(9,10-dioxo-9,10-dihydroanthracen-2-yl)methyl carbamimidothioate hydrochloride

• 分子结构分类: 有机化合物 - 苯类化合物 - 蒽
• 英文名称: (9,10-dioxo-9,10-dihydroanthracen-2-yl)methyl carbamimidothioate hydrochloride
• 英文别名: (9,10-Dioxoanthracen-2-yl)methyl carbamimidothioate;hydrochloride；(9,10-dioxoanthracen-2-yl)methyl carbamimidothioate;hydrochloride
• 化学式: C₁₆H₁₂N₂O₂S*ClH
• 分子量: 332.81
• InChiKey: FVDJVQRCKKMILM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.01
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  109
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氯乙基蒽 、 硫脲 以 乙醇 为溶剂， 反应 3.0h， 以57%的产率得到(9,10-dioxo-9,10-dihydroanthracen-2-yl)methyl carbamimidothioate hydrochloride
  参考文献：
  名称：

  新型硒代和硫脲衍生物对多种癌细胞具有强大的体外活性

  摘要：

  合成了一系列新型硒硒衍生物和相应的硫脲类似物，并针对六种人类癌细胞系进行了测试：黑色素瘤（1205Lu），肺癌（A549），前列腺癌（DU145），结直肠癌（HCT116），胰腺上皮样癌（PANC-1）和胰腺腺癌（BxPC3）。总的来说，我们发现含硒的衍生物比等规硫类似物更有效。四个硒硒衍生物（1e，1f，1g和1i）在72 h的所有测试细胞系中的IC 50值均低于10μM。根据其有效活性，化合物1g选择在不同结肠癌细胞系中进行进一步的生物学评估。我们的结果表明，化合物1g通过半胱天冬酶激活诱导细胞凋亡，同时抑制抗凋亡蛋白。

  DOI：

  10.1016/j.ejmech.2016.02.042

文献信息

• Identification of a Novel Quinoxaline-Isoselenourea Targeting the STAT3 Pathway as a Potential Melanoma Therapeutic
  作者：Verónica Alcolea、Deepkamal Karelia、Manoj Pandey、Daniel Plano、Parvesh Singh、Juan Palop、Shantu Amin、Carmen Sanmartín、Arun Sharma

  DOI：10.3390/ijms20030521

  日期：——

  The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032.

  转移性黑色素瘤患者的预后仍然非常差。固有的信号转导和转录激活因子3（STAT3）激活已与转移、患者生存率降低、肿瘤大小增加以及对维姆拉芬尼（PLX-4032）的获得性抵抗相关联，表明其作为分子靶点的潜力。我们最近设计了一系列异硒和异硫脲衍生物，用于合成多种生物活性杂环骨架。在包括B-RAFV600E突变和野生型（WT）细胞在内的五种黑色素瘤细胞系中研究了首要的异硒和异硫脲衍生物（化合物1和3）的细胞毒性作用。化合物1（IC50范围为0.8-3.8μM）显示比化合物3（IC50范围为8.1-38.7μM）和突变B-RAF特异性抑制剂PLX-4032（IC50范围从0.4到>50μM）具有更低的IC50值，尤其是在短时间（24小时）内。这些效应持久存在，因为黑色素瘤细胞在治疗14天后没有恢复其增殖潜力。此外，我们通过使用活细胞/死细胞、Annexin V和Caspase3/7凋亡试验证实，化合物1通过凋亡诱导细胞死亡。此外，化合物1降低了STAT3及其磷酸化的蛋白水平，并减少了与转移和生存有关的STAT3调节基因的表达，例如survivin和c-myc。化合物1还上调了细胞周期抑制剂p21。对接研究进一步揭示了化合物1与STAT3的SH2结构域的有利结合，表明其通过STAT3抑制作用。综上所述，我们的结果表明，化合物1通过抑制STAT3途径诱导凋亡，无特异性地靶向B-RAF突变和WT黑色素瘤细胞，其细胞毒性比目前的治疗药物PLX-4032高得多。