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Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning.
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2020-03-09 , DOI: 10.1016/j.bioorg.2020.103740
F Clemente 1 , C Matassini 1 , C Faggi 1 , S Giachetti 1 , C Cresti 1 , A Morrone 2 , P Paoli 3 , A Goti 4 , M Martínez-Bailén 5 , F Cardona 4
Affiliation  

The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids. All the target compounds behave as good GCase inhibitors, with IC50 in the micromolar range. Moreover, compound 11a behaves as a PC in fibroblasts derived from Gaucher patients bearing the N370/RecNcil mutation and the homozygous L444P mutation, rescuing the activity of the deficient enzyme by up to 1.9- and 1.8-fold, respectively. Rescues of 1.2-1.4-fold were also observed in wild-type fibroblasts, which is important for targeting sporadic forms of PD.

中文翻译:

2-烷基三羟基哌啶对葡萄糖脑苷脂酶(GCase)活性的调节:抑制作用和药理伴侣作用。

葡糖脑苷脂酶(GCase)已成为重要的治疗靶标,因为它参与了因酶缺乏导致的病理性疾病,例如溶酶体贮藏戈谢病(GD)和神经性帕金森病(PD)。药理伴侣(PCs)是小的化合物,当以亚抑制浓度使用时能够稳定酶,从而拯救酶的活性。我们报道了通过在有或没有路易斯酸存在下将格氏试剂向碳水化合物衍生的硝酮进行立体选择性加成的方式,在两个构型的C-2处烷基化的三羟基哌啶的立体发散性合成。所有目标化合物均表现为良好的GCase抑制剂,IC50在微摩尔范围内。此外,化合物11a在源自带有N370 / RecNcil突变和纯合L444P突变的Gaucher患者的成纤维细胞中起PC的作用,分别将缺乏酶的活性提高了1.9倍和1.8倍。在野生型成纤维细胞中也观察到1.2-1.4倍的抢救,这对于靶向散发的PD很重要。
更新日期:2020-03-09
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