3-acetyl-8,9-dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 3-acetyl-8,9-dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline
• 英文别名: 1-(8,9-dimethoxy-1-phenyl-1,5,6,10b-tetrahydro[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)ethan-1-one；3-Acetyl-8,9-dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline；1-(8,9-dimethoxy-1-phenyl-6,10b-dihydro-5H-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)ethanone
• 化学式: C₂₀H₂₁N₃O₃
• 分子量: 351.405
• InChiKey: PPADIZPYOOWNCE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  54.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-acetyl-8,9-dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline 在 hydrazine hydrate 、 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 1.0h， 生成 8,9-dimethoxy-1-phenyl-3-(5-(4-(piperidin-1-yl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline
  参考文献：
  名称：

  含有异喹啉部分的新型查尔酮的合成、反应、抗菌和对接研究

  摘要：

  摘要 异喹啉1与肼酰氯2A-E反应生成相应的三唑并异喹啉4A-E。后一种产物4A-E与 4-(哌啶-1-基)苯甲醛5a和 4-吗啉代苯甲醛5b反应得到相应的查耳酮6a,b。一些查尔酮6在回流乙醇中与水合肼反应，得到相应的 8,9-dimethoxy-1-aryl-4,5-dihydro-1 H -pyrazol-3-yl-1,5,6,10 b -四氢-[1,2,4]三唑并[3,4- a ]异喹啉衍生物7A–C. 使用革兰氏阴性菌（大肠杆菌）和（肺炎克雷伯菌）、革兰氏阳性菌（变形链球菌）和（金黄色葡萄球菌）、丝状真菌（黑曲霉）和酵母（白色念珠菌）进行抗菌研究。数据显示，查尔酮6Aa对敏感菌株大肠杆菌的MIC值最低（高效衍生物），MIC值为130 µg/ml。最有效的化合物6Aa使用 MOE 2014.09 软件对接显示对测试蛋白质 [胸苷磷酸化酶，(PDB ID:4EAD)] 的最高结合亲和力。

  DOI：

  10.1080/00397911.2022.2119415
• 作为产物：
  描述：

  6,7-二甲氧基-3,4-二氢异喹啉 、 1-氯-1-(2-苯基亚肼基)乙酮 在 三乙胺 作用下， 以 乙腈 为溶剂， 生成 3-acetyl-8,9-dimethoxy-1-phenyl-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline
  参考文献：
  名称：

  含有异喹啉部分的新型查尔酮的合成、反应、抗菌和对接研究

  摘要：

  摘要 异喹啉1与肼酰氯2A-E反应生成相应的三唑并异喹啉4A-E。后一种产物4A-E与 4-(哌啶-1-基)苯甲醛5a和 4-吗啉代苯甲醛5b反应得到相应的查耳酮6a,b。一些查尔酮6在回流乙醇中与水合肼反应，得到相应的 8,9-dimethoxy-1-aryl-4,5-dihydro-1 H -pyrazol-3-yl-1,5,6,10 b -四氢-[1,2,4]三唑并[3,4- a ]异喹啉衍生物7A–C. 使用革兰氏阴性菌（大肠杆菌）和（肺炎克雷伯菌）、革兰氏阳性菌（变形链球菌）和（金黄色葡萄球菌）、丝状真菌（黑曲霉）和酵母（白色念珠菌）进行抗菌研究。数据显示，查尔酮6Aa对敏感菌株大肠杆菌的MIC值最低（高效衍生物），MIC值为130 µg/ml。最有效的化合物6Aa使用 MOE 2014.09 软件对接显示对测试蛋白质 [胸苷磷酸化酶，(PDB ID:4EAD)] 的最高结合亲和力。

  DOI：

  10.1080/00397911.2022.2119415

文献信息

• Cytotoxicity, molecular modeling, cell cycle arrest, and apoptotic induction induced by novel tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline chalcones
  作者：Magda F. Mohamed、Hamdi M. Hassaneen、Ismail A. Abdelhamid

  DOI：10.1016/j.ejmech.2017.11.045

  日期：2018.1

  Novel tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-arylprop-2-en-1-one derivatives were synthesized and their structures were confirmed by different spectral tools. Cytotoxicity test revealed that some compounds exhibited strong to moderate effect, while others showed weak action against different cancer cell lines (MCF7, A549, HCT116, and Hepg2). Breast carcinoma revealed higher sensitivity

  合成了新的四氢-[1,2,4]三唑并[3,4- a ]异喹啉-3-基）-3-芳基丙-2-烯-1-酮衍生物，并用不同的光谱工具证实了其结构。细胞毒性测试表明，某些化合物对不同癌细胞系（MCF7，A549，HCT116和Hepg2）表现出强至中度的作用，而另一些则表现出微弱的作用。乳腺癌对所有衍生物，尤其是化合物5和8的敏感性更高，相对于阳性对照5-氟尿嘧啶（5-FU）（IC 50），它们分别具有最低的IC 50值（50.05和27.15μg/ ml）。 = 178μg/ ml）。此外，这两种化合物对正常黑素细胞（HFB4）的毒性较小。进行了若干理论和实验研究，以揭示使用两种有前途的小说5和8来控制乳腺癌转移的分子机制。对两种蛋白质EGFR和DHFR的对接模拟研究表明，化合物8对两种蛋白质的结合亲和力比化合物5高，表明三甲氧基可能是通过与活性结构域（4r3r）形成五个氢键以及与活性结构域（1d
• Synthesis, Reactions and Antibacterial Activity of 3-Acetyl[1,2,4]triazolo[3,4-a]isoquinoline Derivatives using Chitosan as Heterogeneous Catalyst under Microwave Irradiation
  作者：Hamdi M. Hassaneen、Huwaida M. E. Hassaneen、Yasmin Sh. Mohammed、Richard M. Pagni

  DOI：10.1515/znb-2011-0313

  日期：2011.3.1

  3-Acetyl[1,2,4]triazolo[3,4-a]isoquinolines were prepared using chitosan as a catalyst. These compounds were used to prepare a novel series of enaminones 5, and their reactions with hydrazonoyl halides 1 and 11 gave triazoloisoquinolines 8 and 13, respectively, with a carbonylpyrazole side chain. Hydrazinolysis of 8 and 13 gave the pyrazolopyridazines 10 and pyrazolopyridazinones 14. Reaction of 5

  3-乙酰基[1,2,4]三唑并[3,4-a]异喹啉以壳聚糖为催化剂制备。这些化合物被用来制备一系列新的烯胺酮 5，它们与腙酰卤化物 1 和 11 的反应分别得到具有羰基吡唑侧链的三唑异喹啉 8 和 13。8和13的肼解得到吡唑并哒嗪10和吡唑并哒嗪酮14。5与羟甲基卤化物15的反应产生具有羰基异恶唑侧链的三唑并异喹啉16。研究了化合物8和10的抗菌作用。微波辐照下以壳聚糖为多相催化剂的 3-乙酰基[1,2,4]三唑并[3,4-a]异喹啉衍生物的图形摘要合成、反应和抗菌活性
• Synthesis of [1,2,4]triazolo[3,4-a]isoquinolines and pyrrolo[2,1-a]isoquinolines using α-keto hydrazonoyl halides
  作者：Nehal M. Elwan、Hyam A. Abdelhadi、Taysser A. Abdallah、Hamdi M. Hassaneen

  DOI：10.1016/0040-4020(96)00024-5

  日期：1996.3

  Treatment of α-keto hydrazonoyl halides 1 with 3,4-dihydro-6,7-dimethoxyisoquinoline 3 and its 1-methyl derivative 4 in the presence of triethylamine in tetrahydrofuran at reflux afforded the corresponding cycloadducts 6 and 9, respectively. The same halides 1 react with 1-cyanomethyl-3,4-dihydro-6,7-dimethoxyisoquinoline 5 and afforded pyrrolo[2,1-a]isoquinoline derivatives 12 in high yield.

  在三乙胺存在下于四氢呋喃中，在回流下用3,4-二氢-6,7-二甲氧基异喹啉3及其1-甲基衍生物4处理α-酮卤代酰卤1，分别得到相应的环加合物6和9。相同的卤化物1与1-氰基甲基-3，4-二氢-6，7-二甲氧基异喹啉5反应，并以高收率得到吡咯并[2，1-a]异喹啉衍生物12。
• Novel [l,2,4]triazolo[3,4-a]isoquinoline chalcones as new chemotherapeutic agents: Block IAP tyrosine kinase domain and induce both intrinsic and extrinsic pathways of apoptosis
  作者：Magda F. Mohamed、Farid M. Sroor、Nada S. Ibrahim、Ghada S. Salem、Hadeer H. El-Sayed、Marwa M. Mahmoud、Menna-Allah M. Wagdy、Amina M. Ahmed、Aya-Allah T. Mahmoud、Somia S. Ibrahim、Mariam M. Ismail、Sanaa Mohy Eldin、Fatma M. Saleh、Hamdi M. Hassaneen、Ismail A. Abdelhamid

  DOI：10.1007/s10637-020-00987-2

  日期：2021.2

  Two novel chemotherapeutic chalcones were synthesized and their structures were confirmed by different spectral tools. Theoretical studies such as molecular modeling were done to detect the mechanism of action of these compounds. In vitro cytotoxicity showed a strong effect against all tested cell lines (MCF7, A459, HepG2, and HCT116), and low toxic effect against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies. Real-time PCR demonstrated that the two compounds upregulated gene expression of (BAX, p53, casp-3, casp-8, casp-9) genes and decreased the expression of anti-apoptotic genes bcl2, CDK4, and MMP1. Flow-cytometry indicated that cell cycle arrest of A459 was induced at the G2/M phase and the apoptotic percentage increased significantly compared to the control sample. Cytochrome c oxidase and VEGF enzyme activity were detected by ELISA assay. SEM tool was used to follow the morphological changes that occurred on the cell surface, cell granulation, and average roughness of the cell surface. The change in the number and morphology of mitochondria, cell shrinkage, increase in the number of cytoplasmic organelles, membrane blebbing, chromatin condensation, and apoptotic bodies were observed using TEM. The obtained data suggested that new chalcones exerted their pathways on lung carcinoma through induction of two pathways of apoptosis.

  合成了两种新型化疗查尔酮，并通过不同的光谱工具确认了其结构。进行了理论研究，如分子建模，以检测这些化合物的作用机制。体外细胞毒性实验显示出对所有测试的细胞系（MCF7、A459、HepG2 和 HCT116）具有强效，而对正常人类黑素细胞（HFB4）的毒性影响较低。选择肺癌细胞系进行进一步的分子研究。实时PCR表明，这两种化合物上调了（BAX、p53、casp-3、casp-8、casp-9）基因的表达，并下调了抗凋亡基因bcl2、CDK4和MMP1的表达。流式细胞术表明，A459细胞在G2/M阶段发生了细胞周期停滞，且凋亡百分比相较于对照样本显著增加。通过ELISA实验检测到细胞色素c氧化酶和VEGF酶活性。使用扫描电子显微镜（SEM）观察了细胞表面发生的形态变化、细胞颗粒化及细胞表面的平均粗糙度。利用透射电子显微镜（TEM）观察到线粒体的数量和形态变化、细胞收缩、细胞质细胞器数量增加、膜突起、染色质浓缩及凋亡小体的形成。获得的数据表明，新型查尔酮通过诱导两条凋亡途径在肺癌中发挥作用。
• [1,2,4] Triazolo [3,4-a]isoquinoline chalcone derivative exhibits anticancer activity via induction of oxidative stress, DNA damage, and apoptosis in Ehrlich solid carcinoma-bearing mice
  作者：Amr Ahmed WalyEldeen、Haidan M. El-Shorbagy、Hamdi M. Hassaneen、Ismail A. Abdelhamid、Salwa Sabet、Sherif Abdelaziz Ibrahim

  DOI：10.1007/s00210-022-02269-5

  日期：2022.10

  Despite the advances made in cancer therapeutics, their adverse effects remain a major concern, putting safer therapeutic options in high demand. Since chalcones, a group of flavonoids and isoflavonoids, act as promising anticancer agents, we aimed to evaluate the in vivo anticancer activity of a synthetic isoquinoline chalcone (CHE) in a mice model with Ehrlich solid carcinoma. Our in vivo pilot experiments revealed that the maximum tolerated body weight-adjusted CHE dose was 428 mg/kg. Female BALB/c mice were inoculated with Ehrlich ascites carcinoma cells and randomly assigned to three different CHE doses administered intraperitoneally (IP; 107, 214, and 321 mg/kg) twice a week for two consecutive weeks. A group injected with doxorubicin (DOX; 4 mg/kg IP) was used as a positive control. We found that in CHE-treated groups: (1) tumor weight was significantly decreased; (2) the total antioxidant concentration was substantially depleted in tumor tissues, resulting in elevated oxidative stress and DNA damage evidenced through DNA fragmentation and comet assays; (3) pro-apoptotic genes p53 and Bax, assessed via qPCR, were significantly upregulated. Interestingly, CHE treatment reduced immunohistochemical staining of the proliferative marker ki67, whereas BAX was increased. Notably, histopathological examination indicated that unlike DOX, CHE treatment had minimal toxicity on the liver and kidney. In conclusion, CHE exerts antitumor activity via induction of oxidative stress and DNA damage that lead to apoptosis, making CHE a promising candidate for solid tumor therapy.