Structure-activity relationship of coumarin derivatives on xanthine oxidase-inhibiting and free radical-scavenging activities

Hsiu Chen Lin, Shin Hui Tsai, Chien Shu Chen, Yuan Ching Chang, Chi Ming Lee, Zhi Yang Lai, Chun Mao Lin

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

We employed 1,1-diphenyl-2-picrylhydrazyl hydrate (DPPH)- and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)-electron spin resonance (ESR) to study the effects of suppression of reactive oxygen species (ROS) by eight selected coumarin derivatives under oxidative conditions. Esculetin was the most potent radical scavenger among the eight tested compounds. Our results suggest that the number of hydroxyl groups on the ring structure of coumarins is correlated with the effects of ROS suppression. We also investigated the effect of the derivatives on the inhibition of xanthine oxidase (XO) activity, and the structure-activity relationships (SARs) of these derivatives against XO activity were further examined using computer-aided molecular modeling. All determined derivatives competitively inhibited XO. The results of the structure-based molecular modeling exhibited interactions between coumarins and the molybdopterin region of XO. The carbonyl pointed toward the Arg880, and the ester O atom formed hydrogen bonds with Thr1010. Esculetin, which bears two hydroxyl moieties on its benzene rings, had the highest affinity toward the binding site of XO, and this was mainly due to the interaction of 6-hydroxyl with the E802 residue of XO. The hypoxanthine/XO reaction in the DMPO-ESR technique was used to assess the combined effect on enzyme inhibition and ROS suppression by these coumarins, and the results showed that esculetin was the most potent agent among the tested compounds. We further evaluated the effects of the test compounds on living cells, and esculetin was still the most potent agent at protecting cells against ROS-mediated Aβ-damage among the tested coumarins.

Original languageEnglish
Pages (from-to)1416-1425
Number of pages10
JournalBiochemical Pharmacology
Volume75
Issue number6
DOIs
Publication statusPublished - Mar 15 2008

Fingerprint

Coumarins
Xanthine Oxidase
Scavenging
Structure-Activity Relationship
Free Radicals
Reactive Oxygen Species
Hydroxyl Radical
Molecular modeling
Electron Spin Resonance Spectroscopy
Derivatives
Paramagnetic resonance
Molecular Computers
Enzyme inhibition
Benzene
Molecular Structure
Hydrates
Oxides
Hydrogen
Hydrogen bonds
Esters

Keywords

  • Coumarin
  • Esculetin
  • Molecular modeling
  • ROS
  • Xanthine oxidase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Structure-activity relationship of coumarin derivatives on xanthine oxidase-inhibiting and free radical-scavenging activities. / Lin, Hsiu Chen; Tsai, Shin Hui; Chen, Chien Shu; Chang, Yuan Ching; Lee, Chi Ming; Lai, Zhi Yang; Lin, Chun Mao.

In: Biochemical Pharmacology, Vol. 75, No. 6, 15.03.2008, p. 1416-1425.

Research output: Contribution to journalArticle

Lin, Hsiu Chen ; Tsai, Shin Hui ; Chen, Chien Shu ; Chang, Yuan Ching ; Lee, Chi Ming ; Lai, Zhi Yang ; Lin, Chun Mao. / Structure-activity relationship of coumarin derivatives on xanthine oxidase-inhibiting and free radical-scavenging activities. In: Biochemical Pharmacology. 2008 ; Vol. 75, No. 6. pp. 1416-1425.
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AU - Lin, Hsiu Chen

AU - Tsai, Shin Hui

AU - Chen, Chien Shu

AU - Chang, Yuan Ching

AU - Lee, Chi Ming

AU - Lai, Zhi Yang

AU - Lin, Chun Mao

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AB - We employed 1,1-diphenyl-2-picrylhydrazyl hydrate (DPPH)- and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)-electron spin resonance (ESR) to study the effects of suppression of reactive oxygen species (ROS) by eight selected coumarin derivatives under oxidative conditions. Esculetin was the most potent radical scavenger among the eight tested compounds. Our results suggest that the number of hydroxyl groups on the ring structure of coumarins is correlated with the effects of ROS suppression. We also investigated the effect of the derivatives on the inhibition of xanthine oxidase (XO) activity, and the structure-activity relationships (SARs) of these derivatives against XO activity were further examined using computer-aided molecular modeling. All determined derivatives competitively inhibited XO. The results of the structure-based molecular modeling exhibited interactions between coumarins and the molybdopterin region of XO. The carbonyl pointed toward the Arg880, and the ester O atom formed hydrogen bonds with Thr1010. Esculetin, which bears two hydroxyl moieties on its benzene rings, had the highest affinity toward the binding site of XO, and this was mainly due to the interaction of 6-hydroxyl with the E802 residue of XO. The hypoxanthine/XO reaction in the DMPO-ESR technique was used to assess the combined effect on enzyme inhibition and ROS suppression by these coumarins, and the results showed that esculetin was the most potent agent among the tested compounds. We further evaluated the effects of the test compounds on living cells, and esculetin was still the most potent agent at protecting cells against ROS-mediated Aβ-damage among the tested coumarins.

KW - Coumarin

KW - Esculetin

KW - Molecular modeling

KW - ROS

KW - Xanthine oxidase

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