title: Green fluorescent protein chromophore derivatives as a new class of aldose reductase inhibitors.
abstract: A number of (Z)-4-arylmethylene-1H-imidazol-5(4H)-ones, which are related to the fluorescent chromophore of the Aequorea green fluorescent protein (GFP), have been synthesized and evaluated their in vitro inhibitory activity against recombinant human aldose reductase for the first time. The GFP chromophore model 1a, with a p-hydroxy group on the 4-benzylidene and a carboxymethyl group on the N1 position, exhibited strong bioactivity with an IC50value of 0.36 μM. This efficacy is higher than that of sorbinil, a known highly potent aldose reductase inhibitor. Compound 1h, the 2-naphtylmethylidene analogue of 1a, exhibited the best inhibitory effect among the tested copounds with an IC50value of 0.10 μM. Structure-activity relationship studies combined with docking simulations revealed the interaction mode of the newly synthesized inhibitors toward the target protein as well as the structural features required to gain a high inhibitory activity. In conclusion, the GFP chromophore model compounds synthesized in this study have proved to be potential drugs for diabetic complications.
authors: Department of Chemistry, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510 Japan; Research Center for Materials with Integrated Properties, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan. Electronic address: saito@chem.sci.toho-u.ac.jp.
authors: Ryota
authors: R
authors: Saito
authors: Department of Chemistry, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510 Japan.
authors: Maiko
authors: M
authors: Hoshi
authors: Department of Chemistry, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510 Japan.
authors: Akihiro
authors: A
authors: Kato
authors: Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510 Japan.
authors: Chikako
authors: C
authors: Ishikawa
authors: Kowa Company, Ltd., 3-4-14 Nihonbashi-honcho, Chuo-ku, Tokyo 103-8433, Japan.
authors: Toshiya
authors: T
authors: Komatsu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D048909:Diabetes Complications / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; C117197:imidazolone; D049452:Green Fluorescent Proteins; D000449:Aldehyde Reductase
keywords: (Z)-4-Arylmethylene-1H-imidazol-5(4H)-ones; Aldose reductase inhibitor; Docking study; Drug candidates for diabetic complications; GFP chromophore model