[(R)-[(4S,5S)-5-[(R)-methoxy(phenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-phenylmethyl] 2-oxoacetate | 936730-86-8

• 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: [(R)-[(4S,5S)-5-[(R)-methoxy(phenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-phenylmethyl] 2-oxoacetate
• CAS: 936730-86-8
• 化学式: C₂₂H₂₄O₆
• 分子量: 384.429
• InChiKey: VDFHYRKHUXAZGV-CGXNFDGLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  71.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  [(R)-[(4S,5S)-5-[(R)-methoxy(phenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-phenylmethyl] 2-oxoacetate 、 在 zinc(II) chloride 作用下， 以 二氯甲烷 为溶剂， 反应 15.17h， 以9%的产率得到(R)-((4S,5S)-5-((R)-methoxy(phenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)(phenyl)methyl(3R, 4S)-3-hexyl-3-methyl-4-oxooxetane-2-carboxylate
  参考文献：
  名称：

  A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids

  摘要：

  The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, B-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and fatty acid synthase-thioesterase (FAS-TE) enabling a new approach for the development of drug-candidates with potential to overcome resistance. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2017.01.020
• 作为产物：
  描述：

  (R)-[(4S,5S)-5-[(R)-methoxy(phenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-phenylmethanol 在 sodium periodate 、 四氧化锇 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 14.0h， 生成 [(R)-[(4S,5S)-5-[(R)-methoxy(phenyl)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-phenylmethyl] 2-oxoacetate
  参考文献：
  名称：

  通过双非对映选择性串联mukaiyama aldol内酯化的（-）-半乳糖苷C及其衍生物的全合成。

  摘要：

  [反应：见正文]采用串联的Mukaiyama aldol-lactonizaton（TMAL）方法以简明的方式完成了（-）-半乳糖苷酶C及其衍生物的对映选择性合成。一种方法涉及与二肽乙二酰乙酰胺的远端双非对映选择性TMAL反应，而第二种方法涉及二肽与β-内酯羧酸的酰胺偶联，这是通过使用手性甲硅烷基乙烯酮缩醛的TMAL工艺获得的。非对映选择性的显着改善是在近端双非对映选择性TMAL过程中实现的。

  DOI：

  10.1021/ol070275k

文献信息

• WO2008/6113
  申请人：——

  公开号：——

  公开（公告）日：——
• Total Synthesis of (−)-Belactosin C and Derivatives via Double Diastereoselective Tandem Mukaiyama Aldol Lactonizations
  作者：Sung Wook Cho、Daniel Romo

  DOI：10.1021/ol070275k

  日期：2007.4.1

  [reaction: see text] The enantioselective synthesis of (-)-belactosin C and derivatives was accomplished in a concise manner employing the tandem, Mukaiyama aldol-lactonizaton (TMAL) process. One approach involved a distal double diastereoselective TMAL reaction with a dipeptide glyoxamide, whereas a second approach involved amide coupling of a dipeptide with a beta-lactone carboxylic acid, obtained

  [反应：见正文]采用串联的Mukaiyama aldol-lactonizaton（TMAL）方法以简明的方式完成了（-）-半乳糖苷酶C及其衍生物的对映选择性合成。一种方法涉及与二肽乙二酰乙酰胺的远端双非对映选择性TMAL反应，而第二种方法涉及二肽与β-内酯羧酸的酰胺偶联，这是通过使用手性甲硅烷基乙烯酮缩醛的TMAL工艺获得的。非对映选择性的显着改善是在近端双非对映选择性TMAL过程中实现的。
• A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids
  作者：Mingzhao Zhu、Wayne D. Harshbarger、Omar Robles、Joanna Krysiak、Kenneth G. Hull、Sung Wook Cho、Robyn D. Richardson、Yanyan Yang、Andres Garcia、Lindsey Spiegelman、Bianca Ramirez、Christopher T. Wilson、Ju Anne Yau、James T. Moore、Caitlen B. Walker、James C. Sacchettini、Wenshe R. Liu、Stephan A. Sieber、Jeffrey W. Smith、Daniel Romo

  DOI：10.1016/j.bmc.2017.01.020

  日期：2017.6

  The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, B-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and fatty acid synthase-thioesterase (FAS-TE) enabling a new approach for the development of drug-candidates with potential to overcome resistance. (C) 2017 Elsevier Ltd. All rights reserved.