Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
Department of Chemistry, University of York, Heslington, York YO10 5DD, North Yorkshire, UK.
Molecules. 2020 Sep 3;25(17):4025. doi: 10.3390/molecules25174025.
Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4--isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a "strategic" hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for G-gangliosidosis and Morquio B disease.
糖苷酶抑制剂作为溶酶体贮积病的药理学伴侣具有巨大的潜力。有鉴于此，我们合成了一系列新型环戊烷β-半乳糖苷酶抑制剂，并对其抑制活性和药理学伴侣活性进行了测定，同时与强效β-半乳糖苷酶抑制剂 4--异野尻霉素的亲脂性类似物进行了比较。通过 X 射线晶体学以及对环戊烷部分的改变，如脱氧和“策略性”羟基的氟取代，研究了构效关系。新化合物在一系列β-半乳糖苷酶功能受损的人类细胞系中表现出了非常有前景的活性，可能成为治疗 G 型神经节苷脂贮积症和 Morquio B 病的新型药理学伴侣的先导化合物。
