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

Endo, Shunsuke; Hu, Dawei; Suyama, Miho; Matsunaga, Toshiyuki; Sugimoto, Kenji; Matsuya, Yûji; El‐Kabbani, Ossama; Kuwata, Kazuo; Hara, Akira; Kitade, Yukio; Toyooka, Naoki

doi:10.1016/j.bmc.2013.08.059

Cited by 24 publications

(22 citation statements)

References 23 publications

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“…Furthermore, the compounds were checked manually for their interactions with the active site residues of AKR1B10. The reference inhibitor showed a similar binding mode to that reported by Endo et al [17] . A total of 30 compounds that have shown hydrogen bond interactions with active site residues such as Tyr49, His111, and Trp112 were chosen for calculating the molecular orbital energies by DFT.…”

Section: Molecular Dockingsupporting

confidence: 80%

“…The 7-hydroxyl group of the reference inhibitor formed a hydrogen bond with the important residue Tyr49 in the active site of AKR1B10 ( Figure 10A) and showed hydrogen bond interactions with Lys22, Lys78 and a weak hydrogen bond with His111 (3.356 Å, not shown in the figure). Apart from hydrogen bond formation, the inhibitor showed interactions with hydrophobic pocket residues such as Val48, Trp112, Phe123, Cys299, and Val301, which may have imparted its specificity as an AKR1B10 inhibitor [17] . Hit 1 formed hydrogen bonds with Tyr49, Lys22, and Gln50 ( Figure 10B).…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

“…2-phenyliminochromene derivatives are the most potent known inhibitors of AKR1B10. Among them, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide is a selective inhibitor of AKR1B10 (IC 50 =4.7 nmol/L) [17] that has been used as reference compound in this study. Due to a low number of AKR1B10 inhibitors, there is a need to identify new scaffolds that are more selective and possess higher inhibitory activities.…”

Section: Introductionmentioning

confidence: 99%

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Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

et al. 2015

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Aim: Recent evidence suggests that aldo-keto reductase family 1 B10 (AKR1B10) may be a potential diagnostic or prognostic marker of human tumors, and that AKR1B10 inhibitors offer a promising choice for treatment of many types of human cancers. The aim of this study was to identify novel chemical scaffolds of AKR1B10 inhibitors using in silico approaches. Methods: The 3D QSAR pharmacophore models were generated using HypoGen. A validated pharmacophore model was selected for virtual screening of 4 chemical databases. The best mapped compounds were assessed for their drug-like properties. The binding orientations of the resulting compounds were predicted by molecular docking. Density functional theory calculations were carried out using B3LYP. The stability of the protein-ligand complexes and the final binding modes of the hit compounds were analyzed using 10 ns molecular dynamics (MD) simulations. Results: The best pharmacophore model (Hypo 1) showed the highest correlation coefficient (0.979), lowest total cost (102.89) and least RMSD value (0.59). Hypo 1 consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one ring aromatic and one hydrophobic feature. This model was validated by Fischer's randomization and 40 test set compounds. Virtual screening of chemical databases and the docking studies resulted in 30 representative compounds. Frontier orbital analysis confirmed that only 3 compounds had sufficiently low energy band gaps. MD simulations revealed the binding modes of the 3 hit compounds: all of them showed a large number of hydrogen bonds and hydrophobic interactions with the active site and specificity pocket residues of AKR1B10. Conclusion: Three compounds with new structural scaffolds have been identified, which have stronger binding affinities for AKR1B10 than known inhibitors.

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Section: Molecular Dockingsupporting

confidence: 80%

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

et al. 2015

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“…Lately, the inhibitory effect of some 25-based synthetic derivatives on AKR1B10 was evaluated and the most potent inhibitor among them was 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide (26) [31]. Not the 4-methoxy group, but its 7-hydroxyl group in the chromene ring is an essential structure base for inhibitory activity.…”

Section: Non-drug Synthetic Compoundsmentioning

confidence: 99%

“…The development of potent and selective AKR1B10 inhibitor as anticancer drugs has attracted growing attentions. Recently, many AKR1B10 inhibitors have been developed rapidly [24][25][26][27][28][29][30][31][32][33][34][35][36][37]. We here, review the recent publications and patents related to AKR1B10 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

Li¹,

He²,

Luo³

et al. 2016

PRA

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Cytosolic NADPH-dependent reductase AKR1B10 is a member of the aldo-keto reductase (AKR) superfamily. This enzyme is normally expressed in the gastrointestinal tract. However, it is overexpressed in many solid tumors, such as hepatocarcinoma, lung cancer and breast cancer. AKR1B10 may play a role in the formation and development of carcinomas through multiple mechanisms including detoxification of cytotoxic carbonyls, modulation of retinoic acid level, and regulation of cellular fatty acid synthesis and lipid metabolism. Studies have suggested that AKR1B10 may be a useful biomarker for cancer diagnosis and a potential target for cancer treatment. Over the last decade, a number of AKR1B10 inhibitors including aldose reductase inhibitors (ARIs), endogenous substances, natural-based derivatives and synthetic compounds have been developed, which could be novel anticancer drugs. This review provides an overview on related articles and patents about AKR1B10 inhibitors, with a focus on their inhibition selectivity and mechanism of function.

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Structural Basis for the Inhibition of AKR1B10 by Caffeic Acid Phenethyl Ester (CAPE)

Zhang

Zheng

et al. 2014

ChemMedChem

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Caffeic acid phenethyl ester (CAPE), the major bioactive component of honeybee propolis, is a potent selective inhibitor of aldo-keto reductase family member 1B10 (AKR1B10), and a number of derivatives hold promise as potential anticancer agents. However, sequence homology between AKR1B10 and other members of the superfamily, including critical phase I metabolizing enzymes, has resulted in a concern over the selectivity of any potential therapeutic agent. To elucidate the binding mode of CAPE with AKR1B10 and to provide a tool for future in silico efforts towards identifying selective inhibitors, the crystal structure of AKR1B10 in complex with CAPE was determined. The observed interactions provide an explanation for the selectivity exhibited by CAPE for AKR1B10, and could be used to guide further derivative design.

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

Cited by 24 publications

References 23 publications

Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

Structural Basis for the Inhibition of AKR1B10 by Caffeic Acid Phenethyl Ester (CAPE)

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