3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one | 1082076-98-9

• 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: 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one
• 英文别名: 3-(4-chlorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one；3-(4-chlorophenyl)-3-[[1-(hydroxymethyl)cyclopropyl]methoxy]-2-[(4-nitrophenyl)methyl]isoindol-1-one
• CAS: 1082076-98-9
• 化学式: C₂₆H₂₃ClN₂O₅
• 分子量: 478.932
• InChiKey: FWMIQNMFNBHEKJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  95.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one 在 Daicel Chiralpac AD-H 250x10 mm 作用下， 以 乙醇 、 正己烷 为溶剂， 生成 (-)-S-3-(4-chlorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one 、 (+)-R-3-(4-chlorophenyl)-3-(1-hydroxymethylcyclopropylmethoxy)-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one
  参考文献：
  名称：

  Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein−Protein Interaction: Structure−Activity Studies Leading to Improved Potency

  摘要：

  Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors.. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-nitrobenzyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 +/- 0.01 mu M). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)R-enantiomer (74a; IC(50) = 0.17 +/- 0.02 mu M). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.

  DOI：

  10.1021/jm1011929
• 作为产物：
  描述：

  3-(4-chloro-phenyl)-3-hydroxy-2-(4-nitro-benzyl)-2,3-dihydro-isoindol-1-one 、 1,1-环丙烷二甲醇 以obtained as an off-white solid (305 mg, 63%)的产率得到3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one
  参考文献：
  名称：

  New Therapeutic Agents

  摘要：

  化合物(I)或化合物(II)或其药学上可接受的盐的公式，其中R1-R7和X的定义如描述中所定义，并且这些化合物在治疗中的用途，特别是在治疗癌症或作为MDM2蛋白与p53相互作用的抑制剂。

  公开号：

  US20110224274A1

文献信息

• [EN] HETERO-BIFUNCTIONAL DEGRADER COMPOUNDS AND THEIR USE AS MODULATORS OF TARGETED UBIQUINATION (VHL)<br/>[FR] COMPOSÉS DE DÉGRADATION HÉTÉRO-BIFONCTIONNELS ET LEUR UTILISATION EN TANT QUE MODULATEURS DE L'UBIQUINATION CIBLÉE (VHL)
  申请人：GENENTECH INC

  公开号：WO2019183523A1

  公开（公告）日：2019-09-26

  The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds that contain on one end a VHL ligand moiety, which binds to the VHL ubiquitin ligase (E3), and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. The target protein may be EGFR. Also disclosed are VHL ligands.

  本公开涉及双功能化合物，可用作靶向泛素化的调节剂。特别是，本公开是针对包含在一端具有VHL配体基团的化合物，该基团结合到VHL泛素连接酶(E3)，而在另一端具有结合目标蛋白的基团，从而实现目标蛋白/多肽的降解。目标蛋白可以是EGFR。还公开了VHL配体。
• THERAPEUTIC AGENTS
  申请人：CANCER RESEARCH TECHNOLOGY LIMITED

  公开号：US20140194486A1

  公开（公告）日：2014-07-10

  A compound of formula (I) or a compound of formula (II) or pharmaceutically acceptable salts thereof, wherein R1-R7 and X are as defined in the description, and the use of these compounds in therapy, in particular in treating cancer or as an inhibitor of the interaction of the MDM2 protein with p53.

  一种式子为(I)的化合物或式子为(II)的化合物或其药学上可接受的盐，其中R1-R7和X的定义如说明书中所述，并且这些化合物在治疗中的使用，特别是在治疗癌症或作为MDM2蛋白与p53相互作用的抑制剂。
• Therapeutic agents
  申请人：Golding Bernard Thomas

  公开号：US08618158B2

  公开（公告）日：2013-12-31

  A compound of formula (I) or a compound of formula (II) or pharmaceutically acceptable salts thereof, wherein R1-R7 and X are as defined in the description, and the use of these compounds in therapy, in particular in treating cancer or as an inhibitor of the interaction of the MDM2 protein with p53.

  公式（I）化合物或公式（II）化合物或其药学上可接受的盐，其中R1-R7和X的定义如描述中所述，并且这些化合物在治疗中的使用，特别是在治疗癌症或作为MDM2蛋白与p53相互作用的抑制剂。
• COMPOSITIONS FOR USE IN THE TREATMENT OF SENESCENCE-ASSIOCATED DISEASE AND DISORDERS
  申请人：Buck Institute for Research on Aging

  公开号：EP3669881A1

  公开（公告）日：2020-06-24

  Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

  本文提供了选择性杀死衰老细胞和通过施用衰老分解剂治疗衰老相关疾病和紊乱的方法。可通过使用本文所述衰老分解剂的方法治疗的衰老相关疾病和失调包括与动脉硬化相关或由动脉硬化引起的心血管疾病和失调，如动脉粥样硬化；特发性肺纤维化；慢性阻塞性肺病；骨关节炎；衰老相关眼科疾病和失调；以及衰老相关皮肤病和失调。
• Treatment of ophthalmic conditions by selectively removing senescent cells from the eye
  申请人：Buck Institute for Research on Aging

  公开号：US10010546B2

  公开（公告）日：2018-07-03

  Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

  本文提供了选择性杀死衰老细胞和通过施用衰老分解剂治疗衰老相关疾病和紊乱的方法。可通过使用本文所述衰老分解剂的方法治疗的衰老相关疾病和失调包括与动脉硬化相关或由动脉硬化引起的心血管疾病和失调，如动脉粥样硬化；特发性肺纤维化；慢性阻塞性肺病；骨关节炎；衰老相关眼科疾病和失调；以及衰老相关皮肤病和失调。