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

Midori Soda, Dawei Hu, Satoshi Endo, Mayuko Takemura, Jie Li, Ryogo Wada, Syohei Ifuku, Hai Tao Zhao, Ossama El-Kabbani, Shozo Ohta, Keiko Yamamura, Naoki Toyooka, Akira Hara, Toshiyuki Matsunaga

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)321-329
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume48
DOIs
Publication statusPublished - 02-2012

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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