(E)-N'-(1-naphthylmethylene)-3,4,5-trimethoxybenzohydrazide | 1265608-66-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (E)-N'-(1-naphthylmethylene)-3,4,5-trimethoxybenzohydrazide
• 英文别名: 3,4,5-trimethoxy-~{N}-[(~{E})-naphthalen-1-ylmethylideneamino]benzamide；3,4,5-trimethoxy-N-[(E)-naphthalen-1-ylmethylideneamino]benzamide
• CAS: 1265608-66-9
• 化学式: C₂₁H₂₀N₂O₄
• 分子量: 364.401
• InChiKey: MMNQIKXMVWECIH-LPYMAVHISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  69.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (E)-N'-(1-naphthylmethylene)-3,4,5-trimethoxybenzohydrazide 、 乙酸酐 反应 3.0h， 以35%的产率得到1-(2-(naphthalen-1-yl)-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-3(2H)-yl)ethanone
  参考文献：
  名称：

  N-(1′-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia

  摘要：

  Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.02.041
• 作为产物：
  描述：

  没食子酸 在 四丁基碘化铵 、 potassium carbonate 、 一水合肼 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 14.0h， 生成 (E)-N'-(1-naphthylmethylene)-3,4,5-trimethoxybenzohydrazide
  参考文献：
  名称：

  N-(1′-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia

  摘要：

  Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.02.041

文献信息

• ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF
  申请人：Universidade Federal de Santa Catarina

  公开号：US20150191445A1

  公开（公告）日：2015-07-09

  The present invention relates to acyl-hydrazone compounds, in particular 3,4,5-trimethoxyphenyl-hydrazide derivatives, as well as the oxadiazole analogs thereof and other similar compounds, and to the pharmaceutical use of the same for the treatment of various diseases associated with cell proliferation, such as leukemias, including acute lymphoblastic leukemia (ALL), tumours and inflammation. Acyl-hydrazones have been obtained having activity similar to that of the compound used as a standard in experiments (colchicine). The greater selectivity of the compounds according to the invention is an important feature, associated with fewer side effects than the pharmaceuticals used at present in clinical treatments. The synthetised acyl-hydrazones, more particularly the compounds 02 and 07, exhibited important antileukemic activity, which suggests 02 and 07 as candidates to pharmaceutical prototypes, or to pharmaceuticals for the treatment of leukemias, in particular acute lymphoblastic leukemia (ALL), tumours and other proliferative diseases, such as inflammation. The action mechanism of the most active compounds was determined by using DNA microarrays and subsequent tests indicated by the chip, besides selectivity studies in healthy human lymphocytes.

  本发明涉及酰基腙化合物，特别是3,4,5-三甲氧基苯基腙衍生物，以及其噁二唑类似物和其他类似化合物，以及它们在治疗与细胞增殖相关的各种疾病，如白血病（包括急性淋巴细胞白血病（ALL））、肿瘤和炎症方面的药用。已获得具有与实验中使用的化合物（秋水仙碱）相似活性的酰基腙。根据本发明的化合物具有更大的选择性，与目前在临床治疗中使用的药物相比，副作用更少是一个重要特征。合成的酰基腙，尤其是化合物02和07，表现出重要的抗白血病活性，这表明02和07可能成为药物原型的候选，或用于治疗白血病，特别是急性淋巴细胞白血病（ALL）、肿瘤和其他增殖性疾病，如炎症的药物。最活性化合物的作用机制是通过使用DNA微阵列确定的，并且通过芯片指示的后续测试，以及对健康人类淋巴细胞的选择性研究。
• Biochemical evaluation of a series of synthetic chalcone and hydrazide derivatives as novel inhibitors of cruzain from Trypanosoma cruzi
  作者：Deise M. Borchhardt、Alessandra Mascarello、Louise Domeneghini Chiaradia、Ricardo J. Nunes、Glaucius Oliva、Rosendo A. Yunes、Adriano D. Andricopulo

  DOI：10.1590/s0103-50532010000100021

  日期：——

  Chagas' disease, a parasitic infection widely distributed throughout Latin America, is a major public health problem with devastating consequences in terms of human morbidity and mortality. The enzyme cruzain is the major cysteine protease from Trypanosoma cruzi, the etiologic agent of American trypanosomiasis or Chagas' disease, and has been selected as an attractive target for the development of novel trypanocidal drugs. In the present work, we describe the synthesis and inhibitory effects of a series of thirty-three chalcone and seven hydrazide derivatives against the enzyme cruzain from T. cruzi. Most of the compounds showed promising in vitro inhibition (IC50 values in the range of 20-60 mu M), which suggest the potential of these compounds as lead candidates for further development. Twelve compounds have not been reported before, and four of them (7, 13, 16 e 18) are among the most potent inhibitors of the series.
• [EN] ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF<br/>[FR] COMPOSÉS ACYL-HYDRAZONES ET OXADIAZOLS, COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT ET UTILISATIONS CORRESPONDANTES<br/>[PT] "COMPOSTOS ACIL-HIDRAZONAS E OXADIAZÓIS, COMPOSIÇÕES FARMACÊUTICAS COMPREENDENDO OS MESMOS E SEUS USOS
  申请人：UNIV FED DE SANTA CATARINA UFSC

  公开号：WO2013075199A1

  公开（公告）日：2013-05-30

  A presente invenção refere-se a compostos acil-hidrazonas, especialmente as derivados da 3,4,5-trimetoxifenil-hidrazida, bem como a seus análogos oxadiazóis e outros compostos semelhantes, e aplicação farmacêutica dos mesmos no tratamento de diferentes doenças associadas à proliferação celular, como leucemias, incluindo leucemia linfóide aguda (LLA), tumores e inflamação. Foram obtidas acil-hidrazonas com atividade semelhante ao composto utilizado como padrão nos experimentos (colchicina). A maior seletividade dos compostos apresentados nesta invenção é uma característica importante relacionada com menores efeitos colaterais que os fármacos atualmente empregados na clínica. As acil- hidrazonas sintetizadas, mais especificamente os compostos 02 e 07, apresentaram importante atividade antileucêmica, o que indica 02 e 07 como candidatos a protótipos de fármacos, ou fármacos, para o tratamento de leucemias, especialmente leucemia linfóide aguda (LLA), tumores e outras doenças proliferativas, como inflamação. A determinação do mecanismo de ação dos compostos mais ativos foi realizada pela utilização de microarranjos de DNA e testes subsequentes indicados através do chip, além dos estudos de seletividade em linfócitos humanos saudáveis.
• N-(1′-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia
  作者：Lívia B. Salum、Alessandra Mascarello、Rafael R. Canevarolo、Wanessa F. Altei、Angelo B.A. Laranjeira、Patrícia D. Neuenfeldt、Taisa R. Stumpf、Louise D. Chiaradia-Delatorre、Laura L. Vollmer、Hikmat N. Daghestani、Carolina P. de Souza Melo、André B. Silveira、Paulo C. Leal、Marisa J.S. Frederico、Leandro F. do Nascimento、Adair R.S. Santos、Adriano D. Andricopulo、Billy W. Day、Rosendo A. Yunes、Andreas Vogt、José A. Yunes、Ricardo J. Nunes

  DOI：10.1016/j.ejmech.2015.02.041

  日期：2015.5

  Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg. (C) 2015 Elsevier Masson SAS. All rights reserved.