dimethyl 3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate | 35105-58-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: dimethyl 3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate
• 英文别名: dimethyl 3-methyl-6,11-dihydro-5H-indolizino [6,7-b]indole-1,2-dicarboxylate；dimethyl 1-methyl-9,10-dihydro-4H-indolizino[6,7-b]indole-2,3-dicarboxylate
• CAS: 35105-58-9
• 化学式: C₁₉H₁₈N₂O₄
• 分子量: 338.363
• InChiKey: VNYTXXJDRUXOQW-UHFFFAOYSA-N

物化性质

• 沸点：
  534.2±50.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  73.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  dimethyl 3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate 在 lithium aluminium tetrahydride 、 sodium hydride 、 三乙胺 作用下， 以 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 10.5h， 生成 [6-ethyl-3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-diyl]bis(methylene)bis(ethylcarbamate)
  参考文献：
  名称：

  Novel Antitumor Indolizino[6,7-b]indoles with Multiple Modes of Action: DNA Cross-Linking and Topoisomerase I and II Inhibition

  摘要：

  A series of bis(hydroxymethyl)indolizino[6,7-b]indoles and their bis(alkylcarbamates) were synthesized for antitumor studies. These agents were designed as hybrid molecules of beta-carboline (topoisomerase inhibition moiety) and bis(hydroxymethyl)pyrrole (DNA cross-linking moiety). The preliminary antitumor studies indicated that these agents exhibited significant cytotoxicity against a variety of human tumor cells in vitro. Treatment of human breast carcinoma MX-1 xenograft-bearing nude mice with compounds 18b and 28c achieved more than 99% tumor remission. We also observed that 18a displayed potent therapeutic efficacy against human lung adenocarcinoma A549 and colon cancer HT 29 xenografts. These results revealed that compound 18a was more potent than irinotecan against HT 29 cells and was as potent as irinotecan against A549 cells in xenograft models. Furthermore, we demonstrated that these derivatives possess multiple modes of action, such as induction of DNA cross-linking, inhibition of topoisomerase I and II, and cell-cycle arrest at the S-phase.

  DOI：

  10.1021/jm301788a
• 作为产物：
  描述：

  L-色氨酸 在 硫酸 作用下， 反应 6.0h， 生成 dimethyl 3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate
  参考文献：
  名称：

  SYNTHESIS OF 4H-BENZO[D]PYRROLO[1,2-A]THIAZOLES AND INDOLIZINO[6,7-b]INDOLE DERIVATIVES AND THEIR USE AS ANTITUMOR THERAPEUTIC AGENTS

  摘要：

  本发明提供了一系列2,3-双(羟甲基)-4H-苯并[d]吡咯-[1,2-a]噻唑和1,2-双(羟甲基)吲哚并[6,7-b]吲哚衍生物及其双(烷基氨基甲酸酯)衍生物。这些衍生物被设计为具有双功能DNA交联作用的剂。对这些化合物进行的体外细胞毒性研究表明，它们在抑制人淋巴母细胞白血病和各种实体肿瘤细胞生长方面表现出显著的抗增殖活性。这些化合物还在异种移植模型中对人类乳腺癌和肺癌表现出治疗效果。这些化合物通常具有强大的抗肿瘤活性，可以杀死各种人类实体肿瘤，并具有高潜力用于临床应用。

  公开号：

  US20130178629A1

文献信息

• SYNTHESIS OF 4H-BENZO[D]PYRROLO[1,2-A]THIAZOLES AND INDOLIZINO[6,7-b]INDOLE DERIVATIVES AND THEIR USE AS ANTITUMOR THERAPEUTIC AGENTS
  申请人：Su Tsann-Long

  公开号：US20130178629A1

  公开（公告）日：2013-07-11

  The present invention provides a series of 2,3-bis(hydroxymethyl)-4H-benzo[d]pyrrolo-[1,2-a]thiazoles and 1,2-bis(hydroxymethyl)indolizino[6,7-b]indole derivatives and their bis(alkylcarbamates) derivatives. These derivatives were designed as bi-functional DNA cross-linking agents. The in vitro cytotoxicity study of these compounds revealed that they exhibit significant anti-proliferative activity in inhibiting human lymphoblastic leukemia and various solid tumor cell growth. The compounds also exhibit therapeutic efficacy against human breast carcinoma and lung cancer in xenograft model. The compounds generally possess potent antitumor activity to kill various human solid tumors and have high potential for clinical applications.

  本发明提供了一系列2,3-双(羟甲基)-4H-苯并[d]吡咯-[1,2-a]噻唑和1,2-双(羟甲基)吲哚并[6,7-b]吲哚衍生物及其双(烷基氨基甲酸酯)衍生物。这些衍生物被设计为具有双功能DNA交联作用的剂。对这些化合物进行的体外细胞毒性研究表明，它们在抑制人淋巴母细胞白血病和各种实体肿瘤细胞生长方面表现出显著的抗增殖活性。这些化合物还在异种移植模型中对人类乳腺癌和肺癌表现出治疗效果。这些化合物通常具有强大的抗肿瘤活性，可以杀死各种人类实体肿瘤，并具有高潜力用于临床应用。
• Synthesis of 4H-benzo[D]pyrrolo[1,2-A]thiazoles and indolizino[6,7-b]indole derivatives and their use as antitumor therapeutic agents
  申请人：Su Tsann-Long

  公开号：US08703951B2

  公开（公告）日：2014-04-22

  The present invention provides a series of 2,3-bis(hydroxymethyl)-4H-benzo[d]pyrrolo-[1,2-a]thiazoles and 1,2-bis(hydroxymethyl)indolizino[6,7-b]indole derivatives and their bis(alkylcarbamates) derivatives. These derivatives were designed as bi-functional DNA cross-linking agents. The in vitro cytotoxicity study of these compounds revealed that they exhibit significant anti-proliferative activity in inhibiting human lymphoblastic leukemia and various solid tumor cell growth. The compounds also exhibit therapeutic efficacy against human breast carcinoma and lung cancer in xenograft model. The compounds generally possess potent antitumor activity to kill various human solid tumors and have high potential for clinical applications.

  本发明提供了一系列2,3-双(羟甲基)-4H-苯并[d]吡咯并[1,2-a]噻唑和1,2-双(羟甲基)吲哚并[6,7-b]吲哚衍生物及其双(烷基氨基甲酸酯)衍生物。这些衍生物被设计为双功能DNA交联剂。这些化合物的体外细胞毒性研究表明，它们在抑制人淋巴母细胞白血病和各种实体肿瘤细胞生长方面表现出显著的抗增殖活性。这些化合物在异种移植模型中也表现出对人乳腺癌和肺癌的治疗疗效。这些化合物通常具有强大的抗肿瘤活性，可以杀死各种人类实体肿瘤，并具有高度的临床应用潜力。
• US8703951B2
  申请人：——

  公开号：US8703951B2

  公开（公告）日：2014-04-22
• Novel Antitumor Indolizino[6,7-<i>b</i>]indoles with Multiple Modes of Action: DNA Cross-Linking and Topoisomerase I and II Inhibition
  作者：Ravi Chaniyara、Satishkumar Tala、Chi-Wei Chen、Xiuguo Zang、Rajesh Kakadiya、Li-Fang Lin、Ching-Huang Chen、Shin-I Chien、Ting-Chao Chou、Tung-Hu Tsai、Te-Chang Lee、Anamik Shah、Tsann-Long Su

  DOI：10.1021/jm301788a

  日期：2013.2.28

  A series of bis(hydroxymethyl)indolizino[6,7-b]indoles and their bis(alkylcarbamates) were synthesized for antitumor studies. These agents were designed as hybrid molecules of beta-carboline (topoisomerase inhibition moiety) and bis(hydroxymethyl)pyrrole (DNA cross-linking moiety). The preliminary antitumor studies indicated that these agents exhibited significant cytotoxicity against a variety of human tumor cells in vitro. Treatment of human breast carcinoma MX-1 xenograft-bearing nude mice with compounds 18b and 28c achieved more than 99% tumor remission. We also observed that 18a displayed potent therapeutic efficacy against human lung adenocarcinoma A549 and colon cancer HT 29 xenografts. These results revealed that compound 18a was more potent than irinotecan against HT 29 cells and was as potent as irinotecan against A549 cells in xenograft models. Furthermore, we demonstrated that these derivatives possess multiple modes of action, such as induction of DNA cross-linking, inhibition of topoisomerase I and II, and cell-cycle arrest at the S-phase.