硫化氢供体型ADT-OH衍生物的合成及其活性

李玉姚; 宋恒; 程坚; 敖桂珍

doi:10.11665/j.issn.1000-5048.20170304

硫化氢供体型ADT-OH衍生物的合成及其活性

1.
苏州大学药学院
2.
神经科学研究所

基金项目: 苏州市科技计划资助项目(No.N313202713)

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- 刊出日期: 2017-06-24

Synthesis and biological evaluation of H₂S donor ADT-OH derivatives

摘要

摘要: 二硫杂环化合物5-对羟基苯基-3H-1，2-二硫杂环戊烯-3-硫酮(ADT-OH)是一种缓释硫化氢供体，并具有一定的神经保护作用。为了研究其构效关系，对其芳环进行改造，合成了17个 Y 类化合物( Y₁ ~ Y₁₇)，其结构均经 ¹H NMR、¹³C NMR 和HR-MS确证，其中6个化合物( Y₄，Y₁₃ ~ Y₁₇ )结构是全新的。采用MTT法评价了该类化合物对谷氨酸诱导损伤的HT-22海马神经元细胞生存率的影响，结果发现，这些化合物在1~100 μmol/L浓度范围内具有很强的神经保护作用，其中化合物 Y₁ ~ Y₉，Y₁₁ 在全部测试浓度内均能非常显著地提高受损神经元的生存率(P<0.01)，特别是化合物 Y₁，Y₄，Y₆ ~ Y₉，Y₁₁ 在1~10 μmol/L浓度范围内活性比ADT-OH强，值得进一步研究。

关键词:
ADT-OH /

H₂S供体 /

合成 /

抗谷氨酸活性 /

神经保护
Abstract: 5-(4-Hydroxyphenyl)-3H-1, 2-dithiole-3-thione(ADT-OH)is a slowly releasing H₂S donor with some neuroprotective effect. In order to study the structure-activity relationships, seventeen compounds( Y₁ - Y₁₇ )were synthesized by modification of ADT-OH at the aromatic ring position, and their structures were confirmed by ¹H NMR, ¹³C NMR and HR-MS. Among them, 6 compounds( Y₄, Y₁₃ - Y₁₇ )were novel compounds. Their effects had been evaluated on HT-22 hippocampal neuron cells damaged by glutamate with MTT method. The pharmacological results demonstrated that all the Y compounds had potent neuroprotection at most of the tested concentrations(1-100 μmol/L). Compounds Y₁ - Y₉ and Y₁₁ significantly improved the survival rates of the damaged cells at 1-100 μmol/L(P<0. 01). Specially, compounds Y₁, Y₄, Y₆ - Y₉, Y₁₁ are more potent than their parent compound ADT-OH at concentration of 1-10 μmol/L, which is worthy of further study.

Keywords:
ADT-OH /

hydrogen sulfide donor /

synthesis /

anti-glutamic acid /

neuroprotection

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参考文献(11)

[1] Deb P,Sharma S,Hassan KM.Pathophysiologic mechanisms of acute ischemic stroke:an overview with emphasis on therapeutic significance beyond thrombolysis[J].Pathophysiology,2010,17(3):197-218.

[2] Viscoli CM,Brass LM,Carolei A,et al.Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack:rationale and design of the insulin resistance intervention after stroke trial[J].Am Heart J,2014,168(6):823-829.

[3] Durukan A, Tatlisumak T. Acute ischemic stroke: overview of major experimental rodent models,pathophysiology,and therapy of focal cerebral ischemia[J].Pharm Biochem Behav,2007,87(1):179-197.

[4] Cheng J,Ao GZ,Jia J,et al.Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress[J].Neurochem Int,2013,62(8):1072-1078.

[5] Ao GZ,Jia J,Cheng J,et al.CaMKKβ-dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation[J].Antioxid Redox Signal, 2014,21(12):1741-1758.

[6] Wang Y,Jia J,Ao GZ,et al.Hydrogen sulfide protects blood-brain barrier integrity following cerebral ischemia[J].J Neurochem,2014,129(5):827-838.

[7] Sun YX,Wu Y,Song H,et al.Synthesis and biological evaluation of H₂S donor memantine derivatives[J].J China Pharm Univ(中国药科大学学报),2016,47(5):543-547.

[8] Borowiecki P,Bretner M.Studies on the chemo enzymatic synthesis of(R)-and(S)-methyl 3-aryl-3-hydroxypropionates:the influence of toluene-pretreatment of lipase preparations on enantioselective transesterifications[J].Tetrahedron Asymmetry,2013,24(15/16):925-936.

[9] Wang X,Wang L,Sheng X,et al.Design,synthesis and biological evaluation of hydrogen sulfide releasing derivatives of 3-n-butylphthalide as potential antiplatelet and antithrombotic agents[J].Org Biomol Chem,2014,12(31):5995-6004.

[10] Rothman SM,Olney JW.Glutamate and the pathophysiology of hypoxic-ischemic brain damage[J].Ann Neurol,1986,19(2):105-110.

[11] Van LK,Siddiq A,Ratan RR,et al.Proteasome inhibition protects HT22 neuronal cells from oxidative glutamate toxicity[J].J Neurochem,2005,92(4):824-830.

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文章访问数: 958

HTML全文浏览量: 8

PDF下载量: 1947

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出版历程

刊出日期: 2017-06-24

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摘要
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参考文献(11)
相关文章
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[1]	Deb P,Sharma S,Hassan KM.Pathophysiologic mechanisms of acute ischemic stroke:an overview with emphasis on therapeutic significance beyond thrombolysis[J].Pathophysiology,2010,17(3):197-218.
[2]	Viscoli CM,Brass LM,Carolei A,et al.Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack:rationale and design of the insulin resistance intervention after stroke trial[J].Am Heart J,2014,168(6):823-829.
[3]	Durukan A, Tatlisumak T. Acute ischemic stroke: overview of major experimental rodent models,pathophysiology,and therapy of focal cerebral ischemia[J].Pharm Biochem Behav,2007,87(1):179-197.
[4]	Cheng J,Ao GZ,Jia J,et al.Differential mechanisms underlying neuroprotection of hydrogen sulfide donors against oxidative stress[J].Neurochem Int,2013,62(8):1072-1078.
[5]	Ao GZ,Jia J,Cheng J,et al.CaMKKβ-dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation[J].Antioxid Redox Signal, 2014,21(12):1741-1758.
[6]	Wang Y,Jia J,Ao GZ,et al.Hydrogen sulfide protects blood-brain barrier integrity following cerebral ischemia[J].J Neurochem,2014,129(5):827-838.
[7]	Sun YX,Wu Y,Song H,et al.Synthesis and biological evaluation of H₂S donor memantine derivatives[J].J China Pharm Univ(中国药科大学学报),2016,47(5):543-547.
[8]	Borowiecki P,Bretner M.Studies on the chemo enzymatic synthesis of(R)-and(S)-methyl 3-aryl-3-hydroxypropionates:the influence of toluene-pretreatment of lipase preparations on enantioselective transesterifications[J].Tetrahedron Asymmetry,2013,24(15/16):925-936.
[9]	Wang X,Wang L,Sheng X,et al.Design,synthesis and biological evaluation of hydrogen sulfide releasing derivatives of 3-n-butylphthalide as potential antiplatelet and antithrombotic agents[J].Org Biomol Chem,2014,12(31):5995-6004.
[10]	Rothman SM,Olney JW.Glutamate and the pathophysiology of hypoxic-ischemic brain damage[J].Ann Neurol,1986,19(2):105-110.
[11]	Van LK,Siddiq A,Ratan RR,et al.Proteasome inhibition protects HT22 neuronal cells from oxidative glutamate toxicity[J].J Neurochem,2005,92(4):824-830.

硫化氢供体型ADT-OH衍生物的合成及其活性

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Synthesis and biological evaluation of H2S donor ADT-OH derivatives

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Synthesis and biological evaluation of H₂S donor ADT-OH derivatives