Li Yi-Xian, Zhang Ming, Shimadate Yuna, Kato Atsushi, Wang Jun-Zhe, Jia Yue-Mei, Fleet George W J, Yu Chu-Yi
Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Org Biomol Chem. 2025 Mar 19;23(12):2854-2877. doi: 10.1039/d4ob01542h.
C-2 Fluorinated castanospermines have been synthesized from a well-protected aldehyde precursor and evaluated as glycosidase inhibitors in comparison with castanospermine, 1--castanospermine and C-1 fluorinated castanospermines. While C-1 fluorinated castanospermines lose nearly all the glycosidase inhibition shown by castanospermine and 1--castanospermine, C-2 fluorinated derivatives of castanospermine were found to be potent and highly specific α-glucosidase inhibitors; however, the C-2 fluorinated 1--castanospermines showed a sharp decrease in inhibition towards all tested enzymes. Docking calculations attributed the sharp decrease of glycosidase inhibition of C-1 fluorinated castanospermines to the disappearance of hydrogen bonds between the original C-1 hydroxyls and residues Arg-526 and Asp-327. The retained potent and specific α-glucosidase inhibition of C-2 fluorinated castanospermines was achieved by the fluorine-induced reestablishment of the docking mode in the active site; and the sharply decreased inhibition of C-2 fluorinated 1--castanospermines can be attributed to obvious binding distorsion and disappearance of the hydrogen bonding with residues His-600 and Arg-526. Reliability of the docking results was evaluated by Molecular Dynamics (MD) simulation, which provided necessary calibrations to the calculation results. The interaction modes of fluorine reported herein are different from the "mimic effect" of fluorine for hydrogen, offering insights and extending our previous work on fluorinated casuarines. These results would be important for the development of castanospermine-related drug candidates for the treatment of diabetes, viral infections and Pompe disease.
C-2 氟代栗精胺已从一种保护良好的醛前体合成，并与栗精胺、1-脱氧栗精胺和 C-1 氟代栗精胺相比，作为糖苷酶抑制剂进行了评估。虽然 C-1 氟代栗精胺几乎失去了栗精胺和 1-脱氧栗精胺所显示的所有糖苷酶抑制活性，但栗精胺的 C-2 氟代衍生物被发现是强效且高度特异性的α-葡萄糖苷酶抑制剂；然而，C-2 氟代 1-脱氧栗精胺对所有测试酶的抑制作用急剧下降。对接计算将 C-1 氟代栗精胺糖苷酶抑制作用的急剧下降归因于原始 C-1 羟基与残基 Arg-526 和 Asp-327 之间氢键的消失。C-2 氟代栗精胺保留的强效和特异性α-葡萄糖苷酶抑制作用是通过氟诱导活性位点对接模式的重新建立实现的；而 C-2 氟代 1-脱氧栗精胺抑制作用的急剧下降可归因于明显的结合畸变以及与残基 His-600 和 Arg-526 氢键的消失。通过分子动力学 (MD) 模拟评估了对接结果的可靠性，该模拟为计算结果提供了必要的校准。本文报道的氟的相互作用模式不同于氟对氢的“模拟效应”，为我们之前关于氟代木麻黄碱的研究提供了见解并进行了拓展。这些结果对于开发用于治疗糖尿病、病毒感染和庞贝病的与栗精胺相关的候选药物具有重要意义。
