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In this study we revealed that the addition of an N-phenylacetamide substituent to the C-1 position of 1-deoxyfuconojirimycin (DFJ) can lead to highly potent inhibitors of α-l-fucosidases. A structure-activity relationship study showed that a fluoro group on the phenyl ring greatly increased its potency and selectivity. In contrast the addition of two or three fluoro groups decreased their inhibition potency. Consequently, N-(2-fluorophenyl)-2β-DFJ acetamide (18j) was found to display very potent and selective inhibition of bovine kidney, rat epididymis, and human lysosome α-l-fucosidases, with IC50 value of 0.012, 0.044, and 0.0079μM respectively. It is noteworthy that our designed N-phenyl-2β-DFJ acetamide derivative exhibited about 18-fold stronger effects on human lysosomal α-l-fucosidase than original DFJ and it occupied the active-site of this enzyme. We therefore expect that this compound may find applications in new therapeutic trials against genetic deficiency disorders. Copyright © 2013 Elsevier Ltd. All rights reserved.

Citation

Atsushi Kato, Toru Okaki, Syohei Ifuku, Kasumi Sato, Yuki Hirokami, Ren Iwaki, Akiko Kamori, Shinpei Nakagawa, Isao Adachi, Peter G Kiria, Osamu Onomura, Daishiro Minato, Kenji Sugimoto, Yuji Matsuya, Naoki Toyooka. Synthesis and biological evaluation of N-(2-fluorophenyl)-2β-deoxyfuconojirimycin acetamide as a potent inhibitor for α-l-fucosidases. Bioorganic & medicinal chemistry. 2013 Nov 1;21(21):6565-73

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PMID: 24026016

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