N-(4-acetylphenyl)-2-((4-allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-(4-acetylphenyl)-2-((4-allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide
• 英文别名: N-(4-acetylphenyl)-2-[[5-(2-phenylquinolin-4-yl)-4-prop-2-enyl-1,2,4-triazol-3-yl]sulfanyl]acetamide
• 化学式: C₃₀H₂₅N₅O₂S
• 分子量: 519.627
• InChiKey: RETTWYOIJLAVDT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(4-acetylphenyl)-2-((4-allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide 在 盐酸羟胺 、 sodium acetate 作用下， 以 乙醇 为溶剂， 以55%的产率得到2-((4-allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-yl)-thio)-N-(4-(1-(hydroxyimino)ethyl)phenyl)acetamide
  参考文献：
  名称：

  NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth

  摘要：

  Constitutive activation of STAT3 can play a vital role in the development of melanoma. STAT3-targeted therapeutics are reported to show efficacy in melanomas harboring the BRAFV600E mutant and also in vemurafenib-resistant melanomas. We designed and synthesized a series of substituted nitric oxide (NO)-releasing quinolone-1,2,4-triazoleioxime hybrids, hypothesizing that the introduction of a STAT3 binding scaffold would augment their cytotoxicity. All the hybrids tested showed a comparable level of in vitro NO production. 7b and 7c exhibited direct binding to the STAT3-SH domain with IC50 of similar to 0.5 mu M. Also, they abrogated STAT3 tyrosine phosphorylation in several cancer cell lines, including the A375 melanoma cell line that carries the BRAFV600E mutation. At the same time, they did not affect the phosphorylation of upstream kinases or other STAT isoforms. 7c inhibited STAT3 nuclear translocation in mouse embryonic fibroblast while 7b and 7c inhibited STAT3 DNA-binding activity in the A375 cell line. Their anti-proliferating activity is attributed to their ability to trigger the production of reactive oxygen species and induce G1 cell cycle arrest in the A375 cell line. Interestingly, 7b and 7c showed robust cell growth suppression and apoptosis induction in two pairs of BRAF inhibitor-naive (-S) and resistant (-R) melanoma cell lines containing a BRAF V600E mutation. Surprisingly, MEL1617-R cells that are known to be more resistance to MEK inhibition by GSK1120212 than MEL1617-S cells exhibit a similar response to 7b and 7c. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111885
• 作为产物：
  描述：

  2-苯基-4-喹啉羧酸 在 硫酸 、 一水合肼 、 三乙胺 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 17.0h， 生成 N-(4-acetylphenyl)-2-((4-allyl-5-(2-phenylquinolin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide
  参考文献：
  名称：

  NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth

  摘要：

  Constitutive activation of STAT3 can play a vital role in the development of melanoma. STAT3-targeted therapeutics are reported to show efficacy in melanomas harboring the BRAFV600E mutant and also in vemurafenib-resistant melanomas. We designed and synthesized a series of substituted nitric oxide (NO)-releasing quinolone-1,2,4-triazoleioxime hybrids, hypothesizing that the introduction of a STAT3 binding scaffold would augment their cytotoxicity. All the hybrids tested showed a comparable level of in vitro NO production. 7b and 7c exhibited direct binding to the STAT3-SH domain with IC50 of similar to 0.5 mu M. Also, they abrogated STAT3 tyrosine phosphorylation in several cancer cell lines, including the A375 melanoma cell line that carries the BRAFV600E mutation. At the same time, they did not affect the phosphorylation of upstream kinases or other STAT isoforms. 7c inhibited STAT3 nuclear translocation in mouse embryonic fibroblast while 7b and 7c inhibited STAT3 DNA-binding activity in the A375 cell line. Their anti-proliferating activity is attributed to their ability to trigger the production of reactive oxygen species and induce G1 cell cycle arrest in the A375 cell line. Interestingly, 7b and 7c showed robust cell growth suppression and apoptosis induction in two pairs of BRAF inhibitor-naive (-S) and resistant (-R) melanoma cell lines containing a BRAF V600E mutation. Surprisingly, MEL1617-R cells that are known to be more resistance to MEK inhibition by GSK1120212 than MEL1617-S cells exhibit a similar response to 7b and 7c. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111885

文献信息

• NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth
  作者：Tamer S. Kaoud、Aliaa M. Mohassab、Heba A. Hassan、Chunli Yan、Sabrina X. Van Ravenstein、Dalia Abdelhamid、Kevin N. Dalby、Mohamed Abdel-Aziz

  DOI：10.1016/j.ejmech.2019.111885

  日期：2020.1

  Constitutive activation of STAT3 can play a vital role in the development of melanoma. STAT3-targeted therapeutics are reported to show efficacy in melanomas harboring the BRAFV600E mutant and also in vemurafenib-resistant melanomas. We designed and synthesized a series of substituted nitric oxide (NO)-releasing quinolone-1,2,4-triazoleioxime hybrids, hypothesizing that the introduction of a STAT3 binding scaffold would augment their cytotoxicity. All the hybrids tested showed a comparable level of in vitro NO production. 7b and 7c exhibited direct binding to the STAT3-SH domain with IC50 of similar to 0.5 mu M. Also, they abrogated STAT3 tyrosine phosphorylation in several cancer cell lines, including the A375 melanoma cell line that carries the BRAFV600E mutation. At the same time, they did not affect the phosphorylation of upstream kinases or other STAT isoforms. 7c inhibited STAT3 nuclear translocation in mouse embryonic fibroblast while 7b and 7c inhibited STAT3 DNA-binding activity in the A375 cell line. Their anti-proliferating activity is attributed to their ability to trigger the production of reactive oxygen species and induce G1 cell cycle arrest in the A375 cell line. Interestingly, 7b and 7c showed robust cell growth suppression and apoptosis induction in two pairs of BRAF inhibitor-naive (-S) and resistant (-R) melanoma cell lines containing a BRAF V600E mutation. Surprisingly, MEL1617-R cells that are known to be more resistance to MEK inhibition by GSK1120212 than MEL1617-S cells exhibit a similar response to 7b and 7c. (C) 2019 Elsevier Masson SAS. All rights reserved.