Synthesis and structure-activity relationship of 2-phenyliminochromene derivatives as inhibitors for aldo-keto reductase (AKR) 1B10.
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.
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: sendo@gifu-pu.ac.jp.
Satoshi
S
Endo
Dawei
D
Hu
Miho
M
Suyama
Toshiyuki
T
Matsunaga
Kenji
K
Sugimoto
Yuji
Y
Matsuya
Ossama
O
El-Kabbani
Kazuo
K
Kuwata
Akira
A
Hara
Yukio
Y
Kitade
Naoki
N
Toyooka
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
C588113:7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide; D001549:Benzamides; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase
AKR; AKR1B10; Aldose reductase; Aldose reductase-like protein; FBS; Molecular docking; SAR; Structure–activity relationship; aldo–keto reductase; fetal bovine serum; structure–activity relationship