(E)-N’-(1-(pyridin-2-yl)ethylidene)azetidine-1-carbothiohydrazide | 71555-25-4

• 物质功能分类: 生物化工 - 抑制剂 - 细胞凋亡(Apoptosis)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (E)-N’-(1-(pyridin-2-yl)ethylidene)azetidine-1-carbothiohydrazide
• 英文别名: NSC319726；N'-(1-(Pyridin-2-yl)ethylidene)azetidine-1-carbothiohydrazide；N-[(E)-1-pyridin-2-ylethylideneamino]azetidine-1-carbothioamide
• CAS: 71555-25-4
• 化学式: C₁₁H₁₄N₄S
• 分子量: 234.325
• InChiKey: XDHBUMNIQRLHGO-UKTHLTGXSA-N

物化性质

• 熔点：
  175-176 °C(Solv: acetonitrile (75-05-8))
• 沸点：
  367.7±34.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Predicted)
• 溶解度：
  不溶于水； ≥3.43 mg/mL，乙醇溶液，温和加热并超声； DMSO 中≥8.1 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 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

NSC 319726是一种针对p53(R175)突变型的活化剂，能够抑制表达突变型p53的细胞生长。它对p53(R175)突变型的作用IC50为8 nM，并且不对p53野生型细胞产生抑制作用。此外，NSC 319726比其他热点p53突变型的选择性高10到100倍。

体外研究

NSC319726能够诱导突变型p53(R175)依赖性的凋亡。处理后，该化合物可使p53（R175）突变体蛋白发生野生型样构象变化，并修复序列特异性p53转录。其活性取决于化合物的锌离子螯合特性以及氧化还原状态的变化。

体内研究

在一项实验中，NSC319726以5 mg/kg剂量处理p53(R172H/R172H)小鼠7天后产生了较强的毒性作用，只有30%的小鼠存活。相比之下，对p53+/+ 和 p53-/- 小鼠没有观察到毒性。

此外，NSC 319726能够抑制TOV112D-p53(R175H)移植瘤的生长，但不对H460(p53+/+)和MDAMB468-p53(R273W)移植瘤产生影响。

特征

NSC 319726是一种等位基因特异性的p53突变复活剂。

靶点

• IC50: 8 nM (mutant p53R175 reactivator) [1]

反应信息

• 作为反应物：
  描述：

  (E)-N’-(1-(pyridin-2-yl)ethylidene)azetidine-1-carbothiohydrazide 、 zinc(II) chloride 在 三乙胺 作用下， 以 乙醇 为溶剂， 反应 2.08h， 以99%的产率得到C₂₂H₂₆N₈S₂Zn
  参考文献：
  名称：

  Benzothiazolyl and Benzoxazolyl Hydrazones Function as Zinc Metallochaperones to Reactivate Mutant p53

  摘要：

  DOI：

  10.1021/acs.jmedchem.0c01360
• 作为产物：
  描述：

  杂氮环丁烷 、 3-[1-(2-pyridyl)ethylidene]hydrazinecarbodithioate 以 甲醇 为溶剂， 反应 6.0h， 以77%的产率得到(E)-N’-(1-(pyridin-2-yl)ethylidene)azetidine-1-carbothiohydrazide
  参考文献：
  名称：

  Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells

  摘要：

  Transition metals are essential, but deregulation of their metabolism causes toxicity. Here, we report that the compound NSC319726 binds copper to induce oxidative stress and arrest glioblastoma-patient-derived cells at picomolar concentrations. Pharmacogenomic analysis suggested that NSC319726 and 65 other structural analogs exhibit lethality through metal binding. Although NSC319726 has been reported to function as a zinc ionophore, we report here that this compound binds to copper to arrest cell growth. We generated and validated pharmacogenomic predictions: copper toxicity was substantially inhibited by hypoxia, through an hypoxia-inducible-factor-1 alpha-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of deoxyribosyl purines, resulting in cell-cycle arrest. These results suggest that metal-induced DNA damage may be a consequence of exposure to some xenobiotics, therapeutic agents, as well as other causes of copper dysregulation, and reveal a potent mechanism for targeting glioblastomas.

  DOI：

  10.1016/j.chembiol.2018.02.010

文献信息

• [EN] CHEMICAL ACTIVATORS OF NICOTINAMIDE MONONUCLEOTIDE ADENLYLY TRANSFERASE 2 (NMNAT2) AND USES THEREOF<br/>[FR] ACTIVATEURS CHIMIQUES DE MONONUCLÉOTIDE DE NICOTINAMIDE ADÉNYLYL TRANSFÉRASE 2 (NMNAT2) ET LEURS UTILISATIONS
  申请人：UNIV TSINGHUA

  公开号：WO2020107221A1

  公开（公告）日：2020-06-04

  The present application relates to novel semicarbazones and thiosemicarbazones, to processes for preparing them, to pharmaceutical preparations comprising them, to the use of the novel semicarbazones and thiosemicarbazones for treatment and/or prophylaxis of diseases and to the use thereof for production of a medicament for treatment and/or prophylaxis of diseases, especially of neurodegeneration and age-associated diseases or conditions associated with NAD loss. The present application also provides a method for high throughput screening of NMNAT2 activators.

  本申请涉及新型半胱氨酮和硫代半胱氨酮，以及制备它们的方法，包括含有它们的药物制剂，以及利用新型半胱氨酮和硫代半胱氨酮治疗和/或预防疾病的用途，以及用于生产治疗和/或预防疾病的药物的用途，特别是神经退行性疾病和与NAD损失相关的老年疾病或状况。本申请还提供了一种高通量筛选NMNAT2激活剂的方法。
• [EN] HYDRAZNE DERIVATIVES FOR THE TREATMENT OF CANCER<br/>[FR] DÉRIVÉS D'HYDRAZINE POUR LE TRAITEMENT DU CANCER
  申请人：UNIV RUTGERS

  公开号：WO2016123253A1

  公开（公告）日：2016-08-04

  The invention provides compounds of formula (I): and salts thereof, wherein ring A, R2, HET, X, n, and R3 have any of the meanings described in the specification, as well as compositions comprising such compounds and salts, and methods for treating cancer using such compounds and salts.

  该发明提供了式（I）的化合物及其盐，其中环A、R2、HET、X、n和R3具有规范中描述的任何含义，以及包含这些化合物和盐的组合物，以及使用这些化合物和盐治疗癌症的方法。
• (Thio, oxo, and seleno) semicarbazone complexes with zinc and their use for treating cancer
  申请人：RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY

  公开号：US10221133B2

  公开（公告）日：2019-03-05

  The invention provides organic complexes of Zn2+ of formula (I) that are useful for treating cancer, as well as compositions and kits comprising such complexes, and intermediate monomer compounds that are useful for the preparation of such complexes.

  本发明提供了可用于治疗癌症的式 (I) Zn2+ 有机络合物、包含此类络合物的组合物和试剂盒，以及可用于制备此类络合物的中间单体化合物。
• (Thio, oxo, and seleno) semicarbazone derivatives and their use for treating cancer
  申请人：RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY

  公开号：US10604480B2

  公开（公告）日：2020-03-31

  The invention provides compounds of formula I and II and salts thereof, wherein R1, R2, Y, R3, and R4 have any of the meanings described in the specification, as well as compositions comprising such compounds and salts, and methods for treating cancer using such compounds and salts.

  本发明提供了式 I 和 II 的化合物及其盐类，其中 R1、R2、Y、R3 和 R4 具有说明书中描述的任何含义，还提供了包含此类化合物和盐类的组合物，以及使用此类化合物和盐类治疗癌症的方法。
• Zinc complexes of hydrazones and (thio)semicarbazones and their use for the treatment of cancer
  申请人：RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY

  公开号：US10729671B2

  公开（公告）日：2020-08-04

  The invention provides complexes of Zn2+ of formulae (la) and (IIa) that are useful for treating cancer, as well as compositions and kits comprising such complexes.

  本发明提供了可用于治疗癌症的式 (la) 和 (IIa) 的 Zn2+ 复合物，以及包含此类复合物的组合物和试剂盒。