4-(4-((2, 4-diaminopyrimidin-5-yl)methyl)-2, 6-dimethoxyphenoxy)butanoic acid | 94236-24-5

• 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: 4-(4-((2, 4-diaminopyrimidin-5-yl)methyl)-2, 6-dimethoxyphenoxy)butanoic acid
• 英文别名: Trimethoprim propanoic acid；4-[4-[(2,4-diaminopyrimidin-5-yl)methyl]-2,6-dimethoxyphenoxy]butanoic acid
• CAS: 94236-24-5
• 化学式: C₁₇H₂₂N₄O₅
• 分子量: 362.385
• InChiKey: GMBNQAVADXFXRF-UHFFFAOYSA-N

物化性质

• 沸点：
  667.0±65.0 °C(Predicted)
• 密度：
  1.312±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  143
• 氢给体数：
  3
• 氢受体数：
  9

制备方法与用途

Trimethoprim propanoic acid 是一种半抗原。

反应信息

• 作为反应物：
  描述：

  三氟乙酸五氟苯酯 、 4-(4-((2, 4-diaminopyrimidin-5-yl)methyl)-2, 6-dimethoxyphenoxy)butanoic acid 在 吡啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成
  参考文献：
  名称：

  Conditional Glycosylation in Eukaryotic Cells Using a Biocompatible Chemical Inducer of Dimerization

  摘要：

  Chemical inducers of dimerization (CIDs) are cell-permeable small molecules capable of dimerizing two protein targets. The most widely used CID, the natural product rapamycin and its relatives, is immunosuppressive due to interactions with endogenous targets and thus has limited utility in vivo. Here we report a new biocompatible CID, Tmp-SLF, which dimerizes E. coli DHFR and FKBP and has no endogenous mammalian targets that would lead to unwanted in vivo side effects. We employed Tmp-SLF to modulate gene expression in a yeast three-hybrid assay. Finally, we engineered the Golgi-resident glycosyltransferase FucT7 for tunable control by Tmp-SLF in mammalian cells.

  DOI：

  10.1021/ja8037728
• 作为产物：
  描述：

  甲氧苄啶 在 氢溴酸 、 potassium carbonate 、 caesium carbonate 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.5h， 生成 4-(4-((2, 4-diaminopyrimidin-5-yl)methyl)-2, 6-dimethoxyphenoxy)butanoic acid
  参考文献：
  名称：

  使用甲氧苄啶 PROTAC 调节 eDHFR 标记蛋白

  摘要：

  对细胞和活体动物中蛋白质水平的时间控制可用于提高我们对蛋白质功能的理解。此外，工程蛋白质的控制可用于治疗应用。蛋白水解靶向嵌合体 (PROTAC) 已成为一种小分子驱动策略，通过将 E3 连接酶招募到目标蛋白上，实现蛋白丰度的快速翻译后调节。在这里，我们通过将抗生素甲氧苄啶 (TMP) 与 Pomalidomide（E3 连接酶 Cereblon 的配体）共价连接来开发几种 PROTAC 分子。这些分子诱导与小蛋白结构域、大肠杆菌二氢叶酸还原酶 (eDHFR) 基因融合的感兴趣蛋白 (POI) 的降解，这是 TMP 的分子靶点。我们表明，使用 PROTAC 分子7c可以将各种 eDHFR 标记蛋白稳健地降解至最大表达量的 95%。此外，使用蛋白质组学和生化测定，基于 TMP 的 PROTAC 对免疫调节酰亚胺药物 (IMiD) 敏感的新底物的表达影响最小。最后，我们展示了另一个已知的降解决定子-PROTAC

  DOI：

  10.1038/s41467-023-42820-3

文献信息

• Receptor-based design of dihydrofolate reductase inhibitors: comparison of crystallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogs
  作者：Lee F. Kuyper、Barbara Roth、David P. Baccanari、Robert Ferone、Christopher R. Beddell、John N. Champness、David K. Stammers、John G. Dann、Frank E. A. Norrington

  DOI：10.1021/jm00381a008

  日期：1985.3

  Escherichia coli dihydrofolate reductase (DHFR), analogues of trimethoprim (TMP) were designed which incorporated various 3'-carboxyalkoxy moieties in order to acquire ionic interactions with positively charged active-site residues. Certain of these compounds have shown exceptionally high affinity for this enzyme. For example, the 3'-(carboxypentyl)oxy analogue was found to be 55-fold more inhibitory than

  通过使用大肠杆菌二氢叶酸还原酶（DHFR）的分子模型，设计了甲氧苄氨嘧啶（TMP）的类似物，该类似物并入了各种3'-羧基烷氧基部分，以便获得带正电荷的活性位点残基的离子相互作用。这些化合物中的某些已显示出对该酶的极高亲和力。例如，发现3'-（羧基戊基）氧基类似物对大肠杆菌DHFR的抑制作用是TMP的55倍（Ki = 0.024 nM，而TMP为1.32 nM）。大肠杆菌DHFR与TMP的二元复合物的X射线晶体学研究和该含酸系列化合物的两个成员定义了这些抑制剂的结合并显示了后两个抑制剂的羧基与Arg-57离子结合。
• Generic Hapten Synthesis, Broad-Specificity Monoclonal Antibodies Preparation, and Ultrasensitive ELISA for Five Antibacterial Synergists in Chicken and Milk
  作者：Hongfang Li、Shaoqin Ma、Xiya Zhang、Chenglong Li、Baolei Dong、Mari Ghulam Mujtaba、Yujie Wei、Xiao Liang、Xuezhi Yu、Kai Wen、Wenbo Yu、Jianzhong Shen、Zhanhui Wang

  DOI：10.1021/acs.jafc.8b03834

  日期：2018.10.24

  i.e., diaminopyrimidine, was intentionally and maximally exposed to the immune system in animals in order to induce antibodies with broad specificity against ASGs. Five monoclonal antibodies (mAbs) were finally obtained, and 5C4 from the hapten with a short spacer arm, named Hapten A, showed not only uniform broad specificity but also high affinity to all five ASGs. We further determined the possible

  具有广泛特异性并且主要取决于半抗原结构和大小的抗体是用于开发类选择性免疫测定法的关键试剂。在本研究中，使用甲氧苄啶为起始分子，提出了三种新的抗菌增效剂（ASG）通用半抗原。这些半抗原在间位上含有羧基在三甲氧基苯的位置结合蛋白质，而有意地和最大程度地将ASG的共同部分，即二氨基嘧啶暴露于动物的免疫系统中，以诱导具有针对ASG的广泛特异性的抗体。最终获得了五种单克隆抗体（mAb），带有短间隔臂的半抗原5C4命名为Hapten A，不仅显示出均一的广泛特异性，而且对所有五个ASG均显示出高亲和力。我们从构象和电子方面进一步确定了单克隆抗体的可能识别机制。建立了基于间接竞争ELISA（icELISA）的5C4，其IC 50值为0.067–0.139μgL –1在最佳条件下，缓冲液中的五个ASG的交叉反应率为48.2％–418.7％。鸡肉和牛奶的icELISA检测极限分别为0.06–0.8μgkg –1和0
• Broad-spectrum monoclonal antibody and a sensitive multi-residue indirect competitive enzyme-linked immunosorbent assay for the antibacterial synergists in samples of animal origin
  作者：Xiaoya Han、Feng Sheng、Dexin Kong、Yulian Wang、Yuanhu Pan、Mo Chen、Yanfei Tao、Zhenli Liu、Saeed Ahmed、Zonghui Yuan、Dapeng Peng

  DOI：10.1016/j.foodchem.2018.12.040

  日期：2019.5

  To monitor the abuse of antibacterial synergists, a hapten, trimethoprim carboxylic derivative (TMPCOOH), was designed by using molecular modelling technology. A broad-spectrum monoclonal antibody (mAb) TMP/2G1 was prepared, for which the IC50 values of trimethoprim, diaveridine, aditoprim, baquiloprim, ormetoprim, and brodimoprim were 0.232, 0.527, 1.479, 4.354, 0.965, and 0.119 mu g L-1, respectively. Based on the broad spectrum mAb, an indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) was developed to determine the residues of antibacterial synergists. The limit of detection regarding the developed ic-ELISA for antibacterial synergists ranged from 0.025 to 1.126 mu g L-1 in milk, honey and edible animal tissues. The recoveries ranged from 81.4% to 107.7%, with a coefficient of variation less than 20%. A good correlation (R-2 = 0.994) between the ic-ELISA and HPLC-MS/MS showed the reliability of the developed ic-ELISA.
• Conditional Glycosylation in Eukaryotic Cells Using a Biocompatible Chemical Inducer of Dimerization
  作者：Jennifer L. Czlapinski、Michael W. Schelle、Lawrence W. Miller、Scott T. Laughlin、Jennifer J. Kohler、Virginia W. Cornish、Carolyn R. Bertozzi

  DOI：10.1021/ja8037728

  日期：2008.10.8

  Chemical inducers of dimerization (CIDs) are cell-permeable small molecules capable of dimerizing two protein targets. The most widely used CID, the natural product rapamycin and its relatives, is immunosuppressive due to interactions with endogenous targets and thus has limited utility in vivo. Here we report a new biocompatible CID, Tmp-SLF, which dimerizes E. coli DHFR and FKBP and has no endogenous mammalian targets that would lead to unwanted in vivo side effects. We employed Tmp-SLF to modulate gene expression in a yeast three-hybrid assay. Finally, we engineered the Golgi-resident glycosyltransferase FucT7 for tunable control by Tmp-SLF in mammalian cells.