4-(3-bromo-4-methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 4-(3-bromo-4-methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one
• 英文别名: (3R,4S)-4-(3-bromo-4-methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one
• 化学式: C₂₅H₂₄BrNO₅
• 分子量: 498.373
• InChiKey: DZPOPTNHYMBERG-DHIUTWEWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  57.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-溴-4-甲氧基苯甲醛 在 三乙胺 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 9.0h， 生成 4-(3-bromo-4-methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one
  参考文献：
  名称：

  β-Lactams with antiproliferative and antiapoptotic activity in breast and chemoresistant colon cancer cells

  摘要：

  A series of novel 1,4-diaryl-2-azetidinone analogues of combretastatin A-4 (CA-4) have been designed, synthesised and evaluated in vitro for antiproliferative activity, antiapoptotic activity and inhibition of tubulin polymerisation. Glucuronidation of CA-4 by uridine 5-diphosphoglucuronosyl transferase enzymes (UGTs) has been identified as a mechanism of resistance in cancer cells. Potential sites of ring B glucuronate conjugation are removed by replacing the B ring meta-hydroxy substituent of selected series of beta-lactams with alternative substituents e.g. F, Cl, Br, I, CH3. The 3-phenyl-beta-lactam 11 and 3-hydroxy-beta-lactam 46 demonstrate improved activity over CA-4 in CA-4 resistant HT-29 colon cancer cells (IC50 = 9 nM and 3 nM respectively compared with IC50 = 4.16 mu M for CA-4), while retaining potency in MCF-7 breast cancer cells (IC50 = 17 nM and 22 nM respectively compared with IC50 = for 4 nM for CA-4). Compound 46 binds at the colchicine site of tubulin, and strongly inhibits tubulin assembly at micromolar concentrations comparable to CA-4. In addition, compound 46 induced mitotic arrest at low concentration in both cell lines MCF-7 and HT-29 together with downregulation of expression of antiapoptotic proteins Mcl-1, Bcl-2 and survivin in MCF-7 cells. These novel antiproliferative and antiapoptotic beta-lactams are potentially useful scaffolds in the development of tubulin-targeting agents for the treatment of breast cancers and chemoresistant colon cancers.(C) 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

  DOI：

  10.1016/j.ejmech.2020.112050

文献信息

• Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe
  作者：Niamh M. O’Boyle、Miriam Carr、Lisa M. Greene、Niall O. Keely、Andrew J.S. Knox、Thomas McCabe、David G. Lloyd、Daniela M. Zisterer、Mary J. Meegan

  DOI：10.1016/j.ejmech.2011.07.039

  日期：2011.9

  The structure-activity relationships of antiproliferative beta-lactams, focusing on modifications at the 4-position of the beta-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC(50) value of 0.22 mu M. The mechanism of action was demonstrated to be by inhibition of tubulin polymerisation. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for combretastatin A-4 and for 26 was demonstrated in breast cancer cells for the first time, as evidenced by the formation of giant, multinucleated cells. (C) 2011 Elsevier Masson SAS. All rights reserved.
• β-Lactams with antiproliferative and antiapoptotic activity in breast and chemoresistant colon cancer cells
  作者：Azizah M. Malebari、Darren Fayne、Seema M. Nathwani、Fiona O’Connell、Sara Noorani、Brendan Twamley、Niamh M. O’Boyle、Jacintha O’Sullivan、Daniela M. Zisterer、Mary J. Meegan

  DOI：10.1016/j.ejmech.2020.112050

  日期：2020.3

  A series of novel 1,4-diaryl-2-azetidinone analogues of combretastatin A-4 (CA-4) have been designed, synthesised and evaluated in vitro for antiproliferative activity, antiapoptotic activity and inhibition of tubulin polymerisation. Glucuronidation of CA-4 by uridine 5-diphosphoglucuronosyl transferase enzymes (UGTs) has been identified as a mechanism of resistance in cancer cells. Potential sites of ring B glucuronate conjugation are removed by replacing the B ring meta-hydroxy substituent of selected series of beta-lactams with alternative substituents e.g. F, Cl, Br, I, CH3. The 3-phenyl-beta-lactam 11 and 3-hydroxy-beta-lactam 46 demonstrate improved activity over CA-4 in CA-4 resistant HT-29 colon cancer cells (IC50 = 9 nM and 3 nM respectively compared with IC50 = 4.16 mu M for CA-4), while retaining potency in MCF-7 breast cancer cells (IC50 = 17 nM and 22 nM respectively compared with IC50 = for 4 nM for CA-4). Compound 46 binds at the colchicine site of tubulin, and strongly inhibits tubulin assembly at micromolar concentrations comparable to CA-4. In addition, compound 46 induced mitotic arrest at low concentration in both cell lines MCF-7 and HT-29 together with downregulation of expression of antiapoptotic proteins Mcl-1, Bcl-2 and survivin in MCF-7 cells. These novel antiproliferative and antiapoptotic beta-lactams are potentially useful scaffolds in the development of tubulin-targeting agents for the treatment of breast cancers and chemoresistant colon cancers.(C) 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).