dimethyl 3-(4-fluorophenyl)-6-methyl-6,11-dihydro-5H-indolizino-[6,7-b]indole-1,2-dicarboxylate | 1422376-97-3

• 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-(4-fluorophenyl)-6-methyl-6,11-dihydro-5H-indolizino-[6,7-b]indole-1,2-dicarboxylate
• 英文别名: Dimethyl 1-(4-fluorophenyl)-9-methyl-4,10-dihydroindolizino[6,7-b]indole-2,3-dicarboxylate；dimethyl 1-(4-fluorophenyl)-9-methyl-4,10-dihydroindolizino[6,7-b]indole-2,3-dicarboxylate
• CAS: 1422376-97-3
• 化学式: C₂₅H₂₁FN₂O₄
• 分子量: 432.451
• InChiKey: CMGZYMUJSQWVFZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  62.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  dimethyl 3-(4-fluorophenyl)-6-methyl-6,11-dihydro-5H-indolizino-[6,7-b]indole-1,2-dicarboxylate 在 lithium aluminium tetrahydride 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 0.5h， 以78%的产率得到(3-(4-fluorophenyl)-6-methyl-6,11-dihydro-5H-indolizino [6,7-b]indole-1,2-diyl)dimethanol
  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：

  methyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate 在 乙酸酐 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 18.25h， 生成 dimethyl 3-(4-fluorophenyl)-6-methyl-6,11-dihydro-5H-indolizino-[6,7-b]indole-1,2-dicarboxylate
  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

文献信息

• 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.