title: Synthesis and inhibitory activity of substrate-analog fructosyl peptide oxidase inhibitors.
abstract: Fructosyl peptide oxidases (FPOXs) play a crucial role in the diagnosis of diabetes. Their main function is to cleave fructosyl amino acids or fructosyl peptides into glucosone and the corresponding amino acids/dipeptides. In this study, the substrate-analog FPOX inhibitors 1a-c were successfully designed and synthesized. These inhibitors mimic N(α)-fructosyl-L-valine (Fru-Val), [N(α)-fructosyl-L-valyl]-L-histidine (Fru-ValHis), and N(ε)-fructosyl-L-lysine (εFru-Lys), respectively. The secondary nitrogen atom in the natural substrates, linking fructose and amino acid or dipeptide moieties, was substituted in 1a-c with a sulfur atom to avoid enzymatic cleavage. Kinetic studies revealed that 1a-c act as competitive inhibitors against an FPOX obtained from Coniochaeta sp., and Ki values of 11.1, 66.8, and 782 μM were obtained for 1a-c, respectively.
authors.affiliation: Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. Electronic address: bunta@scl.kyoto-u.ac.jp.
authors.forename: Bunta
authors.initials: B
authors.lastname: Watanabe
authors.affiliation: Research and Development Division, Kikkoman Corporation, 399 Noda, Noda, Chiba 278-0037, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ichiyanagi
authors.affiliation: Research and Development Division, Kikkoman Corporation, 399 Noda, Noda, Chiba 278-0037, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Hirokawa
authors.affiliation: Research and Development Division, Kikkoman Corporation, 399 Noda, Noda, Chiba 278-0037, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Gomi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakatsu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Research and Development Division, Kikkoman Corporation, 399 Noda, Noda, Chiba 278-0037, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kajiyama
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001203:Ascomycota / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C045420:fructosylvaline; C033186:fructosyl-lysine; D000594:Amino Acid Oxidoreductases; C520096:fructosyl-peptide oxidase; D014633:Valine; D008239:Lysine
keywords: Diabetes; Fructosyl peptide oxidase; Glycation; Hemoglobin A1c; Substrate-analog inhibitor