methyl 4-((3-formyl-2-methyl-1H-indol-1-yl)methyl)benzoate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl 4-((3-formyl-2-methyl-1H-indol-1-yl)methyl)benzoate
• 英文别名: methyl 4-[(3-formyl-2-methyl-1H-indol-1-yl)methyl]benzoate；methyl 4-[(3-formyl-2-methylindol-1-yl)methyl]benzoate
• 化学式: C₁₉H₁₇NO₃
• 分子量: 307.349
• InChiKey: GFRDXSLSPFRBIA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 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：

  methyl 4-((3-formyl-2-methyl-1H-indol-1-yl)methyl)benzoate 在 palladium 10% on activated carbon 、 氢气 、 三乙酰氧基硼氢化钠 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 4-((3-((dimethylamino)methyl)-2-methyl-1H-indol-1-yl)methyl)-N-hydroxybenzamide
  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
• 作为产物：
  描述：

  2-甲基吲哚-3-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82%的产率得到methyl 4-((3-formyl-2-methyl-1H-indol-1-yl)methyl)benzoate
  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

• 1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1)
  作者：Narsimha Reddy Penthala、Amit Ketkar、Konjeti R. Sekhar、Michael L. Freeman、Robert L. Eoff、Ramesh Balusu、Peter A. Crooks

  DOI：10.1016/j.bmc.2015.10.019

  日期：2015.11

  In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolylmethylene barbituric acid analogs (7a-7h) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogs (7i-7l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogs 7i, 7j, and 7k demonstrated potent growth inhibitory effects in various cancer cell types with GI(50) values < 2 mu M. Compound 7k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI(50) values in the range 0.22-0.35 mu M. Analog 7i also exhibited GI(50) values < 0.35 mu M against three of the leukemia cell lines in the sub-panel. Analogs 7i, 7j, 7k and 7l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds 7k and 7l were found to cause dose-dependent apoptosis (AP(50) = 1.75 mu M and 3.3 mu M, respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: that is, A498 renal cancer (GI(50) = 0.19 mu M), HOP-92 and NCI-H522 lung cancer (GI(50) = 0.25 mu M), COLO 205 and HCT-116 colon cancer (GI(50) = 0.20 and 0.26 mu M, respectively), CNS cancer SF-539 (GI(50) = 0.22 mu M), melanoma MDA-MB-435 (GI(50) = 0.22 mu M), and breast cancer HS 578T (GI(50) = 0.22 mu M) cell lines. Molecular docking studies suggest that compounds 7k and 7l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors 7i, 7j, 7k, and 7l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors. (C) 2015 Elsevier Ltd. All rights reserved.
• Ring-opened tetrahydro-γ-carbolines display cytotoxicity and selectivity with histone deacetylase isoforms
  作者：Kunal Nepali、Hsueh-Yun Lee、Mei-Jung Lai、Ritu Ojha、Tung-Yun Wu、Gu-Xian Wu、Mei-Chuan Chen、Jing-Ping Liou

  DOI：10.1016/j.ejmech.2016.12.039

  日期：2017.2

  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.