(9ci)-4-[(3-甲酰基-1H-吲哚-1-基)甲基]-苯甲酸甲酯 | 592546-73-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (9ci)-4-[(3-甲酰基-1H-吲哚-1-基)甲基]-苯甲酸甲酯
• 英文名称: methyl 4-((3-formyl-1H-indol-1-yl)methyl)benzoate
• 英文别名: methyl 4-[(3-formylindol-1-yl)methyl]benzoate
• CAS: 592546-73-1
• 化学式: C₁₈H₁₅NO₃
• 分子量: 293.322
• InChiKey: LVUBHSKGHORVSZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  48.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (9ci)-4-[(3-甲酰基-1H-吲哚-1-基)甲基]-苯甲酸甲酯 在 potassium carbonate 作用下， 以 甲醇 、 乙二醇二甲醚 、 二氯甲烷 为溶剂， 反应 25.0h， 生成 methyl 4-((3-(1-methyl-1H-imidazol-5-yl)-1H-indol-1-yl)methyl)benzoate
  参考文献：
  名称：

  Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated

  摘要：

  The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.

  DOI：

  10.1021/acs.jmedchem.8b01936
• 作为产物：
  描述：

  3-吲哚甲醛 、 4-溴甲基苯甲酸甲酯 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 以80%的产率得到(9ci)-4-[(3-甲酰基-1H-吲哚-1-基)甲基]-苯甲酸甲酯
  参考文献：
  名称：

  Ring-opened tetrahydro-γ-carbolines display cytotoxicity and selectivity with histone deacetylase isoforms

  摘要：

  This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5-18) were synthesized and structure -activity relationship studies indicated that the change of the tetrahydro-gamma-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials. In addition, attachment of different hydroxamic acid groups, the zinc binding motif at the N1 position, contributes to the antiproliferative activity in cancer cells. Several synthetic compounds exhibited potent growth inhibition in a broad spectrum of tumor cell lines, induced irreversible growth arrest capacities by suppressing colony formation ability and activated the apoptosis pathway. The data provide compelling evidence that our newly synthesized compounds with type B to D hydroxamic acid groups as the zinc binding motif at the N1 position are potent selective inhibitors of HDAC6 and could be investigated preclinically as potential anticancer drugs. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.12.039

文献信息

• INDOLE COMPOUNDS AND THEIR USE AS RADIATION SENSITIZING AGENTS AND CHEMOTHERAPEUTIC AGENTS
  申请人：Crooks Peter A.

  公开号：US20100081678A1

  公开（公告）日：2010-04-01

  Indole derivatives that are useful in the treatment of cancer as a chemotherapeutic agent or radiosensitizing agent.

  对癌症治疗有用的吲哚衍生物，可作为化疗药物或放射敏感剂。
• Indole compounds and their use as radiation sensitizing agents and chemotherapeutic agents
  申请人：Vanderbilt University

  公开号：US08304421B2

  公开（公告）日：2012-11-06

  Indole derivatives that are useful in the treatment of cancer as a chemotherapeutic agent or radiosensitizing agent.

  吲哚衍生物是一种在癌症化疗或放射增敏剂治疗中有用的化学治疗药物。
• Novel substituted (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-diones and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones as potent radio-sensitizing agents
  作者：Y. Thirupathi Reddy、Konjeti R. Sekhar、Nidhish Sasi、P. Narsimha Reddy、Michael L. Freeman、Peter A. Crooks

  DOI：10.1016/j.bmcl.2009.11.082

  日期：2010.1

  A series of (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-dione (9a-9m) and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (10a-10i) derivatives that incorporate a variety of aromatic substituents in both the indole and N-benzyl moieties have been synthesized. These analogs were evaluated for their radiosensitization activity against the HT-29 cell line. Three analogs, 10a, 10b, and 10c were identified as the most potent radiosensitizing agents. (C) 2009 Elsevier Ltd. All rights reserved.
• Aplysinopsin analogs: Synthesis and anti-proliferative activity of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones
  作者：Y. Thirupathi Reddy、P. Narsimha Reddy、Srinivas Koduru、Chendil Damodaran、Peter A. Crooks

  DOI：10.1016/j.bmc.2010.03.054

  日期：2010.5

  A series of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione ( 3) analogs structurally related to aplysinopsin, and that incorporate a variety of substituents in both the indole and N-benzyl moieties have been synthesized under microwave irradiation and conventional heating methods These analogs were evaluated for their anti-proliferative activity against MCF-7 and MDA-231 breast cancer cell lines, and A549 and H460 lung cancer cell lines. Two analogs, 3f and 3j had IC50 values of 4.4 and 5.2 mu M, respectively, compared to 5-fluorouracil (IC50 = 15.2 mu M) against MCF-7 cells. (C) 2010 Elsevier Ltd. All rights reserved.
• Microwave assisted synthesis and in vitro cytotoxicities of substituted (Z)-2-amino-5-(1-benzyl-1H-indol-3-yl)methylene-1-methyl-1H-imidazol-4(5H)-ones against human tumor cell lines
  作者：Narsimha Reddy Penthala、Thirupathi Reddy Yerramreddy、Peter A. Crooks

  DOI：10.1016/j.bmcl.2009.11.083

  日期：2010.1

  The synthesis of several novel substituted (Z)-2-amino-5-(1-benzyl-1H-indol-3-yl)methylene-1-methyl-1H-imidazol-4(5H)-ones structurally related to aplysinopsin have been carried out under microwave irradiation and conventional heating methods. The analogs 3a, 3b, 3d-3g, 3k and 3l were evaluated for their in vitro cytotoxic activity against an NCI 60 human tumor cell line panel. Compound 3f exhibited good growth inhibitory properties against all but four of the human cancer cell lines examined, and afforded LC50 values < 10 mu M for 30% of the cell lines in the panel. Compound 3e was an effective inhibitor of leukemia, CNS, melanoma, and breast cancer cell growth, but generally less effective as a cytotoxic agent. Thus, the aplysinopsin analog 3f was regarded as a useful lead compound for further structural optimization. (C) 2009 Elsevier Ltd. All rights reserved.