6,7-Dihydroxy-4-phenylcoumarin as inhibitor of aldose reductase 2

Atsushi Kato, Kaori Kobayashi, Kayo Narukawa, Yuka Minoshima, Isao Adachi, Shuichi Hirono, Robert J. Nash

Research output: Contribution to journalArticlepeer-review

14 Citations (SciVal)

Abstract

We report the structure–activity relationship of a series of coumarins as aldose reductase 2 (ALR2) inhibitors and their suppressive effect on the accumulation of galactitol in the rat lens. We evaluated their ALR2 selectivity profile against sorbitol dehydrogenase and aldehyde reductase (ALR1). Our study revealed that substitutions in the C7 OH group enhanced the potency toward ALR2, while the C6 OH group interferes with ALR1 inhibition activity. Having the phenyl moiety at C4 leads to improved potency and improved selectivity. A molecular docking study suggested that 6,7-dihydroxy-4-phenylcoumarin (15) binds to ALR2 in a different manner from epalrestat. Furthermore, compound 15 clearly suppressed galactitol accumulation in a dose-dependent manner. These results provide an insight into the structural requirements of coumarins for developing a new-type of selective ALR2 inhibitor.
Original languageEnglish
Pages (from-to)5630-5633
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number19
Early online date12 Aug 2010
DOIs
Publication statusPublished - 01 Oct 2010

Keywords

  • aldose reductase 2
  • 6,7-dihydroxy-4-phenylcoumarin
  • ALR2 inhibitor
  • structure-activity relationships
  • molecular docking stody
  • galacitol accumulation

Fingerprint

Dive into the research topics of '6,7-Dihydroxy-4-phenylcoumarin as inhibitor of aldose reductase 2'. Together they form a unique fingerprint.

Cite this