2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxy-propoxy)-2,3-dihydro-isoindolin-1-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxy-propoxy)-2,3-dihydro-isoindolin-1-one
• 英文别名: 2-Benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one；2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)isoindol-1-one
• 化学式: C₂₄H₂₂ClNO₃
• 分子量: 407.897
• InChiKey: RDFQXKACQGFINF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxy-propoxy)-2,3-dihydro-isoindolin-1-one 在 4-二甲氨基吡啶 、 水 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.17h， 生成 (3R)-2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)isoindol-1-one
  参考文献：
  名称：

  Diastereotopic derivatives of chiral alkoxyisoindolinones

  摘要：

  A method for synthesis of 2,3-substituted 3-hydroxyisoindolin-1-one acyl derivatives, modified reactivators of tumor suppressor protein p53, was developed; these compounds were synthesized and characterized. It was shown that diastereomeric esters of Boc-N-protected amino acids, unlike esters with a free amino group, can be preparatively isolated by flash chromatography using achiral media.

  DOI：

  10.1134/s1070363216110098
• 作为产物：
  描述：

  4'-chloro-o-benzoylbenzoic acid chloride 在 氯化亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxy-propoxy)-2,3-dihydro-isoindolin-1-one
  参考文献：
  名称：

  取代异吲哚啉酮作为 MDM2-p53 抑制剂的促凋亡修饰

  摘要：

  合成了一系列 2,3-取代异吲哚啉酮的新型氨基酸酯衍生物，并评估了 p53 介导的细胞凋亡活性。增加 2,3-取代异吲哚啉酮的目标活性的基本原理是基于在抑制剂结构中引入新片段，这将在 MDM2 的疏水腔中提供额外的结合位点。为了选择预期的修改，我们采用了分子对接。通过膜联蛋白 V 染色评估合成的分子在两种癌细胞系及其衍生物中诱导细胞凋亡的能力，这些细胞系具有不同的 p53 状态（结肠直肠 HCT116 和骨肉瘤 U2OS 细胞）。使用高内涵成像系统 Operetta 估计目标活动。

  DOI：

  10.1016/j.bmcl.2017.10.049

文献信息

• [EN] ISOINDOLIN-1-ONE DERIVATIVES<br/>[FR] DÉRIVÉS D'ISOINDOLIN-1-ONE
  申请人：CANCER REC TECH LTD

  公开号：WO2006024837A1

  公开（公告）日：2006-03-09

  A compound of formula (1) or a prodrug and/or pharmaceutically acceptable salt thereof, wherein X is selected from O, N or S; R1 is selected from hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroaralkyl; R2 is selected from hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; R3 is selected from hydrogen, halo, hydroxy, substituted or unsubstituted alloy substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; and R4-R7, is used to represent groups R4, R5, R6 and R7 which are independently selected from H, OH, alkyl, alkoxy, alkylamine, hydroxyalkyl, halo, CF3, NH2, NO2, COOH, C=0.

  式（1）的化合物或其前药和/或药用可接受的盐，其中X选择自O、N或S；R1选择自氢、卤素、羟基、取代或未取代的烷基、取代或未取代的羟基烷基、取代或未取代的烷基胺、烷氧基、取代或未取代的芳基或杂环芳基、取代或未取代的芳基或杂环芳基；R2选择自氢、卤素、羟基、取代或未取代的烷基、取代或未取代的羟基烷基、取代或未取代的烷基胺、烷氧基、取代或未取代的芳基或杂环芳基、取代或未取代的芳基或杂环芳基；R3选择自氢、卤素、羟基、取代或未取代的合金取代或未取代的羟基烷基、取代或未取代的烷基胺烷氧基、取代或未取代的芳基或杂环芳基、取代或未取代的芳基或杂环芳基；R4-R7，用于表示独立选择自H、OH、烷基、烷氧基、烷基胺、羟基烷基、卤素、CF3、NH2、NO2、COOH、C=0的基团R4、R5、R6和R7。
• Amino acids as chiral derivatizing agents for antiproliferative substituted N-benzyl isoindolinones
  作者：Tatyana A. Grigoreva、Daria S. Novikova、Maxim A. Gureev、Alexander V. Garabadzhiu、Vyacheslav G. Tribulovich

  DOI：10.1002/chir.22854

  日期：2018.6

  significance of N‐benzyl fragment for the determination of the diastereomer absolute configuration by NMR methods was established; it is determined by a number of factors inherent in this fragment and the structural features of the studied substrates. Analysis of the individual isomer activity showed that the target inhibitory effect of S‐ and R‐isoindolinone L‐valinates differs by less than 20%. It can be

  使用NMR和计算方法确定了2,3-取代的异吲哚满酮的新型氨基酸酯衍生物的非对映异构体的绝对构型，由于其抑制MDM2-p53 PPI的能力而被称为凋亡激活剂。开发了用于非对映异构体分离和确定绝对构型的程序以进行研究。建立了N-苄基片段对于通过NMR方法测定非对映异构体绝对构型的重要意义；它由该片段固有的许多因素和所研究底物的结构特征决定。对单个异构体活性的分析表明，S-和R-异吲哚啉酮L的靶抑制作用戊酸酯的差异小于20％。可以通过在异吲哚满酮核心和氨基酸片段之间存在柔性接头来解释，这为两种异构体提供了分子在MDM2疏水腔中的最佳排列。
• Isoindolin-1-One Derivatives
  申请人：Willems Hendrika Maria Gerarda

  公开号：US20080261917A1

  公开（公告）日：2008-10-23

  A compound of formula or a prodrug and/or a pharmaceutically acceptable salt thereof, wherein X is O, N or S; R 1 is hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroaralkyl; R 2 is hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; R 3 is hydrogen, halo, hydroxy, substituted or unsubstituted alloy substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; and R 4 -R 7 , is used to represent groups R 4 , R 5 , R 6 and R 7 which are H, OH, alkyl, alkoxy, alkylamine, hydroxyalkyl, halo, CF 3 , NH 2 , NO 2 , COOH, C=0.

  该化合物的化学式为，或其前体药物和/或其药学上可接受的盐，其中X为O、N或S；R1为氢、卤、羟基、取代或未取代的烷基、取代或未取代的羟基烷基、取代或未取代的烷基胺、烷氧基、取代或未取代的芳基或杂环芳基、取代或未取代的芳基烷基或杂环芳基烷基；R2为氢、卤、羟基、取代或未取代的烷基、取代或未取代的羟基烷基、取代或未取代的烷基胺、烷氧基、取代或未取代的芳基或杂环芳基、取代或未取代的芳基烷基或杂环芳基烷基；R3为氢、卤、羟基、取代或未取代的烷基、取代或未取代的羟基烷基、取代或未取代的烷基胺、烷氧基、取代或未取代的芳基或杂环芳基、取代或未取代的芳基烷基或杂环芳基烷基；R4-R7用于代表R4、R5、R6和R7的基团，其为H、OH、烷基、烷氧基、烷基胺、羟基烷基、卤、CF3、NH2、NO2、COOH、C=0。
• Small-Molecule Inhibitors of the MDM2-p53 Protein−Protein Interaction Based on an Isoindolinone Scaffold
  作者：Ian R. Hardcastle、Shafiq U. Ahmed、Helen Atkins、Gillian Farnie、Bernard T. Golding、Roger J. Griffin、Sabrina Guyenne、Claire Hutton、Per Källblad、Stuart J. Kemp、Martin S. Kitching、David R. Newell、Stefano Norbedo、Julian S. Northen、Rebecca J. Reid、K. Saravanan、Henriëtte M. G. Willems、John Lunec

  DOI：10.1021/jm0601194

  日期：2006.10.1

  From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a series of 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors of the MDM2-p53 interaction. Two of the most potent compounds, 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC50 = 15.9 +/- 0.8 mu M) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC50) 5.3 (0.9 mu M), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.
• Isoindolinone-based inhibitors of the MDM2–p53 protein–protein interaction
  作者：Ian R. Hardcastle、Shafiq U. Ahmed、Helen Atkins、A. Hilary Calvert、Nicola J. Curtin、Gillian Farnie、Bernard T. Golding、Roger J. Griffin、Sabrina Guyenne、Claire Hutton、Per Källblad、Stuart J. Kemp、Martin S. Kitching、David R. Newell、Stefano Norbedo、Julian S. Northen、Rebecca J. Reid、K. Saravanan、Henriëtte M.G. Willems、John Lunec

  DOI：10.1016/j.bmcl.2004.12.061

  日期：2005.3

  A series of 2-N-alkyl-3-aryl-3-alkoxyisoindolinones has been synthesised and evaluated as inhibitors of the MDM2-p53 interaction. The most potent compound, 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (NU8231), exhibited an IC50 of 5.3 +/- 0.9 mu M in an ELISA assay, and induced p53-dependent gene transcription in a dose-dependent manner, in the SJSA human sarcoma cell line. (c) 2005 Elsevier Ltd. All rights reserved.