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

doi:10.1016/j.bmc.2005.01.037

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 journal › Article › peer-review

11 Scopus citations

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 V_max and increased the K_m 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 language	English (US)
Pages (from-to)	2501-2507
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	13
Issue number	7
DOIs	https://doi.org/10.1016/j.bmc.2005.01.037
State	Published - Apr 1 2005

All Science Journal Classification (ASJC) codes

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

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10.1016/j.bmc.2005.01.037

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title = "Benzotropolone inhibitors of estradiol methylation: Kinetics and in silico modeling studies",

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.",

author = "Lambert, {Joshua D.} and Dapeng Chen and Wang, {Ching Y.} and Ni Ai and Shengmin Sang and Ho, {Chi Tang} and Welsh, {William J.} and Yang, {Chung S.}",

note = "Funding Information: This work was supported by NIH grant P01 CA 88961 (to C.S.Y.).",

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AU - Lambert, Joshua D.

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AU - Ai, Ni

AU - Sang, Shengmin

AU - Ho, Chi Tang

AU - Welsh, William J.

AU - Yang, Chung S.

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PY - 2005/4/1

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N2 - 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.

AB - 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.

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

Abstract

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