MALI-271 | 908074-72-6

• 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: MALI-271
• 英文别名: 115-7c；4-[6-(2,4-Dichlorophenyl)-4-methyl-2-oxo-5-phenylmethoxycarbonyl-1,6-dihydropyrimidin-3-yl]butanoic acid
• CAS: 908074-72-6
• 化学式: C₂₃H₂₂Cl₂N₂O₅
• 分子量: 477.344
• InChiKey: UHBVLBSCOSTTAV-UHFFFAOYSA-N

物化性质

• 沸点：
  688.6±55.0 °C(Predicted)
• 密度：
  1.360±0.06 g/cm3(Predicted)
• 溶解度：
  溶于DMSO（高达20mg/ml）。

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

制备方法与用途

HSP70调节剂115-7c是一种人工共伴侣，同时也是HSP70的增强子，能够刺激原核HSP70（DnaK）的ATP酶和蛋白质折叠活性，并部分补偿酵母中HSP40功能丧失突变；此外，它还能减少α-syn聚集在神经胶质瘤细胞中。

反应信息

• 作为反应物：
  描述：

  1-溴-2-丁烯 、 MALI-271 在 caesium carbonate 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 81.17h， 以72%的产率得到
  参考文献：
  名称：

  Synthesis and evaluation of esterified Hsp70 agonists in cellular models of protein aggregation and folding

  摘要：

  Over-expression of the Hsp70 molecular chaperone prevents protein aggregation and ameliorates neurodegenerative disease phenotypes in model systems. We identified an Hsp70 activator, MAL1-271, that reduces alpha-synuclein aggregation in a Parkinson's Disease model. We now report that MAL1-271 directly increases the ATPase activity of a eukaryotic Hsp70. Next, twelve MAL1-271 derivatives were synthesized and examined in a refined alpha-synuclein aggregation model as well as in an assay that monitors maturation of a disease-causing Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutant, which is also linked to Hsp70 function. Compared to the control, MAL1-271 significantly increased the number of cells lacking alpha-synuclein inclusions and increased the steady-state levels of the CFTR mutant. We also found that a nitrile-containing MAL1-271 analog exhibited similar effects in both assays. None of the derivatives exhibited cellular toxicity at concentrations up to 100 mu m, nor were cellular stress response pathways induced. These data serve as a gateway for the continued development of a new class of Hsp70 agonists with efficacy in these and potentially other disease models.

  DOI：

  10.1016/j.bmc.2018.11.011