(4R)-2,2-dimethyl-3-[2-oxo-2-(2,4,6-trimethylphenyl)acetyl]-1,3-thiazolidine-4-carboxylic acid | 906069-48-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (4R)-2,2-dimethyl-3-[2-oxo-2-(2,4,6-trimethylphenyl)acetyl]-1,3-thiazolidine-4-carboxylic acid
• CAS: 906069-48-5
• 化学式: C₁₇H₂₁NO₄S
• 分子量: 335.424
• InChiKey: COONGGWAMXEBLX-LBPRGKRZSA-N

物化性质

• 沸点：
  541.2±60.0 °C(Predicted)
• 密度：
  1.245±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (4R)-2,2-dimethyl-3-[2-oxo-2-(2,4,6-trimethylphenyl)acetyl]-1,3-thiazolidine-4-carboxylic acid 、 1-苯氧基-丙醇 在 4-二甲氨基吡啶 、 camphor-10-sulfonic acid 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以67.4%的产率得到1-phenoxy-2-propyl(2R)-5,5-dimethyl-1-[1,2-dioxo-2-(2,4,6-trimethylphenyl)]ethyl-2-(4-thiazolidine)carboxylate
  参考文献：
  名称：

  FK506-Binding Protein Ligands:  Structure-Based Design, Synthesis, and Neurotrophic/Neuroprotective Properties of Substituted 5,5-Dimethyl-2-(4-thiazolidine)carboxylates

  摘要：

  Structure-based design and discovery of novel neuroimmunophilin FK506-binding protein (FKBP) ligands were pursued in the present study. The binding mode of the known FKBP ligand 1 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate) in complex with FKBP12 was investigated using LUDI simulation and upon which a novel scaffold structure predicted to possess improved binding affinity was designed. A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK. Forty-three candidate compounds that displayed favorable binding with the receptor were identified and synthesized. The neurotrophic activity of the candidate compounds was evaluated on chick dorsal root ganglion cultures in vitro. As a result, 15 compounds exhibited positive effects on ganglion neurite outgrowth in the presence of 0.15 ng/mL NGF, among which 7 compounds at testing concentrations of 1 pM and 100 pM showed greater efficacy than 1 at 100 pM. Compound 18 (3-(3-pyridyl)-1-propyl (2S)- 5,5-dimethyl- 1-(3,3-dimethyl-1,2-dioxobutyl)-2-(4-thiazolidine) carboxylate) afforded the most potent effect in promoting the processes of neurite outgrowth and which was in a concentration-dependent manner from 1 pM to 100 pM. Half-maximal effect occurred at about 10 pM. Moreover, 18 at a dosage of 10 mg/kg was found to be significantly neuroprotective in a mouse peripheral sympathetic nerve injury model induced by 8 mg/kg 6-hydroxydopamine. This study further suggests the clinical potential of novel FKBP ligands as a new therapeutic approach in the treatment of neurodegenerative disorders, such as Parkinson's disease.

  DOI：

  10.1021/jm0502384
• 作为产物：
  描述：

  ethyl(2R)-5,5-dimethyl-1-(1,2-dioxo-2-ethoxyethyl)-2-(4-thiazolidine)carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 为溶剂， 反应 5.0h， 生成 (4R)-2,2-dimethyl-3-[2-oxo-2-(2,4,6-trimethylphenyl)acetyl]-1,3-thiazolidine-4-carboxylic acid
  参考文献：
  名称：

  FK506-Binding Protein Ligands:  Structure-Based Design, Synthesis, and Neurotrophic/Neuroprotective Properties of Substituted 5,5-Dimethyl-2-(4-thiazolidine)carboxylates

  摘要：

  Structure-based design and discovery of novel neuroimmunophilin FK506-binding protein (FKBP) ligands were pursued in the present study. The binding mode of the known FKBP ligand 1 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate) in complex with FKBP12 was investigated using LUDI simulation and upon which a novel scaffold structure predicted to possess improved binding affinity was designed. A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK. Forty-three candidate compounds that displayed favorable binding with the receptor were identified and synthesized. The neurotrophic activity of the candidate compounds was evaluated on chick dorsal root ganglion cultures in vitro. As a result, 15 compounds exhibited positive effects on ganglion neurite outgrowth in the presence of 0.15 ng/mL NGF, among which 7 compounds at testing concentrations of 1 pM and 100 pM showed greater efficacy than 1 at 100 pM. Compound 18 (3-(3-pyridyl)-1-propyl (2S)- 5,5-dimethyl- 1-(3,3-dimethyl-1,2-dioxobutyl)-2-(4-thiazolidine) carboxylate) afforded the most potent effect in promoting the processes of neurite outgrowth and which was in a concentration-dependent manner from 1 pM to 100 pM. Half-maximal effect occurred at about 10 pM. Moreover, 18 at a dosage of 10 mg/kg was found to be significantly neuroprotective in a mouse peripheral sympathetic nerve injury model induced by 8 mg/kg 6-hydroxydopamine. This study further suggests the clinical potential of novel FKBP ligands as a new therapeutic approach in the treatment of neurodegenerative disorders, such as Parkinson's disease.

  DOI：

  10.1021/jm0502384