Design, synthesis and evaluation of caffeic acid phenethyl ester-based inhibitors targeting a selectivity pocket in the active site of human aldo–keto reductase 1B10

• Published in: European journal of medicinal chemistry 2012-02, Vol.48, p.321-329
• Main Authors: Soda, Midori, Hu, Dawei, Endo, Satoshi, Takemura, Mayuko, Li, Jie, Wada, Ryogo, Ifuku, Syohei, Zhao, Hai-Tao, El-Kabbani, Ossama, Ohta, Shozo, Yamamura, Keiko, Toyooka, Naoki, Hara, Akira, Matsunaga, Toshiyuki
• Format: Article
• Language: English
• Subjects: AKR1B10; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - genetics; Aldehyde Reductase - metabolism; Aldose reductase; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Caffeic acid phenethyl ester; Caffeic Acids - chemical synthesis; Caffeic Acids - chemistry; Caffeic Acids - pharmacology; Cancer; Catalytic Domain; Cell Survival - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; HeLa Cells; Humans; Inhibitor; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Models, Molecular; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Pharmacology. Drug treatments; Propolis - chemistry; Propolis - pharmacology; Selectivity; Spectrophotometry, Infrared; Structure-Activity Relationship; U937 Cells
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.12.034

Inhibitors of a human aldo–keto reductase, AKR1B10, are regarded as promising therapeutics for the treatment of cancer, but those with both high potency and selectivity compared to the structurally similar aldose reductase (AKR1B1) have not been reported. In this study, we have found that, among honeybee propolis products, caffeic acid phenethyl ester (CAPE) inhibited AKR1B10 (IC 50 = 80 nM) with 7-fold selectivity over AKR1B1. Based on a model of docked CAPE in AKR1B10, its derivatives were designed, synthesized and evaluated for inhibitory potency. Among them, 3-(4-hydroxy-2-methoxyphenyl)acrylic acid 3-(3-hydroxyphenyl)propyl ester ( 10c) was the most potent competitive inhibitor ( K i = 2.6 nM) with 790-fold selectivity for AKR1B10 over AKR1B1. Molecular docking of 10c and site-directed mutagenesis of AKR1B10 residues suggested that the interactions between the 2-methoxy and 3-hydroxy groups of 10c and the enzyme’s Val301 and Gln114, respectively, are important for the inhibitor’s selectivity. Additionally, the sub-μM concentration of 10c significantly suppressed the farnesal metabolism and cellular proliferation in AKR1B10-overexpressing cells. [Display omitted] ► AKR1B10 inhibitors are regarded as promising therapeutics for cancer treatment. ► Caffeic acid phenethyl ester was found to be a good lead for inhibitor synthesis. ► A newly synthesized derivative shows a K i of 2.6 nM and high selectivity for AKR1B10. ► It effectively inhibits cellular metabolism and proliferation mediated by AKR1B10.