Benzotropolone inhibitors of estradiol methylation: Kinetics and in silico modeling studies

Joshua D. Lambert, Dapeng Chen, Ching Y. Wang, Ni Ai, Shengmin Sang, Chi Tang Ho, William J. Welsh, Chung S. Yang

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Natural and synthetic benzotropolone compounds were assessed in vitro for their ability to inhibit hydroxyestradiol methylation by catechol-O- methyltransferase (COMT). The compounds were also modeled in silico with a homology model of human COMT. Purpurogallin (1), purpurogallin carboxylic acid (2), and theaflavin-3,3′-digallate (6) were the most potent inhibitors of 2-hydroxy and 4-hydroxyestradiol methylation (IC50 0.22-0.50 μM). Compounds 1 and 6 decreased the Vmax and increased the Km of COMT, indicating a mixed-type inhibition. Compounds 1 and 2 bound to COMT by inserting the six-membered ring of the benzotropolone into the active site. Decreased acidity of the hydroxyl groups on this ring or increased bulkiness reduced potency. Compound 6 bound by inserting the galloyl ester into the active site, which allowed the compound to overcome increased bulkiness and resulted in restored potency. Further studies are needed to determine the impact in vivo of COMT inhibition by these compounds.

Original languageEnglish (US)
Pages (from-to)2501-2507
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number7
DOIs
StatePublished - Apr 1 2005

Fingerprint

Catechol O-Methyltransferase
Methylation
Computer Simulation
Estradiol
Kinetics
Catalytic Domain
Carboxylic Acids
Acidity
Hydroxyl Radical
Inhibitory Concentration 50
Esters
benzotropolone

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Lambert, Joshua D. ; Chen, Dapeng ; Wang, Ching Y. ; Ai, Ni ; Sang, Shengmin ; Ho, Chi Tang ; Welsh, William J. ; Yang, Chung S. / Benzotropolone inhibitors of estradiol methylation : Kinetics and in silico modeling studies. In: Bioorganic and Medicinal Chemistry. 2005 ; Vol. 13, No. 7. pp. 2501-2507.
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Benzotropolone inhibitors of estradiol methylation : Kinetics and in silico modeling studies. / Lambert, Joshua D.; Chen, Dapeng; Wang, Ching Y.; Ai, Ni; Sang, Shengmin; Ho, Chi Tang; Welsh, William J.; Yang, Chung S.

In: Bioorganic and Medicinal Chemistry, Vol. 13, No. 7, 01.04.2005, p. 2501-2507.

Research output: Contribution to journalArticle

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