Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/Prof. García González, 1, 41012-Seville, Spain.
Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/Prof. García González, 1, 41012-Seville, Spain.
Bioorg Chem. 2019 May;86:652-664. doi: 10.1016/j.bioorg.2019.02.025. Epub 2019 Feb 12.
The synthesis of a library of pyrrolidine-aryltriazole hybrids through CuAAC between two epimeric dihydroxylated azidomethylpyrrolidines and differently substituted phenylacetylenes is reported. The evaluation of the new compounds as inhibitors of lysosomal β-glucocerebrosidase showed the importance of the substitution pattern of the phenyl moiety in the inhibition. Crystallization and docking studies revealed key interactions of the pyrrolidine motif with aminoacid residues of the catalytic site while the aryltriazole moiety extended along a hydrophobic surface groove. Some of these compounds were able to increase the enzyme activity in Gaucher patient fibroblasts, acting as a new type of chemical chaperone for Gaucher disease.
通过两个差向异构的二羟基叠氮甲基吡咯烷与不同取代的苯乙炔之间的 CuAAC，合成了吡咯烷-芳基三唑杂合体文库。作为溶酶体β-葡糖苷脑苷脂酶抑制剂，新化合物的评估表明苯环取代模式对抑制作用的重要性。结晶和对接研究揭示了吡咯烷基模体与催化部位氨基酸残基的关键相互作用，而芳基三唑基沿疏水性表面槽延伸。这些化合物中的一些能够增加戈谢病患者成纤维细胞中的酶活性，作为戈谢病的一种新型化学伴侣。
