(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (4-carbamoyl-2-methoxyphenyl)amide | 1309684-94-3

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (4-carbamoyl-2-methoxyphenyl)amide
• 英文别名: RO8994；(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)amide；(2'R,3R,3'S,5'S)-N-(4-carbamoyl-2-methoxyphenyl)-6-chloro-3'-(3-chloro-2-fluorophenyl)-5'-(2,2-dimethylpropyl)-2-oxospiro[1H-indole-3,4'-pyrrolidine]-2'-carboxamide
• CAS: 1309684-94-3
• 化学式: C₃₁H₃₁Cl₂FN₄O₄
• 分子量: 613.516
• InChiKey: MURAVORBGFDSMA-ISKXDESKSA-N

物化性质

• 沸点：
  753.5±60.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  DMF:12.5(最大浓度 mg/mL);20.4(最大浓度 mM)DMSO:14.0(最大浓度 mg/mL);22.8(最大浓度 mM)乙醇:5.0(最大浓度 mg/mL);8.1(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  42
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  123
• 氢给体数：
  4
• 氢受体数：
  6

制备方法与用途

生物活性方面，RO8994 是一种高效的选择性 MDM2 抑制剂。其 IC50 值分别为纳摩尔级（HTRF 结合检测）和 20 纳摩尔（MTT 增殖检测）。

反应信息

• 作为反应物：
  描述：

  (2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (4-carbamoyl-2-methoxyphenyl)amide 、 bis(1-chloroethyl)(((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(carbonate) 在 caesium carbonate 作用下， 以 丙酮 为溶剂， 以55 %的产率得到((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) (2'S,2'''S,3R,3”R,4'S,4'''S,5'R,5'''R)-bis(5'-((4-carbamoyl-2-methoxyphenyl)carbamoyl)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate)
  参考文献：
  名称：

  二聚体螺吲哚啉酮吡咯烷甲酰胺的合成及其抗肿瘤活性

  摘要：

  肿瘤抑制因子p53的突变或功能丧失在细胞异常增殖和癌症发生中起着重要作用。小鼠双分钟 2 (MDM2) 是 p53 的关键负调节因子之一。通过抑制 MDM2-p53 相互作用来重新激活 p53 代表了癌症治疗中有前途的治疗选择。在这里，为了开发更有效且脱靶毒性更低的 MDM2 抑制剂，我们合成了一种二聚体螺吲哚啉酮吡咯烷甲酰胺 XR-4，它具有有效的 MDM2-p53 抑制活性。进行蛋白质印迹和 qRT-PCR 以检测 XR-4 对不同癌症中 MDM2 和 p53 蛋白水平以及 p53 下游靶基因水平的影响。还通过 CCK8 测定和集落形成测定研究了癌细胞增殖抑制和克隆形成活性。皮下 22Rv1 异种移植小鼠模型用于研究 XR-4 的体内抗肿瘤活性。结果表明，XR-4可诱导癌细胞中野生型p53的积累，上调p53靶基因p21和PUMA水平，进而抑制癌细胞增殖，诱导细胞凋亡。XR-4 还可以充当诱导

  DOI：

  10.3390/molecules28093912
• 作为产物：
  描述：

  4-氨基-3-甲氧基苯甲腈(9ci) 在 二氧化碳 、 双氧水 、 N,N-二异丙基乙胺 、 sodium hydroxide 、 二苯基次膦酰氯 作用下， 以 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 为溶剂， 35.0 ℃ 、10.0 MPa 条件下， 反应 21.5h， 生成 (2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (4-carbamoyl-2-methoxyphenyl)amide
  参考文献：
  名称：

  Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy

  摘要：

  The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.05.072

文献信息

• SPIROINDOLINONE PYRROLIDINES
  申请人：Bartkovitz David Joseph

  公开号：US20110130398A1

  公开（公告）日：2011-06-02

  There are provided compounds of the formula wherein X, Y and R 1 to R 8 are described herein along with the enantiomers, pharmaceutically acceptable salts and esters thereof. The compounds are useful as anticancer agents.

  提供了以下式中的化合物，其中X、Y和R1至R8如本文所述，以及其对映体、药用可接受的盐和酯。这些化合物可用作抗癌药物。
• [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。
• Spirocyclic indolone polyethylene glycol carbonate compound, composition, preparation method and use thereof
  申请人：Xiao Fei

  公开号：US10471154B2

  公开（公告）日：2019-11-12

  The present invention relates to a spirocyclic indolone polyethylene glycol carbonate compound, a composition thereof, a preparation method therefor, and a use thereof as an anticancer drug due to the antitumor activity thereof. The structural formula of the spirocyclic indolone polyethylene glycol carbonate compound is shown below. The compound has excellent tumor inhibitory activity, water solubility, low toxicity, and can be used for intravenous injection.

  本发明涉及一种螺环吲哚酮聚乙二醇碳酸酯化合物、其组合物、其制备方法以及由于其抗肿瘤活性而作为抗癌药物的用途。螺环吲哚酮聚乙二醇碳酸酯化合物的结构式如下所示。该化合物具有优异的肿瘤抑制活性、水溶性、低毒性，可用于静脉注射。
• Synthesis of a Spiroindolinone Pyrrolidinecarboxamide MDM2 Antagonist
  作者：Lianhe Shu、Zizhong Li、Chen Gu、Dan Fishlock

  DOI：10.1021/op3003213

  日期：2013.2.15

  A practical synthesis of a spiroindolinone pyrrolidinecarboxamide MDM2 antagonist 2 is reported. Cycloaddition of dipolarophile 3 with imine 30 afforded a complex mixture of diastereomers that were isomerized to the desired stereoisomer 31 by heating the mixture in the presence of DBU. After hydrolysis, the resulting product was resolved with a chiral amine to give an enantiopure acid which was converted to the target product 2. The process has been scaled up to a multihundred-gram scale. In addition, an asymmetric synthesis of 31 catalyzed by AgOAc and a chiral phosphine ligand was developed to give enantiomerically enriched 31, which was also converted to enantiopure 2.
• METHODS OF TREATING CANCER
  申请人：Kartos Therapeutics, Inc.

  公开号：EP3787625A1

  公开（公告）日：2021-03-10