(S)-5-ethyl-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one | 1034110-72-9

• 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: (S)-5-ethyl-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one
• 英文别名: (S)-5-ethyl-5,8-dihydroindolo[2,3-d][2]benzazepin-7(6H)-one；(8S)-8-ethyl-9,12-diazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13,15,17-heptaen-10-one
• CAS: 1034110-72-9
• 化学式: C₁₈H₁₆N₂O
• 分子量: 276.338
• InChiKey: XQYCTXUNQHOJSX-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  44.9
• 氢给体数：
  2
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  (S)-5-ethyl-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one 在 sodium hydride 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 36.0h， 生成 (S)-5-ethyl-6-methyl-5,8-dihydroindolo[2,3-d][2]benzazepin-7(6H)-one
  参考文献：
  名称：

  Rigid Analogues of Antimitotic Indolobenzazepinones: New Insights into Tubulin Binding via Molecular Modeling

  摘要：

  Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent c-ytotoxic agent and inhibitor of tubulin polymerization, were prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the pyrrolidine analogue 6, in which the ethyl chain was bound to the lactam nitrogen. While both compounds were considerably less active inhibitors of KB cell growth as compared to 4, inhibition of tubulin polymerization was only moderately reduced. Tubulin docking studies indicated that the aR and aS atropoisomers of 5 and 6 occupy different binding pockets at the colchicine binding site. Conversely, both aS-5 and aS-6 occupy the same binding pocket as aSS-4 but do not benefit from the favorable hydrophobic interactions provided by the CS alkyl group of 4, thus possibly explaining their lower activities.

  DOI：

  10.1021/ml200024y
• 作为产物：
  描述：

  吲哚-2-羧酸甲酯 在 4-二甲氨基吡啶 、 1,1'-双(二苯基膦)二茂铁 、 Ru[(S)-Segphos](OAc)₂ 、 ammonium acetate 、 氢气 、 palladium diacetate 、 cesium fluoride 、 potassium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 2,2,2-三氟乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 63.0h， 生成 (S)-5-ethyl-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one
  参考文献：
  名称：

  不对称还原胺化/闭环级联：对映体富集的联芳基桥联 NH 内酰胺的直接合成。

  摘要：

  我们在此报告了通过不对称还原胺化和酮酯和 NH 4 OAc 以 H 2作为还原剂的自发闭环级联反应，Ru 催化的对映选择性合成联芳基桥连 NH 内酰胺。该反应具有广泛的底物通用性和高对映选择性（高达> 99% ee）。为了展示实用性，快速完成了 5-乙基吲哚苯并氮杂酮C的高度对映选择性合成，这是一种很有前途的抗有丝分裂剂。此外，产品中的酰胺基团可以通过定向 C-H 功能化进行多种加工。

  DOI：

  10.1021/acs.orglett.0c02282

文献信息

• New C5-Alkylated Indolobenzazepinones Acting as Inhibitors of Tubulin Polymerization: Cytotoxic and Antitumor Activities
  作者：Laurent Keller、Stéphane Beaumont、Jian-Miao Liu、Sylviane Thoret、Jérôme S. Bignon、Joanna Wdzieczak-Bakala、Philippe Dauban、Robert H. Dodd

  DOI：10.1021/jm701466p

  日期：2008.6.1

  A series of 5-alkylindolobenzazepin-7-ones was synthesized by Suzuki coupling between 3-iodoindole-2-carboxylates and the appropriate alpha-alkylbenzylamino o-boronic acids followed by cyclization to the lactam. Derivatives having a linear alkyl chain at C5 were found to be highly cytotoxic to KB cells with IC50 values in the 30-80 nM range. These compounds also inhibited the polymerization of tubulin with IC50's of 1-2 mu M. Compound 4f ((S)-5-ethyl) showed comparable antiproliferative activities (IC50's of 30-70 nM) in a variety of cancer cell lines, cell growth being arrested at the G2/M phase. Compound 4f induced apoptosis in a dose-dependent manner in three different cancer cell lines and was shown to affect cell morphology in a manner consistent with its inhibitory action on tubulin polymerization. Using the experimental model of glioma grafted on the chick chorio-allantoic membrane, local treatment with compound 4f markedly reduced tumor progression.
• [EN] NOVEL WATER-SOLUBLE INDOLOBENZAZEPINE MOLECULES DEMONSTRATING ANTIMITOTIC, ANTIVASCULAR, AND ANTITUMOR ACTIVITIES IN VIVO<br/>[FR] NOUVELLES MOLECULES INDOLOBENZAZEPINIQUES HYDROSOLUBLES DEMONTRANT DES ACTIVITES ANTIMITOTIQUES, ANTIVASCULAIRES ET ANTITUMORALES IN VIVO
  申请人：CENTRE NAT RECH SCIENT

  公开号：WO2012059568A1

  公开（公告）日：2012-05-10

  L'objet de la présente demande de brevet concerne des dérivés indolobenzazépiniques à activité antitumorale, leur synthèse, et leur utilisation. En particulier, l'objet de la présente demande de brevet concerne une synthèse stéréocontrôlée de indolobenzazépinones substitués en C5 permettant d'obtenir uniquement l'un ou l'autre des deux isomères possibles en C5 ainsi que des analogues hydrosolubles permettant de démontrer la très grande efficacité de ces molécules à diminuer in vivo la taille de tumeurs.
• Asymmetric Reductive Amination/Ring-Closing Cascade: Direct Synthesis of Enantioenriched Biaryl-Bridged NH Lactams
  作者：Yao Zhang、Yun-Qi Liu、Le’an Hu、Xumu Zhang、Qin Yin

  DOI：10.1021/acs.orglett.0c02282

  日期：2020.8.21

  here a Ru-catalyzed enantioselective synthesis of biaryl-bridged NH lactams through asymmetric reductive amination and a spontaneous ring-closing cascade from keto esters and NH4OAc with H2 as reductant. The reaction features broad substrate generality and high enantioselectivities (up to >99% ee). To showcase the practical utility, a highly enantioselective synthesis of 5-ethylindolobenzazepinone C, a

  我们在此报告了通过不对称还原胺化和酮酯和 NH 4 OAc 以 H 2作为还原剂的自发闭环级联反应，Ru 催化的对映选择性合成联芳基桥连 NH 内酰胺。该反应具有广泛的底物通用性和高对映选择性（高达> 99% ee）。为了展示实用性，快速完成了 5-乙基吲哚苯并氮杂酮C的高度对映选择性合成，这是一种很有前途的抗有丝分裂剂。此外，产品中的酰胺基团可以通过定向 C-H 功能化进行多种加工。
• Rigid Analogues of Antimitotic Indolobenzazepinones: New Insights into Tubulin Binding via Molecular Modeling
  作者：Valérie Pons、Stéphane Beaumont、Marie Elise Tran Huu Dau、Bogdan I. Iorga、Robert H. Dodd

  DOI：10.1021/ml200024y

  日期：2011.8.11

  Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent c-ytotoxic agent and inhibitor of tubulin polymerization, were prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the pyrrolidine analogue 6, in which the ethyl chain was bound to the lactam nitrogen. While both compounds were considerably less active inhibitors of KB cell growth as compared to 4, inhibition of tubulin polymerization was only moderately reduced. Tubulin docking studies indicated that the aR and aS atropoisomers of 5 and 6 occupy different binding pockets at the colchicine binding site. Conversely, both aS-5 and aS-6 occupy the same binding pocket as aSS-4 but do not benefit from the favorable hydrophobic interactions provided by the CS alkyl group of 4, thus possibly explaining their lower activities.