Synthesis and structure–activity relationship of 2-phenyliminochromene derivatives as inhibitors for aldo–keto reductase (AKR) 1B10

• Published in: Bioorganic & medicinal chemistry 2013-11, Vol.21 (21), p.6378-6384
• Main Authors: Endo, Satoshi, Hu, Dawei, Suyama, Miho, Matsunaga, Toshiyuki, Sugimoto, Kenji, Matsuya, Yuji, El-Kabbani, Ossama, Kuwata, Kazuo, Hara, Akira, Kitade, Yukio, Toyooka, Naoki
• Format: Article
• Language: English
• Subjects: AKR1B10; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - genetics; Aldehyde Reductase - metabolism; Aldose reductase; Aldose reductase-like protein; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - metabolism; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - metabolism; Binding Sites; Catalytic Domain; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Humans; Hydrogen Bonding; Kinetics; Molecular docking; Molecular Docking Simulation; Mutagenesis, Site-Directed; Protein Binding; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; screening; site-directed mutagenesis; Structure-Activity Relationship; structure-activity relationships; therapeutics
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.08.059

Inhibitors of a human member (AKR1B10) of the aldo–keto reductase superfamily are regarded as promising therapeutics for the treatment of cancer. Recently, we have discovered (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) as the potent competitive inhibitor using the virtual screening approach, and proposed its 4-methoxy group on the 2-phenylimino moiety as an essential structural prerequisite for the inhibition. In this study, 18 derivatives of 1 were synthesized and their inhibitory potency against AKR1B10 evaluated. Among them, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide (5n) was the most potent inhibitor showing a Ki value of 1.3nM. The structure–activity relationship of the derivatives indicated that the 7-hydroxyl group on the chromene ring, but not the 4-methoxy group, was absolutely required for inhibitory activity, The molecular docking of 5n in AKR1B10 and site-directed mutagenesis of the enzyme residues suggested that the hydrogen-bond interactions between the 7-hydroxyl group of 5n and the catalytic residues (Tyr49 and His111) of the enzyme, together with a π-stacking interaction of the benzylamide moiety of 5n with Trp220, are important for the potent inhibition.