cysteinyldopamine: potentially neuroprotective reactions of relevance to Parkinson's disease

  摘要：

  In recent reports from this laboratory we have hypothesized that a key step underlying the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNc) in Parkinson's disease is an accelerated rate of oxidation of intraneuronal dopamine in the presence of L-cysteine (CySH) to form initially 5-S-cysteinyldopamine (5-S-CyS-DA). 5-S-CyS-DA, however, is more easily oxidized than dopamine in a reaction which leads to the dihydrobenzothiazine (DHBT) 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1), a putative endogenously-formed metabolite that may be responsible for inhibition of mitochondrial complex I and alpha -ketoglutarate dehydrogenase, characteristic defects in the parkinsonian SNc. In this investigation it is demonstrated that glutathione (GSH) dramatically attenuates the oxidative transformation of 5-S-CyS-DA into DHBT-1 by two major pathways. In one pathway GSH displaces the cysteinyl residue from the o-quinone proximate oxidation product of 5-S-CyS-DA forming the corresponding glutathionyl conjugate that is attacked by GSH, to form 2,5-di-S-glutathionyldopamine, or by released CySH to give 2-S-cysteinyl-5-S-glutathionyldopamine. The former is the precursor of 2,5,6-tris-S-glutathionyldopamine, a major reaction product. However, intramolecular cyclization of the o-quinone proximate product of 2-S-cysteinyl-5-S-glutathionyldopamine is the first step in a pathway leading to glutathionyl conjugates of 8-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-5). The second pathway involves nucleophilic addition of GSH to the o-quinone proximate oxidation product of 5-S-CyS-DA forming 2-S-glutathionyl-5-S-cysteinyldopamine the precursor of a number of glutathionyl conjugates of DHBT-1. These results raise the possibility that strategies which elevate intraneuronal levels of GSH in dopaminergic SNc cells in Parkinson's disease patients may block formation of the putative mitochondrial toxin DHBT-1 and hence be neuroprotective. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4020(00)00953-4
• 作为产物：
  描述：

  5-S-半胱氨酰多巴胺 以 phosphate buffer 为溶剂， 生成 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid
  参考文献：
  名称：

  Influence of glutathione on the oxidation chemistry of 5-S-cysteinyldopamine: potentially neuroprotective reactions of relevance to Parkinson's disease

  摘要：

  In recent reports from this laboratory we have hypothesized that a key step underlying the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNc) in Parkinson's disease is an accelerated rate of oxidation of intraneuronal dopamine in the presence of L-cysteine (CySH) to form initially 5-S-cysteinyldopamine (5-S-CyS-DA). 5-S-CyS-DA, however, is more easily oxidized than dopamine in a reaction which leads to the dihydrobenzothiazine (DHBT) 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1), a putative endogenously-formed metabolite that may be responsible for inhibition of mitochondrial complex I and alpha -ketoglutarate dehydrogenase, characteristic defects in the parkinsonian SNc. In this investigation it is demonstrated that glutathione (GSH) dramatically attenuates the oxidative transformation of 5-S-CyS-DA into DHBT-1 by two major pathways. In one pathway GSH displaces the cysteinyl residue from the o-quinone proximate oxidation product of 5-S-CyS-DA forming the corresponding glutathionyl conjugate that is attacked by GSH, to form 2,5-di-S-glutathionyldopamine, or by released CySH to give 2-S-cysteinyl-5-S-glutathionyldopamine. The former is the precursor of 2,5,6-tris-S-glutathionyldopamine, a major reaction product. However, intramolecular cyclization of the o-quinone proximate product of 2-S-cysteinyl-5-S-glutathionyldopamine is the first step in a pathway leading to glutathionyl conjugates of 8-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-5). The second pathway involves nucleophilic addition of GSH to the o-quinone proximate oxidation product of 5-S-CyS-DA forming 2-S-glutathionyl-5-S-cysteinyldopamine the precursor of a number of glutathionyl conjugates of DHBT-1. These results raise the possibility that strategies which elevate intraneuronal levels of GSH in dopaminergic SNc cells in Parkinson's disease patients may block formation of the putative mitochondrial toxin DHBT-1 and hence be neuroprotective. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4020(00)00953-4

文献信息

• Effects of L-Cysteine on the Oxidation Chemistry of Dopamine: New Reaction Pathways of Potential Relevance to Idiopathic Parkinson's Disease
  作者：Fa Zhang、Glenn Dryhurst

  DOI：10.1021/jm00034a006

  日期：1994.4

  Oxidation of the catecholaminergic neurotransmitter dopamine (1) at physiological pH normally results in formation of black, insoluble melanin polymer. In this study, it is demonstrated that L-cysteine (CySH) can divert the melanin pathway by scavenging the proximate o-quinone oxidation product of 1 to give 5-S-cysteinyldopamine (8). This cysteinyl conjugate is further oxidized in the presence of free

  儿茶酚胺能神经递质多巴胺（1）在生理pH值下的氧化通常会导致形成黑色的不溶性黑色素聚合物。在这项研究中，证明了L-半胱氨酸（CySH）可以通过清除1的邻苯二酚近邻氧化产物而转移黑色素途径，从而生成5-S-半胱氨酰多巴胺（8）。该半胱氨酰共轭物在游离CySH的存在下进一步氧化，得到7-（2-氨基乙基）-3,4-二氢-5-羟基-2H-1,4-苯并噻嗪-3-羧酸（11）及其6除许多其他未知化合物外，-S-半胱氨酰（12），8-S-半胱氨酰（14）和6,8-二-S-半胱氨酰（16）偶联物。5-S-半胱氨酰多巴胺（8）和二氢苯并噻嗪11、12、14和16都比1更容易被氧化。随着CySH摩尔过量的增加，黑色素的形成减少，最终，完全被封锁。初步实验表明，当将二氢苯并噻嗪11及其半胱氨酰结合物12和14注入实验室小鼠的大脑时，它们具有致命性，并引起深刻的行为反应，包括活动过度和震颤。基于这些结果和最近的其
• Oxidation of Dopamine in the Presence of Cysteine:  Characterization of New Toxic Products
  作者：Xue-Ming Shen、Fa Zhang、Glenn Dryhurst

  DOI：10.1021/tx960145c

  日期：1997.2.1

  = 1.5 microgram) are lethal when administered into the brains of mice and evoke hyperactivity and tremor. The potential relevance of the in vitro chemistry described in this and earlier reports to reaction that might occur in neuromelanin-pigmented dopaminergic neurons in Parkinson's disease is discussed.

  先前的研究表明，在pH 7.4的L-半胱氨酸（CySH）存在下，多巴胺（DA）的氧化产生了神经递质的半胱氨酰共轭物的复杂混合物，该混合物很容易被进一步氧化为许多二氢苯并噻嗪（DHBT）以及未知的黄色产品。在这项调查中，已经确定了其中三种产品。5-S-半胱氨酰多巴胺（5-S-CyS-DA）和7的氧化反应生成7-（2氨基乙基）-5-羟基-1,4-苯并噻嗪-3-羧酸（BT-1） -（2-氨基乙基）-3,4-二氢-5-羟基-2H-1,4-苯并噻嗪-3-羧酸（DHBT-1）。区域异构体6-（2-氨基乙基）-1,8,9,10-四氢苯并[1,2-b：4,3-b']双[1,4]噻嗪-9-羧酸（12）和6- （2-氨基乙基）-1,2,3,10-四氢苯并[1,2-b：4,3-b']双[1,4]噻嗪-2-羧酸（13）是通过2的氧化而形成的，5-bi-S-CyS-DA），6-S-半胱氨酰基-7-（2-氨基乙基）-
• Influence of glutathione on the oxidation chemistry of 5-S-cysteinyldopamine: potentially neuroprotective reactions of relevance to Parkinson's disease
  作者：Xue-Ming Shen、Glenn Dryhurst

  DOI：10.1016/s0040-4020(00)00953-4

  日期：2001.1

  In recent reports from this laboratory we have hypothesized that a key step underlying the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNc) in Parkinson's disease is an accelerated rate of oxidation of intraneuronal dopamine in the presence of L-cysteine (CySH) to form initially 5-S-cysteinyldopamine (5-S-CyS-DA). 5-S-CyS-DA, however, is more easily oxidized than dopamine in a reaction which leads to the dihydrobenzothiazine (DHBT) 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1), a putative endogenously-formed metabolite that may be responsible for inhibition of mitochondrial complex I and alpha -ketoglutarate dehydrogenase, characteristic defects in the parkinsonian SNc. In this investigation it is demonstrated that glutathione (GSH) dramatically attenuates the oxidative transformation of 5-S-CyS-DA into DHBT-1 by two major pathways. In one pathway GSH displaces the cysteinyl residue from the o-quinone proximate oxidation product of 5-S-CyS-DA forming the corresponding glutathionyl conjugate that is attacked by GSH, to form 2,5-di-S-glutathionyldopamine, or by released CySH to give 2-S-cysteinyl-5-S-glutathionyldopamine. The former is the precursor of 2,5,6-tris-S-glutathionyldopamine, a major reaction product. However, intramolecular cyclization of the o-quinone proximate product of 2-S-cysteinyl-5-S-glutathionyldopamine is the first step in a pathway leading to glutathionyl conjugates of 8-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-5). The second pathway involves nucleophilic addition of GSH to the o-quinone proximate oxidation product of 5-S-CyS-DA forming 2-S-glutathionyl-5-S-cysteinyldopamine the precursor of a number of glutathionyl conjugates of DHBT-1. These results raise the possibility that strategies which elevate intraneuronal levels of GSH in dopaminergic SNc cells in Parkinson's disease patients may block formation of the putative mitochondrial toxin DHBT-1 and hence be neuroprotective. (C) 2000 Elsevier Science Ltd. All rights reserved.