tert-butyl (2-((2-(cyclohex-1-en-1-ylamino)-2-oxo-1-(4-(prop-2-yn-1-ylcarbamoyl)phenyl)ethyl)(2-methoxyethyl)carbamoyl)-4-iodophenyl)carbamate | 1383960-04-0

• 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: tert-butyl (2-((2-(cyclohex-1-en-1-ylamino)-2-oxo-1-(4-(prop-2-yn-1-ylcarbamoyl)phenyl)ethyl)(2-methoxyethyl)carbamoyl)-4-iodophenyl)carbamate
• CAS: 1383960-04-0
• 化学式: C₃₃H₃₉IN₄O₆
• 分子量: 714.6
• InChiKey: PVWLEWQAVFDUOM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.41
• 重原子数：
  44.0
• 可旋转键数：
  11.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  126.07
• 氢给体数：
  3.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  tert-butyl (2-((2-(cyclohex-1-en-1-ylamino)-2-oxo-1-(4-(prop-2-yn-1-ylcarbamoyl)phenyl)ethyl)(2-methoxyethyl)carbamoyl)-4-iodophenyl)carbamate 在 盐酸 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 caesium carbonate 、 苯甲醚 、 乙酰氯 作用下， 以 甲醇 为溶剂， 20.0~80.0 ℃ 、101.33 kPa 条件下， 反应 20.0h， 生成 7-(benzo[d][1,3]dioxole-5-carbonyl)-4-(2-methoxyethyl)-3-(4-(prop-2-yn-1-ylcarbamoyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione
  参考文献：
  名称：

  Fully Functionalized Small-Molecule Probes for Integrated Phenotypic Screening and Target Identification

  摘要：

  Phenotypic screening offers a powerful approach to identify small molecules that perturb complex biological processes in cells and organisms. The tendency of small molecules, however, to interact with multiple protein targets, often with moderate to weak affinities, along with the lack of straightforward technologies to characterize these interactions in living systems, has hindered efforts to understand the mechanistic basis for pharmacological activity. Here we address this challenge by creating a fully functionalized small-molecule library whose membership is endowed with: (1) one or more diversity elements to promote interactions with different protein targets in cells, (2) a photoreactive group for UV light-induced covalent cross-linking to interacting proteins, and (3) an alkyne handle for reporter tag conjugation to visualize and identify cross-linked proteins. A library member was found to inhibit cancer cell proliferation selectively under nutrient-limiting (low glucose) conditions. Quantitative chemoproteomics identified MT-ND1, an integral membrane subunit of the similar to 1 MDa NADH:ubiquinone oxidoreductase (complex 1) involved in oxidative phosphorylation, as a specific target of the active probe. We further demonstrated that the active probe inhibits complex 1 activity in vitro (IC50 = 720 nM), an effect that is known to induce cell death in low-glucose conditions. Based on this proof of principle study, we anticipate that the generation and integration of fully functionalized compound libraries into phenotypic screening programs should facilitate the discovery of bioactive probes that are amenable to accelerated target identification and mechanistic characterization using advanced chemoproteomic technologies.

  DOI：

  10.1021/ja304213w
• 作为产物：
  描述：

  4-formyl-N-(prop-2-yn-1-yl)benzamide 、 异氰基环己烯 、 2-甲氧基乙胺 、 2-[N-(tert-Butyloxycarbonyl)amino]-5-iodobenzoic acid 在 scandium tris(trifluoromethanesulfonate) 作用下， 以 甲醇 为溶剂， 反应 18.5h， 以56%的产率得到tert-butyl (2-((2-(cyclohex-1-en-1-ylamino)-2-oxo-1-(4-(prop-2-yn-1-ylcarbamoyl)phenyl)ethyl)(2-methoxyethyl)carbamoyl)-4-iodophenyl)carbamate
  参考文献：
  名称：

  Fully Functionalized Small-Molecule Probes for Integrated Phenotypic Screening and Target Identification

  摘要：

  Phenotypic screening offers a powerful approach to identify small molecules that perturb complex biological processes in cells and organisms. The tendency of small molecules, however, to interact with multiple protein targets, often with moderate to weak affinities, along with the lack of straightforward technologies to characterize these interactions in living systems, has hindered efforts to understand the mechanistic basis for pharmacological activity. Here we address this challenge by creating a fully functionalized small-molecule library whose membership is endowed with: (1) one or more diversity elements to promote interactions with different protein targets in cells, (2) a photoreactive group for UV light-induced covalent cross-linking to interacting proteins, and (3) an alkyne handle for reporter tag conjugation to visualize and identify cross-linked proteins. A library member was found to inhibit cancer cell proliferation selectively under nutrient-limiting (low glucose) conditions. Quantitative chemoproteomics identified MT-ND1, an integral membrane subunit of the similar to 1 MDa NADH:ubiquinone oxidoreductase (complex 1) involved in oxidative phosphorylation, as a specific target of the active probe. We further demonstrated that the active probe inhibits complex 1 activity in vitro (IC50 = 720 nM), an effect that is known to induce cell death in low-glucose conditions. Based on this proof of principle study, we anticipate that the generation and integration of fully functionalized compound libraries into phenotypic screening programs should facilitate the discovery of bioactive probes that are amenable to accelerated target identification and mechanistic characterization using advanced chemoproteomic technologies.

  DOI：

  10.1021/ja304213w