Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency.
Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency.
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新型肌酸脂肪酸酯的合成和生物学评价表明十二烷基肌酸酯是治疗肌酸转运蛋白缺乏症的有前途的候选药物。
DOI：
10.1021/jm400545n
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发表时间：
2013
影响因子：
7.3
通讯作者：
A. Mabondzo
中科院分区：
文献类型：
--
作者：
Alexandra Trotier;S. Dézard;F. Taran;V. Valayannopoulos;P. de Lonlay;A. Mabondzo
肌酸转运蛋白缺乏症是由肌酸转运蛋白SLC 6A 8受损引起的神经系统疾病，导致与脑内完全缺乏肌酸和神经元细胞的细胞能量扰动相关的智力迟钝。治疗假设之一是施用亲脂性肌酸衍生物，其（1）被认为具有更好的穿过细胞膜的渗透性和（2）不依赖于SLC 6A 8的活性来穿透脑。本文采用有机化学方法合成了肌酸脂肪酸酯。在体外大鼠原代细胞为基础的血脑屏障模型和大鼠原代神经元细胞模型上的筛选证明了这些前药根据结构-活性关系掺入内皮细胞、星形胶质细胞和神经元细胞的有趣特性。与内源性肌酸含量相比，十二烷基肌酸酯在病理性人成纤维细胞中的肌酸含量增加了20倍，表明它可能是一种有前途的候选药物。
The creatine transporter deficiency is a neurological disease caused by impairment of the creatine transporter SLC6A8, resulting in mental retardation associated with a complete absence of creatine within the brain and cellular energy perturbation of neuronal cells. One of the therapeutic hypotheses was to administer lipophilic creatine derivatives which are (1) thought to have better permeability through the cell membrane and (2) would not rely on the activity of SLC6A8 to penetrate the brain. Here, we synthesized creatine fatty esters through original organic chemistry process. A screening on an in vitro rat primary cell-based blood-brain barrier model and on a rat primary neuronal cells model demonstrated interesting properties of these prodrugs to incorporate into endothelial, astroglial, and neuronal cells according to a structure-activity relationship. Dodecyl creatine ester showed then a 20-fold increase in creatine content in pathological human fibroblasts compared with the endogenous creatine content, stating that it could be a promising drug candidate.