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

Satoshi Endo, Dawei Hu Hu, Miho Suyama, Toshiyuki Matsunaga, Kenji Sugimoto, Yuji Matsuya, Ossama El-Kabbani, Kazuo Kuwata, Akira Hara, Yukio Kitade, Naoki Toyooka

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Abstract

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 1.3 nM. 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 p-stacking interaction of the benzylamide moiety of 5n with Trp220, are important for the potent inhibition.
Original languageEnglish
Pages (from-to)6378 - 6384
Number of pages7
JournalBioorganic & Medicinal Chemistry
Volume21
Issue number21
DOIs
Publication statusPublished - 2013

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