2-(3-methoxyphenyl)-6-(pyrrolidin-1-yl)quinolin-4(1H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 2-(3-methoxyphenyl)-6-(pyrrolidin-1-yl)quinolin-4(1H)-one
• 英文别名: 2-(3-Methoxy-phenyl)-6-pyrrolidin-1-yl-1H-quinolin-4-one；2-(3-methoxyphenyl)-6-pyrrolidin-1-yl-1H-quinolin-4-one
• 化学式: C₂₀H₂₀N₂O₂
• 分子量: 320.391
• InChiKey: GVMDHCGKOFHSHB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(3-methoxyphenyl)-6-(pyrrolidin-1-yl)quinolin-4(1H)-one 在 三氯氧磷 作用下， 以70%的产率得到4-chloro-2-(3-methoxyphenyl)-6-(pyrrolidin-1-yl)quinoline
  参考文献：
  名称：

  Potent DNA-directed alkylating agents: Synthesis and biological activity of phenyl N-mustard–quinoline conjugates having a urea or hydrazinecarboxamide linker

  摘要：

  A series of N-mustard-quinoline conjugates bearing a urea or hydrazinecarboxamide linker was synthesized for antitumor evaluation. The in vitro cytotoxicity studies revealed that compounds with hydrazinecarboxamide linkers were generally more cytotoxic than the corresponding urea counterparts in inhibiting human lymphoblastic leukemia and various solid tumor cell growths in culture. The therapeutic efficacy against human tumor xenografts in animal model was studied. It was shown that complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft by 17a, i and 18c, d was achieved. In the present study, it was revealed that both linkers are able to lower the chemically reactive N-mustard pharmacophore and thus the newly synthesized conjugates possess a long half-life in rat plasma. Moreover, the new N-mustard derivatives are able to induce DNA cross-linking either by modified comet assay or by alkaline agarose gel shift assay. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.01.061
• 作为产物：
  描述：

  3-氯苯乙酮 在 palladium on activated charcoal 硫酸 、 potassium tert-butylate 、 氢气 、 硝酸 、 三乙胺 作用下， 以 四氢呋喃 、 叔丁醇 为溶剂， 反应 22.5h， 生成 2-(3-methoxyphenyl)-6-(pyrrolidin-1-yl)quinolin-4(1H)-one
  参考文献：
  名称：

  Antitumor Agents 155. Synthesis and Biological Evaluation of 3',6,7-Substituted 2-Phenyl-4-quinolones as Antimicrotubule Agents

  摘要：

  A series of 3',6,7-substituted 2-phenyl-4-quinolones were designed and synthesized as antimitotic antitumor agents. All compounds showed cytotoxic effects (log GI(50) less than or equal to -4.0; log drug molar concentration required to cause 50% inhibition) against the growth of a variety of human tumor cell lines, including those derived from solid tumors such as non-small cell lung, colon, central nervous system, ovary, prostate, and breast cancers, when evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. The most potent compound (26) demonstrated strong cytotoxic effects with GI(50) values in the nanomolar or subnanomolar range in almost all the tumor cell lines. Compound 26 was also a potent inhibitor of tubulin polymerization and radiolabeled colchicine binding to tubulin, with activity comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4.

  DOI：

  10.1021/jm00046a025

文献信息

• Novel 2-Substituted Quinolin-4-yl-benzenesulfonate Derivatives: Synthesis, Antiproliferative Activity, and Inhibition of Cellular Tubulin Polymerization
  作者：Rajesh Kakadiya、Yi-Chen Wu、Huajin Dong、Hsiao-Hui Kuo、Ling-Huei Yih、Ting-Chao Chou、Tsann-Long Su

  DOI：10.1002/cmdc.201100121

  日期：2011.6.6

  4′‐nitrophenyl sulfonate 10 m exhibit superior cytotoxicity over other sulfonates. The antiproliferative activities of these compounds correlate well with their abilities to induce mitotic arrest and apoptosis. Mechanistic studies indicate that they target the vinblastine binding site of tubulin and inhibit cellular tubulin polymerization. Hence, these compounds induce the formation of aberrant mitotic spindles

  为了评估抗增殖活性，合成了一系列2-取代的喹啉-4-基苯磺酸衍生物。讨论了新合成的化合物对人淋巴细胞白血病和培养中各种实体瘤细胞生长的结构-活性关系。在这些衍生物中，2-苯基-6-吡咯烷基-2-喹啉磺酸盐类似物10 f，10 g和10 k，以及4'-硝基苯磺酸盐10 m表现出优于其他磺酸盐的细胞毒性。这些化合物的抗增殖活性与其诱导有丝分裂停滞和凋亡的能力密切相关。机理研究表明，它们靶向微管蛋白的长春碱结合位点并抑制细胞微管蛋白的聚合。因此，这些化合物诱导异常的有丝分裂纺锤体的形成和有丝分裂停滞，从而导致强烈的细胞凋亡。已证明测试的化合物是膜多药耐药性转运蛋白的不良底物。本研究表明，这些新合成的化合物是有前景的微管蛋白聚合抑制剂，作为抗肿瘤剂值得进一步研究。
• US6433187B1
  申请人：——

  公开号：US6433187B1

  公开（公告）日：2002-08-13
• [EN] TUBULIN-BINDING AGENTS<br/>[FR] AGENTS DE LIAISON DE TUBULINE
  申请人：TULARIK INC

  公开号：WO2000035865A2

  公开（公告）日：2000-06-22

  Derivatives of known tubulin-binding compounds are provided in which a (poly)fluorobenzene, a fluoropyridine, or a fluoronitrobenzene moiety is incorporated or added to the structure. These derivatives can be used as antimitotic agents and can be considered covalent modifiers of tubulin. The strategy developed for each of the compounds is to i) append a fluorinated electrophile (e.g., pentafluorophenylsulfonamido, 2-fluoropyridyl, or 3,5-dinitro-4-fluorophenyl) to an existing functional group in a natural product, ii) replace an aromatic ring in a natural product with a fluorinated electrophile, or iii) attach a fluorinated electrophile to an open valence in a portion of the molecule that will not interfere with recognition and binding to the tubulin site. Derivatives are provided based on colchicine, steganacin, podophyllotoxin, nocodazole, combretastatin, curacin A, vinblastine, vincristine, dolastatin, 2-methoxyestradiol, dihydroxy-pentamethoxyflavanone and others.
• Antitumor Agents 155. Synthesis and Biological Evaluation of 3',6,7-Substituted 2-Phenyl-4-quinolones as Antimicrotubule Agents
  作者：Leping Li、Hui-Kang Wang、Sheng-Chu Kuo、Tian-Shung Wu、Anthony Mauger、Chii M. Lin、Ernest Hamel、Kuo-Hsiung Lee

  DOI：10.1021/jm00046a025

  日期：1994.9

  A series of 3',6,7-substituted 2-phenyl-4-quinolones were designed and synthesized as antimitotic antitumor agents. All compounds showed cytotoxic effects (log GI(50) less than or equal to -4.0; log drug molar concentration required to cause 50% inhibition) against the growth of a variety of human tumor cell lines, including those derived from solid tumors such as non-small cell lung, colon, central nervous system, ovary, prostate, and breast cancers, when evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. The most potent compound (26) demonstrated strong cytotoxic effects with GI(50) values in the nanomolar or subnanomolar range in almost all the tumor cell lines. Compound 26 was also a potent inhibitor of tubulin polymerization and radiolabeled colchicine binding to tubulin, with activity comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4.
• Potent DNA-directed alkylating agents: Synthesis and biological activity of phenyl N-mustard–quinoline conjugates having a urea or hydrazinecarboxamide linker
  作者：Rajesh Kakadiya、Huajin Dong、Amit Kumar、Dodia Narsinh、Xiuguo Zhang、Ting-Chao Chou、Te-Chang Lee、Anamik Shah、Tsann-Long Su

  DOI：10.1016/j.bmc.2010.01.061

  日期：2010.3

  A series of N-mustard-quinoline conjugates bearing a urea or hydrazinecarboxamide linker was synthesized for antitumor evaluation. The in vitro cytotoxicity studies revealed that compounds with hydrazinecarboxamide linkers were generally more cytotoxic than the corresponding urea counterparts in inhibiting human lymphoblastic leukemia and various solid tumor cell growths in culture. The therapeutic efficacy against human tumor xenografts in animal model was studied. It was shown that complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft by 17a, i and 18c, d was achieved. In the present study, it was revealed that both linkers are able to lower the chemically reactive N-mustard pharmacophore and thus the newly synthesized conjugates possess a long half-life in rat plasma. Moreover, the new N-mustard derivatives are able to induce DNA cross-linking either by modified comet assay or by alkaline agarose gel shift assay. (C) 2010 Elsevier Ltd. All rights reserved.