title: Synthesis and biological evaluation of N-(2-fluorophenyl)-2β-deoxyfuconojirimycin acetamide as a potent inhibitor for α-l-fucosidases.
abstract: 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.
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan. Electronic address: kato@med.u-toyama.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Toru
authors.initials: T
authors.lastname: Okaki
authors.forename: Syohei
authors.initials: S
authors.lastname: Ifuku
authors.forename: Kasumi
authors.initials: K
authors.lastname: Sato
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirokami
authors.forename: Ren
authors.initials: R
authors.lastname: Iwaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Kamori
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kiria
authors.forename: Osamu
authors.initials: O
authors.lastname: Onomura
authors.forename: Daishiro
authors.initials: D
authors.lastname: Minato
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuya
authors.forename: Naoki
authors.initials: N
authors.lastname: Toyooka
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004822:Epididymis / Q000201:enzymology; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000737:chemistry*; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; C588116:N-(2-fluorophenyl)-2beta-1-deoxyfuconojirimycin acetamide; D013402:Sugar Alcohols; D017485:1-Deoxynojirimycin; C062662:deoxyfuconojirimycin; D005644:alpha-L-Fucosidase
keywords: 1-Deoxyfuconojirimycin; Fucosidosis; Iminosugar; N-(2-Fluorophenyl)-2β-DFJ acetamide; α-l-Fucosidase