4-[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)azetidin-2-one | 1261242-76-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: 4-[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)azetidin-2-one
• 英文别名: 4-[3-(tert-Butyldimethylsilanyloxy)-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one；4-[3-[tert-butyl(dimethyl)silyl]oxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)azetidin-2-one
• CAS: 1261242-76-5
• 化学式: C₂₅H₃₅NO₆Si
• 分子量: 473.642
• InChiKey: KOPMMNBMKHNZBG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.58
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  66.5
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)azetidin-2-one 在 四丁基氟化铵 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 1.5h， 以73%的产率得到4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one
  参考文献：
  名称：

  3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

  摘要：

  微管靶向药物是各种癌症的重要化疗药物。一系列3-乙烯基-β-内酰胺（2-氮杂环丙酮）被设计、合成并评估为潜在的微管聚合抑制剂，以及它们在乳腺癌细胞中的抗增殖效应。这些化合物在MCF-7乳腺癌细胞中表现出强大的活性，其中化合物7s（4-[3-羟基-4-甲氧基苯基]-1-(3,4,5-三甲氧基苯基)-3-乙烯基氮杂环丙酮）的IC50值为8 nM，与康布雷他定A-4的活性相当。化合物7s对非肿瘤性HEK-293T细胞和小鼠乳腺上皮细胞均具有最小的细胞毒性。这些化合物在体外抑制了微管的聚合，在10 μM的浓度下，化合物7s使微管聚合减少了8.7倍，并且显示出它们与微管上的秋水仙碱结合位点相互作用，导致显著的G2/M期细胞周期阻滞。MCF-7细胞的免疫荧光染色证实了β-内酰胺7s靶向微管，并导致有丝分裂灾难。对于3-乙烯基-β-内酰胺7s在微管秋水仙碱结合区域的潜在结合构象进行的对接模拟表明了潜在的结合构象。这些化合物是作为抗增殖微管破坏剂的发展有前途的候选药物。

  DOI：

  10.3390/ph12020056
• 作为产物：
  描述：

  3-hydroxy-4-methoxybenzylidene-(3,4,5-trimethoxyphenyl)-amine 在 三甲基氯硅烷 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 锌 作用下， 以 二氯甲烷 、 苯 为溶剂， 反应 80.28h， 生成 4-[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)azetidin-2-one
  参考文献：
  名称：

  [EN] COMBRETASTATIN DERIVATIVES AND USES THEREFOR
  [FR] DÉRIVÉS DE COMBRÉTASTATINE ET LEURS APPLICATIONS

  摘要：

  癌症是全球主要死因之一。尽管在治疗和管理该疾病方面取得了许多进展，但化疗耐药的存在意味着仍然迫切需要开发新的治疗策略和药物。本文提供了紫杉醇A-4的合成衍生物，特别是那些其中芳香环被锁定为非可异构活性构象，从而产生改进的稳定化合物。这些新颖的化合物在结构上与紫杉醇A-4（CA-4）相关，并通过将一个含氮杂环环（如β-内酰胺环）并入标准CA-4结构来将环锁定为已知的活性构象。这些化合物表现出强大的抗癌活性。

  公开号：

  WO2011073211A1

文献信息

• Lead identification of conformationally restricted β-lactam type combretastatin analogues: Synthesis, antiproliferative activity and tubulin targeting effects
  作者：Miriam Carr、Lisa M. Greene、Andrew J.S. Knox、David G. Lloyd、Daniela M. Zisterer、Mary J. Meegan

  DOI：10.1016/j.ejmech.2010.09.033

  日期：2010.12

  The synthesis and study of the structure–activity relationships of a series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. The 1,4-diaryl-2-azetidinones are unsubstituted at C-3, or contain methyl substituent(s) at C-3. The most potent

  描述了一系列康布雷他汀A-4刚性类似物的合成和结构-活性关系的研究，这些类似物包含1,4-二芳基-2-氮杂环丁酮（β-内酰胺）环系统，代替了现有的乙烯桥在天然康美他汀二苯乙烯产品中。1，4-二芳基-2-氮杂环丁酮在C-3处未被取代，或在C-3处含有一个或多个甲基取代基。当针对MCF-7和MDA-MB-231人乳腺癌细胞系进行评估时，最有效的化合物12d和12e在纳摩尔浓度下显示出抗增殖活性。12d通过抑制微管蛋白聚合和随后的G 2发挥抗有丝分裂作用/ M抑制人MDA-MB-231乳腺癌细胞的细胞周期，其活性与CA-4相似。这些新的β-内酰胺化合物被认为是潜在的有用的支架，可用于进一步开发靶向微管蛋白的抗肿瘤剂。
• Combretastatin Derivatives and Uses Therefor
  申请人：The Provost, Fellows and Scholars of the College of the Holy and Undivided Trinity of Queen Elizabeth near Dublin

  公开号：EP2338877A1

  公开（公告）日：2011-06-29

  Provided herein are synthetic derivatives of combretastatin A-4 in which the aromatic rings are locked into a non-isomerisable active conformation, thus resulting in improved, stable compounds. The novel compounds are structurally related to combretastatin A-4 (CA-4) and lock the rings into the known active conformation by means of a four membered nitrogen containing heterocyclic ring, such as a beta-lactam ring, incorporated into the standard CA-4 structure. The compounds exhibit potent anti-cancer activity.

  本文提供的是康柏他定A-4的合成衍生物，其中芳香环被锁定在一种不可异构的活性构象中，从而导致改进的、稳定的化合物。这些新颖的化合物在结构上与康柏他定A-4（CA-4）相关，并通过将一个含氮的四元杂环环（如β-内酰胺环）并入标准的CA-4结构中，将环锁定在已知的活性构象中。这些化合物表现出强大的抗癌活性。
• COMBRETASTATIN DERIVATIVES AND USES THEREFOR
  申请人：Meegan Mary J.

  公开号：US20120309734A1

  公开（公告）日：2012-12-06

  Cancer is one of the major causes of death worldwide. Although many advances have been made in the treatment and management of the disease, the existence of chemotherapy-resistance means there is still a great need to develop new strategies and drugs for its treatment. Provided herein are synthetic derivatives of combretastatin A-4, in particular those in which the aromatic rings are locked into a non-isomerisable active conformation, thus resulting in improved, stable compounds. The novel compounds are structurally related to combretastatin A-4 (CA-4) and lock the rings into the known active conformation by means of a four membered nitrogen containing heterocyclic ring, such as a beta-lactam ring, incorporated into the standard CA-4 structure. The compounds exhibit potent anti-cancer activity.

  癌症是全球主要的死因之一。尽管在治疗和管理该疾病方面取得了许多进展，但化疗耐药的存在意味着仍然需要开发新的策略和药物来治疗癌症。本文提供了合成的血树碱A-4的衍生物，特别是那些将芳香环锁定在非可异构的活性构象中，从而产生改进的、稳定的化合物。这些新型化合物与血树碱A-4（CA-4）有结构上的关联，并通过一种四元杂环环（例如β-内酰胺环）将环锁定在已知的活性构象中。这些化合物表现出强大的抗癌活性。
• β-Lactam analogues of combretastatin A-4 prevent metabolic inactivation by glucuronidation in chemoresistant HT-29 colon cancer cells
  作者：Azizah M. Malebari、Lisa M. Greene、Seema M. Nathwani、Darren Fayne、Niamh M. O'Boyle、Shu Wang、Brendan Twamley、Daniela M. Zisterer、Mary J. Meegan

  DOI：10.1016/j.ejmech.2017.02.049

  日期：2017.4

  Glucuronidation by uridine 5-diphosphoglucuronosyl transferase enzymes (UGTs) is a cause of intrinsic drug resistance in cancer cells. Glucuronidation of combretastatin A-4 (CA-4) was previously identified as a mechanism of resistance in hepatocellular cancer cells. Herein, we propose chemical manipulation of blactam bridged analogues of Combretastatin A-4 as a novel means of overcoming drug resistance associated with glucuronidation due to the expression of UGTs in the CA-4 resistant human colon cancer HT-29 cells. The alkene bridge of CA-4 is replaced with a b-lactam ring to circumvent potential isomerisation while the potential sites of glucuronate conjugation are deleted in the novel 3-substituted1,4- diaryl-2-azetidinone analogues of CA-4. We hypothesise that glucuronidation of CA-4 is the mechanism of drug resistance in HT-29 cells. Ring B thioether containing 2-azetidinone analogues of CA-4 such as 4-(4-(methylthio) phenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl) azetidin-2-one (27) and 3hydroxy- 4-(4-(methylthio) phenyl)-1-(3,4,5-trimethoxyphenyl) azetidin-2-one (45) were identified as the most potent inhibitors of tumour cell growth, independent of UGT status, displaying antiproliferative activity in the low nanomolar range. These compounds also disrupted the microtubular structure in MCF7 and HT-29 cells, and caused G(2)/M arrest and apoptosis. Taken together, these findings highlight the potential of chemical manipulation as a means of overcoming glucuronidation attributed drug resistance in CA-4 resistant human colon cancer HT-29 cells, allowing the development of therapeutically superior analogues. (C) 2017 Elsevier Masson SAS. All rights reserved.
• 3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells
  作者：Wang、Malebari、Greene、O’Boyle、Fayne、Nathwani、Twamley、McCabe、Keely、Zisterer、Meegan

  DOI：10.3390/ph12020056

  日期：——

  Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 M for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.

  微管靶向药物是各种癌症的重要化疗药物。一系列3-乙烯基-β-内酰胺（2-氮杂环丙酮）被设计、合成并评估为潜在的微管聚合抑制剂，以及它们在乳腺癌细胞中的抗增殖效应。这些化合物在MCF-7乳腺癌细胞中表现出强大的活性，其中化合物7s（4-[3-羟基-4-甲氧基苯基]-1-(3,4,5-三甲氧基苯基)-3-乙烯基氮杂环丙酮）的IC50值为8 nM，与康布雷他定A-4的活性相当。化合物7s对非肿瘤性HEK-293T细胞和小鼠乳腺上皮细胞均具有最小的细胞毒性。这些化合物在体外抑制了微管的聚合，在10 μM的浓度下，化合物7s使微管聚合减少了8.7倍，并且显示出它们与微管上的秋水仙碱结合位点相互作用，导致显著的G2/M期细胞周期阻滞。MCF-7细胞的免疫荧光染色证实了β-内酰胺7s靶向微管，并导致有丝分裂灾难。对于3-乙烯基-β-内酰胺7s在微管秋水仙碱结合区域的潜在结合构象进行的对接模拟表明了潜在的结合构象。这些化合物是作为抗增殖微管破坏剂的发展有前途的候选药物。