10H-3,6-diazaphenothiazine | 16767-33-2

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 10H-3,6-diazaphenothiazine
• 英文别名: 5H-Dipyrido[2,3-b:4',3'-e][1,4]thiazine；2-thia-4,9,13-triazatricyclo[8.4.0.03,8]tetradeca-1(10),3(8),4,6,11,13-hexaene
• CAS: 16767-33-2
• 化学式: C₁₀H₇N₃S
• 分子量: 201.252
• InChiKey: IONJPFYIUBPWQZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  63.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  10H-3,6-diazaphenothiazine 在 (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate 、 N,N-二异丙基乙胺 、 sodium hydroxide 、 lithium hexamethyldisilazane 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 94.25h， 生成 4-[(5H-dipyrido[2,3-b:4',3'-e][1,4]thiazin-5-yl)methyl]-N-hydroxybenzamide
  参考文献：
  名称：

  酚噻嗪基苯氧肟酸作为选择性组蛋白脱乙酰基酶6抑制剂的合成及生物学研究。

  摘要：

  吩噻嗪系统被确定为有效和选择性组蛋白脱乙酰基酶6（HDAC6）抑制剂的有利封端基团。在这里，我们报告吩噻嗪及其类似物的制备和系统变化，其中吩噻嗪及其类似物含有苯氧肟酸部分作为锌结合基团。我们通过重组HDAC酶分析，通过蛋白质印迹确定细胞中蛋白质的乙酰化水平（微管蛋白与组蛋白乙酰化）以及评估它们对各种癌细胞系的作用，评估了它们选择性抑制HDAC6的能力。构效关系研究表明，将氮原子掺入吩噻嗪骨架中会提高HDAC6的效力和选择性（相对于HDAC1，HDAC4和HDAC8的抑制作用，选择性高500倍以上），通过分子建模和对接研究合理化。通过有效的氮杂吩噻嗪抑制剂与来自Danio rerio HDAC6的催化结构域2的共结晶来确认结合模式。

  DOI：

  10.1021/acs.jmedchem.8b01090
• 作为产物：
  描述：

  2,2'-二硫代-二(3-硝基吡啶) 在 sodium tetrahydroborate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 10H-3,6-diazaphenothiazine
  参考文献：
  名称：

  3,6-Diazaphenothiazines as potential lead molecules – synthesis, characterization and anticancer activity

  摘要：

  3,6-Diazaphenothiazines were obtained in cyclization of 3-amino-3'-nitro-2,4'-dipyridinyl sulfide and the reaction of sodium 3-amino-2-pyridinethiolate with 4-chloro-3-nitropyridine followed by alkylation and heteroarylation. The thiazine ring formation ran via the Smiles rearrangement. The structure elucidation was based on 2D NMR and X-ray analysis of N-methylated product. 3,6-Diazaphenothiazines were investigated for antitumor activity using glioblastoma SNB-19, melanoma C-32 and breast cancer MCF-7 cells. 10H-3,6-diazaphenothiazine was 10 times more active (IC50 < 0.72 mu g/mL) than cisplatin. Two diazaphenothiazines with the 2-pyrimidinyl and dimethylaminopropyl substituents were selectively active against MCF-7 and C-32 cells. The expressions of H3 (proliferation marker), TP53, CDKN1A (cell cycle regulators), BAX and BCL-2 (proapoptopic and antiapoptopic genes) were detected by RT-QPCR method. The expression analysis suggests the cell cycle arrest and the mitochondrial apoptosis pathway activation in MCF-7 and SNB-19 cells.

  DOI：

  10.3109/14756366.2016.1151014

文献信息

• Synthesis and Structural Characterization of Novel Dimers of Dipyridothiazine as Promising Antiproliferative Agents
  作者：Emilia Martula、Beata Morak-Młodawska、Małgorzata Jeleń、Patrick N. Okechukwu、Abbirami Balachandran、Prethika Tehirunavukarasu、Kirthani Anamalay、Vaidehi Ulaganathan

  DOI：10.3390/molecules28227662

  日期：——

  spectrometry (HRMS). In silico analyses of probable molecular targets were performed using the Way2Drug server. All new dimers were tested for anticancer activity against breast cancer line MCF7 and colon cancer line SW480. Cytotoxicity was assessed on normal L6 muscle cells. The tested dimers had high anticancer potential expressed as IC50 and the selectivity index SI. The most active derivative, 4c, showed

  许多新的异构二吡啶并噻嗪二聚体已被视为具有抗癌潜力的分子。这些化合物是通过使用选定的烷基芳族连接体有效合成 1,6-、1,8-、2,7- 和 3,6-二氮杂吩噻嗪而获得的。这些化合物的结构已通过二维光谱技术（COSY、NOESY、HSQC 和 HMBC）和高分辨率质谱 (HRMS) 得到证实。使用 Way2Drug 服务器对可能的分子靶标进行计算机分析。所有新二聚体都经过了针对乳腺癌系 MCF7 和结肠癌系 SW480 的抗癌活性测试。对正常 L6 肌细胞进行细胞毒性评估。测试的二聚体具有高抗癌潜力，以IC50和选择性指数SI表示。最活跃的衍生物 4c 的 IC50 活性低于 1 µM，SI 选择性指数高于 100。此外，该化合物对正常细胞的毒性较低，同时具有较高的细胞抑制潜力。
• 3,6-Diazaphenothiazines as potential lead molecules – synthesis, characterization and anticancer activity
  作者：Beata Morak-Młodawska、Krystian Pluta、Małgorzata Latocha、Kinga Suwińska、Małgorzata Jeleń、Dariusz Kuśmierz

  DOI：10.3109/14756366.2016.1151014

  日期：2016.11.1

  3,6-Diazaphenothiazines were obtained in cyclization of 3-amino-3'-nitro-2,4'-dipyridinyl sulfide and the reaction of sodium 3-amino-2-pyridinethiolate with 4-chloro-3-nitropyridine followed by alkylation and heteroarylation. The thiazine ring formation ran via the Smiles rearrangement. The structure elucidation was based on 2D NMR and X-ray analysis of N-methylated product. 3,6-Diazaphenothiazines were investigated for antitumor activity using glioblastoma SNB-19, melanoma C-32 and breast cancer MCF-7 cells. 10H-3,6-diazaphenothiazine was 10 times more active (IC50 < 0.72 mu g/mL) than cisplatin. Two diazaphenothiazines with the 2-pyrimidinyl and dimethylaminopropyl substituents were selectively active against MCF-7 and C-32 cells. The expressions of H3 (proliferation marker), TP53, CDKN1A (cell cycle regulators), BAX and BCL-2 (proapoptopic and antiapoptopic genes) were detected by RT-QPCR method. The expression analysis suggests the cell cycle arrest and the mitochondrial apoptosis pathway activation in MCF-7 and SNB-19 cells.
• Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors
  作者：Katharina Vögerl、Nghia Ong、Johanna Senger、Daniel Herp、Karin Schmidtkunz、Martin Marek、Martin Müller、Karin Bartel、Tajith B. Shaik、Nicholas J. Porter、Dina Robaa、David W. Christianson、Christophe Romier、Wolfgang Sippl、Manfred Jung、Franz Bracher

  DOI：10.1021/acs.jmedchem.8b01090

  日期：2019.2.14

  lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine

  吩噻嗪系统被确定为有效和选择性组蛋白脱乙酰基酶6（HDAC6）抑制剂的有利封端基团。在这里，我们报告吩噻嗪及其类似物的制备和系统变化，其中吩噻嗪及其类似物含有苯氧肟酸部分作为锌结合基团。我们通过重组HDAC酶分析，通过蛋白质印迹确定细胞中蛋白质的乙酰化水平（微管蛋白与组蛋白乙酰化）以及评估它们对各种癌细胞系的作用，评估了它们选择性抑制HDAC6的能力。构效关系研究表明，将氮原子掺入吩噻嗪骨架中会提高HDAC6的效力和选择性（相对于HDAC1，HDAC4和HDAC8的抑制作用，选择性高500倍以上），通过分子建模和对接研究合理化。通过有效的氮杂吩噻嗪抑制剂与来自Danio rerio HDAC6的催化结构域2的共结晶来确认结合模式。