TubastatinA盐酸盐 | 1310693-92-5

• 物质功能分类: 医药中间体 - 吡啶类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: TubastatinA盐酸盐
• 中文别名: N-羟基-4-[(1,2,3,4-四氢-2-甲基-5H-吡啶并[4,3-B]吲哚-5-基)甲基]苯甲酰胺盐酸盐
• 英文名称: Tubastatin A hydrochloride
• 英文别名: N-hydroxy-4-[(2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5-yl)methyl]benzamide;hydrochloride
• CAS: 1310693-92-5
• 化学式: C20H22ClN3O2
• 分子量: 371.9
• InChiKey: LJTSJTWIMOGKRJ-UHFFFAOYSA-N

物化性质

• 熔点：
  >221°C (subl.)
• 溶解度：
  溶于 DMSO 或水。

计算性质

• 辛醇/水分配系数(LogP)：
  3.22
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  57.5
• 氢给体数：
  3
• 氢受体数：
  3

安全信息

• WGK Germany：
  3
• 海关编码：
  29339900
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

Tubastatin A HCl (TSA)是一种有效的、选择性的HDAC6抑制剂，无细胞试验中IC50为15 nM。它对所有其他同工酶的选择性非常高（1000倍以上），除了对HDAC8的选择性略低（约为57倍）。

Target	Value
HDAC6 (Cell-free assay)	15 nM
HDAC8 (Cell-free assay)	854 nM

体外研究

Tubastatin A 对所有11种HDAC亚型都有选择性，对HDAC6的IC50为15 nM，是除HDAC8以外其他亚型的1000多倍。它对HDAC8的选择性大约为57倍，其IC50值为854 nM。Tubastatin A 对同型半胱氨酸 (HCA) 诱导的神经细胞死亡具有保护作用，从5 μM开始这种保护作用具有剂量依赖特性，到10 μM时基本可以完全保护细胞不受损伤。在体外实验中，100 ng/mL Tubastatin A增强Foxp3+ T-调节性T细胞 (Tregs) 对T细胞增殖的抑制效果。此外，处理C2C12细胞会导致α-微管蛋白高乙酰化时肌管形成不正常；但肌管延长发生在α-微管蛋白高乙酰化后。最近的研究表明，在小鼠卵巢癌细胞系MOSE-E和MOSE-L中，Tubastatin A 处理会增加细胞弹性，这是通过原子力显微镜检测未剧烈改变肌动蛋白微丝和微管网络的情况下得出的结论。

体内研究

在多种实验性结肠炎、主要组织相容性复合体-心脏同种移植排斥等炎症与自身免疫病小鼠模型中，每天用0.5 mg/kg Tubastatin A 处理会抑制HDAC6并促进T-regulatory细胞 (Tregs) 的抑制活性。

用途

一种高效、选择性的HDAC6抑制剂，IC50:15 nM。与已知的HDAC6抑制剂Tubacin相比，Tubastatin A 在所有同工酶中的选择性更高（除HDAC8外），其IC50值为15 nM，在其他HDAC异构体中显示出超过1,000倍的选择性（IC50 > 16 μM），其中对HDAC8的选择性约为0.9 μM。在初级皮层神经元培养物中，Tubastatin A 可在2.5 μM时诱导 α-微管蛋白的高乙酰化。此外，在由谷胱甘肽耗竭引起的氧化应激模型中，Tubastatin A 在5-10 μM剂量下表现出剂量依赖性的神经保护作用。

文献信息

• Production of differentiated enteroendocrine cells and insulin producing cells
  申请人：Massachusetts Institute of Technology

  公开号：US11021687B2

  公开（公告）日：2021-06-01

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  用多种小分子处理哺乳动物产后细胞群，如包括产后干细胞的细胞群，可获得肠内分泌细胞（EEC）群，这些小分子可上调 ChgA 并促进细胞分化以形成肠内分泌细胞。ChgA的上调可以使获得的细胞群中表达CGA的细胞比例（通过ChgA免疫染色法测定）至少达到约1.5%。可用于将出生后细胞分化为肠内分泌细胞的小分子可包括 Wnt 激活剂、Notch 抑制剂、Wnt 抑制剂、MEK/ERK 抑制剂、生长因子、HDAC 抑制剂、组蛋白甲基化抑制剂、Tgf-β 抑制剂和 NeuroD1 激活剂中的至少一种。此外，用多种可增加胰岛素表达的小分子处理哺乳动物细胞群体，可增加该群体的胰岛素表达。
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  A method of treating acute myeloid leukemia, acute lymphoblastic leukemia, high risk myelodysplastic syndrome, and/or HR-MDS/AML in a mammal by administering a solid dispersion comprising an amorphous thienotriazolodiazepine compound of the Formula (1) wherein R1 is alkyl having a carbon number of 1-4, R2 is a hydrogen atom; a halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydroxyl group, R3 is a halogen atom; phenyl optionally substituted by a halogen atom, alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1-4 or cyano; —NR5-(CH2)m R6 wherein R5 is a hydrogen atom or alkyl having a carbon number of 1-4, m is an integer of 0-4, and R6 is phenyl or pyridyl optionally substituted by a halogen atom.
• Production of Differentiated Enteroendocrine Cells and Insulin Producing Cells
  申请人：Massachusetts Institute of Technology

  公开号：US20170349884A1

  公开（公告）日：2017-12-07

  A population of enteroendocrine cells (EEC) is obtained from a mammalian post-natal cell population, such as a population including post-natal stem cells, by treating the population with a plurality of small molecules that upregulate ChgA and promote differentiation of the cells to form the enteroendocrine cells. The upregulation of ChgA is such that the fraction of cells expressing CGA in the obtained cell population, as measured by a ChgA Immunostaining Assay, is at least about 1.5%. Small molecules that can be used to differentiate the post-natal cells into the enteroendocrine cells can include at least one of a Wnt activator, a Notch inhibitor, a Wnt inhibitor, a MEK/ERK inhibitor, a growth factor, a HDAC inhibitor, a Histone Methylation Inhibitor, a Tgf-β inhibitor, and a NeuroD1 activator. Also, the insulin expression of a population of mammalian cells is increased by treating the population with a plurality of small molecules that increase the insulin expression.
• METHOD FOR PRODUCING PLATELETS
  申请人：KYOTO UNIVERSITY

  公开号：US20200216807A1

  公开（公告）日：2020-07-09

  Healthy functional platelets are mass produced. A method for producing platelets, comprising: (1) a culture step of culturing megakaryocytes in a platelet producing medium in the presence of mechanical stress and platelet production promoting factors including MIF, NRDc, IGFBP2, TSP-1, PAI-1, and CCL5, and (2) a harvest step of harvesting the platelets obtained by the culture step; wherein the culture step comprises: (a) a step of promoting a release of the platelet production promoting factors from megakaryocytes by mechanical stress; and/or (b) a step of externally adding platelet production promoting factors including MIF, NRDc, and IGFBP2.
• PRODUCTION OF INSULIN PRODUCING CELLS
  申请人：Massachusetts Institute of Technology

  公开号：US20210363491A1

  公开（公告）日：2021-11-25

  A population of enteroendocrine cells (EEC) is obtained from a mammalian post-natal cell population, such as a population including post-natal stem cells, by treating the population with a plurality of small molecules that upregulate ChgA and promote differentiation of the cells to form the enteroendocrine cells. The upregulation of ChgA is such that the fraction of cells expressing CGA in the obtained cell population, as measured by a ChgA Immunostaining Assay, is at least about 1.5%. Small molecules that can be used to differentiate the post-natal cells into the enteroendocrine cells can include at least one of a Wnt activator, a Notch inhibitor, a Wnt inhibitor, a MEK/ERK inhibitor, a growth factor, a HDAC inhibitor, a Histone Methylation Inhibitor, a Tgf-β inhibitor, and a NeuroD1 activator. Also, the insulin expression of a population of mammalian cells is increased by treating the population with a plurality of small molecules that increase the insulin expression.