Aromatase Inhibition by 4β, 5β-Epoxides of 16α-Hydroxyandrostenedione and Its 19-Oxygenated Analogs, Potential Precursors of Estriol Production in the Feto-Placental Unit

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概要

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• To gain insight into the nature of the substrate binding site and the catalytic function of aromatase, we studied the inhibition of androstenedione aromatization by 4β,5β-epoxy-16α-hydroxyandrostenedione (4) and its 19-hydroxy and 19-oxo derivatives, 5 and 6, as well as the biochemical aromatization of these steroids in human placental microsomes. The 19-methyl and 19-oxo compounds, 4 and 6, were weak competitive inhibitors of aromatase, with apparent Ki values of 246 μM and 270 μM, respectively, whereas the 19-hydroxy compound 5 inhibited aromatase in a non-competitive manner with the Ki of 135 μM. The 19-methyl compound 4 inactivated aromatase in a time-dependent manner with kinact of 0.213 min−1 in the presence of NADPH in air, but the other two did not cause it. The conversion of the three epoxides into estrogen, as well as 19-oxygenation of 19-methyl steroid 4 with human placental microsomes in the presence of NADPH in air, were not detected by gas chromatography-mass spectrometry. The present results are consistent with the two binding sites theory in the active site of aromatase.

• 公益社団法人　日本薬学会の論文
• 2002-12-01

著者

• Yoshimura Akiko

  Tohoku Pharmaceutical University

• Yoshimura Akiko

  Tohoku College Of Pharmacy

• NUMAZAWA Mitsuteru

  Tohoku College of Pharmacy

• WATARI Yoko

  Tohoku Pharmaceutical University

• MATSUZAKI Hisao

  Tohoku Pharmaceutical University

関連論文

• Synthesis and GC-MS of 6-Alkylestradiols, Possible Aromatase Reaction Products of 6-Alkylandrostenediones
• Kinetic Analysis of Reversible Inhibition of 16α-Hydroxyandrostenedione Aromatization in Human Placental Microsomes by Suicide Substrates of Androstenedione Aromatization
• Gas Chromatography-Mass Spectrometric Determination of Activity of Human Placental Aromatase Using 16α-Hydroxyandrostenedione as a Substrate
• Synthesis of 19-Oxygenated 4β, 5β-Epoxy Derivatives of 16α-Hydroxyandrostenedione as Mechanistic and Catalytic Probes for Aromatase Reaction
• C(10)-C(19) Bond Cleavage Reaction of 19-Oxygenated Androst-4-ene-3,6-dione Steroids under Various Conditions
• Improved Synthesis and Molecular Modeling of 4β,19-Dihydroxyandrost-5-en-17-one, an Excellent Inhibitor of Aromatase
• Aromatization of 19-Oxygenated Androst-4-ene-3,6,17-triones with Human Placental Microsomes
• Synthesis and Biochemical Studies of 19-Oxygenated Derivatives of 6α- and 6β-Methylandrostenediones as Catalytic Probes for the Active Site of Aromatase
• Diels-Alder Reaction of 2(1H)-Pyridones Acting as Dienes
• Cycloaddition of 2(1H)-Pyridones Having a Methoxycarbonyl Group to 1, 3-Butadiene Derivatives
• Diels-Alder Reaction of 1, 3-Butadiene Derivatives with 1-Methyl-2(1H)-quinolones Having an Electron-Withdrawing Group at the 4-Position
• Diels-Alder Cycloadditions of 2(1H)-Quinolones Having an Electron-Withdrawing Group at the 3-Position Acting as Dienophiles with Dienes
• Diels-Alder Reactions of Nitro-2(1H)-pyridones with 2, 3-Dimethyl-1, 3-butadiene
• Synthesis of Phenanthridones Using Diels-Alder Reactions of 4-Substituted 2(1H)-Quinolones Acting as Dienophiles
• 19-Oxygenation of C_-Steroids with an A, B-Ring Enone Structure, Competitive Inhibitors of Estrogen Biosynthesis, with Human Placental Aromatase
• Novel Diels-Alder Reaction of 4-Nitro-1(2H)-isoquinolones
• Aromatase Inhibition by 4β, 5β-Epoxides of 16α-Hydroxyandrostenedione and Its 19-Oxygenated Analogs, Potential Precursors of Estriol Production in the Feto-Placental Unit
• Cycloadditions of 1-Substituted 1,3-Butadienes with 4- or 3-Substituted 2(lH)-Quinolones Acting as Dienophiles
• Identification of 16α, 19-Dihydroxyandrostenedione in the Serum of Pregnant Women by Gas Chromatography-Mass Spectrometry
• Studies on the 1,4-Oxazepine Ring Formation Reaction Using the Molecular Orbital Method
• Studies on the Reaction of Benzo[X]quinoline N-Oxides (X=f, h, and g)with Methylsulfinyl Carbanion Using the Semi-empirical Molecular Orbital Method. Liberation of the N-Oxide Group
• Synthesis of Deuterium-Labeled Androst-5-ene-17β, 19-diol and Its 4-Ene Isomer as Internal Standards for the Determination of the 19-Oxygenation of Aromatase Inhibitors Using GC-MS
• Stereochemistry of NaBH_4 Reduction of a 19-Carbonyl Group of 3-Deoxy Androgens. Synthesis of [19S-^3H]- and [19R-^3H]-Labeled Aromatase Inhibitors Having a 19-Hydroxy Group
• Isotope Effects in the Reaction of Benzo[h]quinoline N-Oxides with Methylsulfinyl Carbanion Examined by ab Initio Molecular Orbital Methods
• DETERMINATION OF AROMATASE ACTIVITY INVOLVED IN THE FORMATION OF ESTRIOL WITH HUMAN PLACENTAL MICROSOMES AND ITS KINETIC PROPERTIES
• Synthesis of 5(6H)-Phenanthridones Using Diels-Alder Reaction of 3-Nitro-2(1H)-quinolones Acting as Dienophiles
• Formation of 17β-Alkoxy-16-keto Steroids by Reaction of 16α-Hydroxy-17-keto and 17β-Hydroxy-16-keto Steroids with Trimethylsilyl Iodide in the Presence of Alkyl Alcohols
• Structure-Activity Relationships of Estrogen Derivatives as Aromatase Inhibitors. Effects of Heterocyclic Substituents
• Mechanistic Studies of Deoxygenation of Steroidal Ring-D 16,17-Ketols with trimethylsilyl Iodide
• Deoxygenation of Steroidal Ring-D 16,17-Ketols with Trimethylsilyl Iodide
• Aromatase Inactivation by a Suicide Substrate, Androst-5-ene-4,7,17-trione : The 5β, 6β-Epoxy-19-oxo Derivative, as a Possible Reactive Electrophile Irreversibly Binding to the Active Site
• 19-Oxygenated Derivatives of Androst-4-ene-6,17-dione and Androst-5-ene-4,17-dione as Catalytic Probes for the Active Site of Aromatase
• Gas Chromatography-Mass Spectrometric Study of 19-Oxygenation of the Aromatase Inhibitor 19-Methylandrostenedione with Human Placental Microsomes(Analytical Biochemistry)
• Reduction of 1,4-Dien-3-one Steroids with LiAl^2H_4 or NaB^2H_4 : Stereospecific Deuterium-Labeling at the C-1α Position of a 4-En-3-one Steroid
• Studies of the Time-Dependent Inactivation of Aromatase by 4β, 5β-Epoxy-6-one and 5β, 6β-Epoxy-4-one Steroids under Various Conditions
• Synthesis and Biochemical Properties of 6-Bromoandrostenedione Derivatives with a 2,2-Dimethyl or 2-Methyl Group as Aromatase Inhibitors(Medicinal Chemistry)

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