1-(4-nitrophenyl)-β-carboline-3-carboxylic acid hydrazide | 1085709-09-6

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 1-(4-nitrophenyl)-β-carboline-3-carboxylic acid hydrazide
• 英文别名: 1-(4-nitrophenyl)-9H-pyrido[3,4-b]indole-3-carbohydrazide
• CAS: 1085709-09-6
• 化学式: C₁₈H₁₃N₅O₃
• 分子量: 347.333
• InChiKey: GIEZHVSEXHMPSO-UHFFFAOYSA-N

物化性质

• 密度：
  1.485±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(4-nitrophenyl)-β-carboline-3-carboxylic acid hydrazide 在 盐酸 、 羟胺钾盐 、 potassium carbonate 、 溶剂黄146 、 potassium iodide 、 sodium nitrite 作用下， 以 甲醇 、 水 、 乙腈 为溶剂， 反应 24.0h， 生成
  参考文献：
  名称：

  β-Carboline和N -hydroxycinnamamide杂种作为抗药性肝细胞癌的抗癌药

  摘要：

  为了努力开发可以克服耐药性（导致癌症死亡的首要原因）的抗癌剂，我们开发了一系列新型的β-咔啉和N-羟基肉桂酰胺作为组蛋白脱乙酰基酶（HDAC）抑制剂。大多数杂种13a-p对四种人类癌细胞均表现出很强的抗增殖作用，且低微摩尔IC 50值。13p系列最有效的化合物显示出高HDAC1 / 6抑制作用，并且还提高了组蛋白H3，H4和α-微管蛋白的乙酰化水平。重要的是，13p对药物敏感的HepG2和Bel7402细胞以及耐药的Bel7402 / 5FU细胞表现出很高的抗癌能力。混合13p通过调节这些Bel7402 / 5FU细胞中凋亡相关蛋白的表达，触发了明显的凋亡。最后，13p通过在Bel7402 / 5FU细胞中增加LC3-II的表达以及p62和LC3-I的表达的退化而诱导了大量的自噬通量活性。总体而言，13p是一种新型的β-咔啉/ N-羟基肉桂酰胺杂化物，具有显着的抗癌效力，值得进一步评估其对耐药性肝细胞癌的治疗。

  DOI：

  10.1016/j.ejmech.2019.02.054
• 作为产物：
  描述：

  DL-色氨酸 在 potassium permanganate 、 氯化亚砜 、 一水合肼 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 1-(4-nitrophenyl)-β-carboline-3-carboxylic acid hydrazide
  参考文献：
  名称：

  β-Carboline和N -hydroxycinnamamide杂种作为抗药性肝细胞癌的抗癌药

  摘要：

  为了努力开发可以克服耐药性（导致癌症死亡的首要原因）的抗癌剂，我们开发了一系列新型的β-咔啉和N-羟基肉桂酰胺作为组蛋白脱乙酰基酶（HDAC）抑制剂。大多数杂种13a-p对四种人类癌细胞均表现出很强的抗增殖作用，且低微摩尔IC 50值。13p系列最有效的化合物显示出高HDAC1 / 6抑制作用，并且还提高了组蛋白H3，H4和α-微管蛋白的乙酰化水平。重要的是，13p对药物敏感的HepG2和Bel7402细胞以及耐药的Bel7402 / 5FU细胞表现出很高的抗癌能力。混合13p通过调节这些Bel7402 / 5FU细胞中凋亡相关蛋白的表达，触发了明显的凋亡。最后，13p通过在Bel7402 / 5FU细胞中增加LC3-II的表达以及p62和LC3-I的表达的退化而诱导了大量的自噬通量活性。总体而言，13p是一种新型的β-咔啉/ N-羟基肉桂酰胺杂化物，具有显着的抗癌效力，值得进一步评估其对耐药性肝细胞癌的治疗。

  DOI：

  10.1016/j.ejmech.2019.02.054

文献信息

• A “Double-Locked” and Enzyme/pH-Activated Theranostic Agent for Accurate Tumor Imaging and Therapy
  作者：Jia Luo、Zongyu Guan、Weijie Gao、Chen Wang、Zhongyuan Xu、Chi Meng、Yun Liu、Yuquan Zhang、Qingsong Guo、Yong Ling

  DOI：10.3390/molecules27020425

  日期：——

  Theranostic agents for concurrent cancer therapy and diagnosis have begun attracting attention as a promising modality. However, accurate imaging and identification remains a great challenge for theranostic agents. Here, we designed and synthesized a novel theranostic agent H6M based on the “double-locked” strategy by introducing an electron-withdrawing nitro group into 1-position of a pH-responsive 3-amino-β-carboline and further covalently linking the hydroxamic acid group, a zinc-binding group (ZBG), to the 3-position of β-carboline to obtain histone deacetylase (HDAC) inhibitory effect for combined HDAC-targeted therapy. We found that H6M can be specifically reduced under overexpressed nitroreductase (NTR) to produce H6AQ, which emits bright fluorescence at low pH. Notably, H6M demonstrated a selective fluorescence imaging via successive reactions with NTR (first “key”) and pH (second “key”), and precisely identified tumor margins with a high S/N ratio to guide tumor resection. Finally, H6M exerted robust HDAC1/cancer cell inhibitory activities compared with a known HDAC inhibitor SAHA. Therefore, the NTR/pH-activated theranostic agent provided a novel tool for precise diagnosis and efficient tumor therapy.

  具有同时用于癌症治疗和诊断的治疗性药物已经开始引起人们的关注，作为一种有前途的模式。然而，对于治疗性药物来说，准确的成像和识别仍然是一个巨大挑战。在这里，我们基于“双重锁定”策略设计并合成了一种新型的治疗性药物H6M，通过在pH响应型3-氨基-β-咔啉的1位引入一个电子吸引性硝基基团，并进一步将羟羧酸基团（一种锌结合基团，ZBG）共价连接到β-咔啉的3位，以获得组蛋白去乙酰化酶（HDAC）抑制效果，用于联合HDAC靶向治疗。我们发现H6M可以在过表达的硝基还原酶（NTR）作用下特异性还原，产生H6AQ，在低pH下发出明亮的荧光。值得注意的是，H6M通过与NTR（第一个“关键”）和pH（第二个“关键”）的连续反应，展示出选择性荧光成像，并以高信噪比精确识别肿瘤边缘，指导肿瘤切除。最后，与已知的HDAC抑制剂SAHA相比，H6M在HDAC1/癌细胞抑制活性方面表现出强大的作用。因此，NTR/pH活化的治疗性药物为精确诊断和高效肿瘤治疗提供了一种新工具。
• Synthesis and antitumor activity of β-carboline 3-(substituted-carbohydrazide) derivatives
  作者：Valéria Aquilino Barbosa、Anelise S. Nazari Formagio、Franciele Cristina Savariz、Mary Ann Foglio、Humberto Moreira Spindola、João Ernesto de Carvalho、Emerson Meyer、Maria Helena Sarragiotto

  DOI：10.1016/j.bmc.2011.08.059

  日期：2011.11

  synthesized and evaluated for their antitumor activity against eight human cancer cell lines. The β-carboline N-(substituted-benzylidene)carbohydrazides showed, in general, a greater antitumor activity than their N-(alkylidene)carbohydrazide analogues. The N9-methylation of β-carboline N-(substituted-benzylidene) carbohydrazides resulted in a decrease of antitumor activity. Among compounds tested, the b

  合成了一系列在C-3处带有取代的碳酰肼部分的β-咔啉衍生物，并评估了其对八种人类癌细胞系的抗肿瘤活性。通常，β-咔啉N-（取代的亚苄基）碳酰肼显示出比其N-（亚烷基）碳酰肼类似物更大的抗肿瘤活性。β-咔啉N-（取代的亚苄基）碳酰肼的N 9甲基化导致抗肿瘤活性降低。在所测试的化合物中，苄基碳酰肼3，4，11，13，16，21和22是最活跃的，具有IC对于八种肿瘤细胞系中的六种，有50种小于10μM。衍生物4对所有测试的细胞系表现出最显着的活性，对肾脏（786-0）细胞系具有显着的细胞毒性（IC 50  = 0.04μM）。在Ehrlich实体癌测定中测定化合物4的体内抗肿瘤活性。
• Synthesis and antiviral activity of β-carboline derivatives bearing a substituted carbohydrazide at C-3 against poliovirus and herpes simplex virus (HSV-1)
  作者：Anelise S. Nazari Formagio、Patricia R. Santos、Karine Zanoli、Tania Ueda-Nakamura、Lilian T. Düsman Tonin、Celso V. Nakamura、Maria Helena Sarragiotto

  DOI：10.1016/j.ejmech.2009.07.005

  日期：2009.11

  Several novel 1,3-disubstituted β-carboline derivatives bearing a substituted carbohydrazide group at C-3 were synthesized and evaluated for their antiviral activity against vaccinal poliovirus (VP) and herpes simplex virus type 1 (HSV-1). The cytotoxicity and selectivity index of the active compounds were also evaluated. Among the synthesized derivatives, compounds 10 and 11 displayed potent activity

  合成了几种新颖的在C-3带有一个取代的碳酰肼基团的1,3-二取代的β-咔啉衍生物，并评估了它们对疫苗脊髓灰质炎病毒（VP）和1型单纯疱疹病毒（HSV-1）的抗病毒活性。还评估了活性化合物的细胞毒性和选择性指数。在合成的衍生物中，化合物10和11对疫苗的脊髓灰质炎病毒和HSV-1病毒均显示出有效的活性。化合物10表现出对HSV-1病毒的最高选择性指数（SI = 2446.8）和低细胞毒性（CC 50  = 1150.0±67.3μM）。病毒产量抑制试验表明化合物10能够在病毒吸附之前和期间抑制HSV-1斑块的形成。在化合物处理过的细胞中观察到的特征性小噬斑图案表明，化合物10抑制了病毒向邻近细胞的传播。通过使用Lipinski规则确定亲脂性，拓扑极性表面积（TPSA），吸收率（％ABS）和简单分子描述符，对预测新型合成β-咔啉衍生物的ADME性质进行了计算研究。
• Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells
  作者：Yong Ling、Jing Guo、Qiuxing Yang、Peng Zhu、Jiefei Miao、Weijie Gao、Yanfu Peng、Jiaying Yang、Kun Xu、Biao Xiong、Gongqing Liu、Jinhua Tao、Lin Luo、Qing Zhu、Yanan Zhang

  DOI：10.1016/j.ejmech.2017.12.061

  日期：2018.1

  A series of novel beta-carboline-based hydroxamate derivatives 12a-k were designed and synthesized, and their biological activities in a series of in vitro assays were evaluated. Several of these beta-carboline derivatives not only showed excellent HDAC1/3/6 inhibitory effects, but also displayed significant antitumor activities against five human cancer cells. The most potent compound 12f demonstrated the highest anticancer potency against cancer cell lines with IC50 values of 0.53-1.56 mu M, which was considerably more potent than harmine (IC50 = 46.7-55.3 mu M) and also three-to ten-fold lower than that of SAHA (IC50=4.48-6.26 mu M). Immunoblot analysis revealed that 12f dose-dependently inhibited histone H3 and a-tubulin acetylation, confirming its HDAC inhibitory effects. Moreover, 12f significantly arrested HepG2 cells at G2/M phase through inhibiting cell cycle related protein CDK1 and cyclin B in a concentration dependent manner. Interestingly, 12f also exerted strong anti-metastasis activity by simultaneously reducing the protein level of MMP2 and MMP9 and inhibiting MAPK signaling pathway. (C) 2017 Elsevier Masson SAS. All rights reserved.
• Synthesis and antitumoral activity of novel 3-(2-substituted-1,3,4-oxadiazol-5-yl) and 3-(5-substituted-1,2,4-triazol-3-yl) β-carboline derivatives
  作者：Anelise S. Nazari Formagio、Lilian T. Düsman Tonin、Mary Ann Foglio、Christiana Madjarof、João Ernesto de Carvalho、Willian Ferreira da Costa、Flávia P. Cardoso、Maria Helena Sarragiotto

  DOI：10.1016/j.bmc.2008.10.008

  日期：2008.11

  Several novel 1-substituted-phenyl beta-carbolines bearing the 2-substituted-1,3,4-oxadiazol-5-yl and 5-substituted-1,2,4-triazol-3-yl groups at C-3 were synthesized and evaluated for their in vitro anticancer activity. The assay results pointed thirteen compounds with growth inhibition effect (GI(50) < 100 mu M) for all eight different types of human cancer cell lines tested. The b-carbolines 7a and 7h, bearing the 3-(2-metylthio-1,3,4-oxadiazol-5-yl) group, displayed high selectivity and potent anticancer activity against ovarian cell line with GI50 values lying in the nanomolar concentration range (GI(50) = 10 nM for both compounds). The 1-(N,N-dimethylaminophenyl)-3-(5-thioxo-1,2,4-triazol-3-yl) beta-carboline (8g) was the most active compound, showing particular effectiveness on lung (GI(50) = 0.06 mu M), ovarian and renal cell lines. The potent anticancer activity presented for synthesized compounds 7a, 7h, and 8g, together with their easiness of synthesis, makes these compounds promising anticancer agents. (C) 2008 Elsevier Ltd. All rights reserved.