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
スポンサーリンク
概要
- 論文の詳細を見る
In order to understand the mechanism involved in the aromatase inactivation by androst-5-ene, 4,7,17-trione (4), a suicide substrate of aromatase, 5β, 6β-epoxyandrosta-4,7,17,19-tetraone (6) was synthesized as a candidate for a reactive electrophile involved in irreversible binding to the active site of aromatase upon treatment of 19-oxo-5-ene steroid 5 with hydrogen peroxide in the presence of NaHCO_3. The epoxide 6 was a competitive inhibitor of human placental aromatase (K_1=34 μM); moreover, it inactivated the enzyme in an active-site-directed manner in the absence of NADPH (K_1=36 μM, a rate constant for inactivation (k_<inact>)=0.027 min^<-1>). NADPH stimulated the inactivation rate, but the substrate androst-4-ene-3,17-dione blocked the inactivation. A nucleophile, L-cysteine, did not cause a significant change in the inactivation. When both the epoxide 6 and its 19-methyl analog 7 were subjected separately to a reaction with N-acetyl-L-cycteine in the presence of NaHCO_3,the 19-oxo compound 6 disappeared from the reaction mixture more rapidly (t/_<1/2>=6.0 min) than the 19-methyl analog 7 (t_<1/2>=16 min). On the basis of these results, it is suggested that the 5β, 6β-epoxy-19-oxo steroid 6 may be the reactive electrophile that alkylates a nucleophilic residue of the amino acid of the active site.
- 公益社団法人日本薬学会の論文
- 1997-05-15
著者
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
- 19-Oxygenation of C_-Steroids with an A, B-Ring Enone Structure, Competitive Inhibitors of Estrogen Biosynthesis, with Human Placental Aromatase
- Aromatase Inhibition by 4β, 5β-Epoxides of 16α-Hydroxyandrostenedione and Its 19-Oxygenated Analogs, Potential Precursors of Estriol Production in the Feto-Placental Unit
- Identification of 16α, 19-Dihydroxyandrostenedione in the Serum of Pregnant Women by Gas Chromatography-Mass Spectrometry
- 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
- DETERMINATION OF AROMATASE ACTIVITY INVOLVED IN THE FORMATION OF ESTRIOL WITH HUMAN PLACENTAL MICROSOMES AND ITS KINETIC PROPERTIES
- 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)