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Study on aromatase reaction mechanism using the inhibitors as probes

Research Project

Project/Area Number 15590066
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionTohoku Pharmaceutical University

Principal Investigator

NUMAZAWA Mitsuteru  Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (90006338)

Co-Investigator(Kenkyū-buntansha) NAGAOKA Masao  Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (00104084)
WATARI Yoko  Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手
HANDA Wakako  Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手
TAKAHASHI Madoka  Tohoku Pharmaceutical University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsAromatase / Inhibitor / Anti-breast cancer agent / Hydroxylation / Stereochemistry / Structure-activity relationship / Suicidal substrate / Carbon -carbon bond cleavage reaction / 炭素-炭素結合切断 / 不活性化機構 / 阻害活性 / 19-置換3-デオキシアンドロゲン / 重水素標識 / 同位体効果 / 芳香核化反応 / ヒト胎盤ミクロゾーム / 3-デオキシアンドロゲン / トリチウム標識
Research Abstract

In order to gain insight into the aromatase reaction mechanisms, we explored aromatase reactions of the powerful aromatase inhibitors 3-deoxyandrogens, 3-deoxyandrostenedione (1)and 3-deoxydehydroepiandrosterone (2), in relation to the stereomechanisms of the 19-oxygenation and the C(10)-C(19)bond cleavage reaction.
1.Treatment of the 19-oxo derivatives of compounds 1 and 2, steroids 5 and 6, with NaB^2H_4 or NaB^3H_4 produced the corresponding [19,19^<-2>H_2] 19-ols 3 and 4 or [19R^<-3>H]-ols 3 and 4 as well as their [19S^<-3>H] isomers.
2.Incubation of [19, 19^<-2>H_4] 3 and 4 with human placental microsomes in the presence of NADPH produced the 19-oxo metabolites 5 and 6, respectively, where the deuterium isotope effect was not observed in each case.
3.[19R^<-3>H]- and [19S^<-3>H] 3 and 4 were also incubated with the microsomes described above, and ^3H_2O and ^3HCOOH released into the incubation mixtures were analyzed. The results indicate that a 19-pro-R hydrogen in stereospecifically eliminated in the conversion of Steroid 4 into the 19-oxo steroid 6 whereas a selectivity of 75 : 25 for pro-R : pro-S is observed in the case of steroid 3. In both cases, the C(10)-C(19) bond cleavage reaction, yielding ^3HCOOH, was established.
4.Structure-activity relationships of 4-substituted derivatives of inhibitor 1,2α-substituted ADs as well as 2, 4, or 6-substituted estrogens as aromatase inhibitors were also studied in relation to elucidate the spatial nature of the active site of aromatase.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (30 results)

All 2005 2004 2003 Other

All Journal Article (27 results) Publications (3 results)

  • [Journal Article] Aromatase Reaction of 3-Deoxyandrogens : Steric Mode of the C-19 Oxygenation and Clevage of the C_<10>-C_<19> Bond by Human Placental Aromatase.2005

    • Author(s)
      沼沢 光輝
    • Journal Title

      Biochemistry 44

      Pages: 10839-10845

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Structure Activity Relationships of 2-,4-, or 6-Substituted Estrogens as Aromatase Inhibitors.2005

    • Author(s)
      沼沢 光輝
    • Journal Title

      J. Steroid Biochem. Molec. Biol. 96

      Pages: 51-58

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Gas Chromatography-Mass Spectrometric Analysis of Oxidative Reactions of [19, 19-^2H_2]19-Hydroxy-3-deoxy Androgens by Placental Aromatase. Absence of a Deuterium-Isotope Effect.2005

    • Author(s)
      沼沢 光輝
    • Journal Title

      Steroids 70

      Pages: 831-839

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Structure-Activity Relationships of 2α-Substituted Androstenedione Analogs as Aromatase Inhibitors and Their Aromatization Reactions.2005

    • Author(s)
      沼沢 光輝
    • Journal Title

      J. Steroid Biochem. Molec. Biol. 97

      Pages: 353-359

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Aromatase Reaction of 3-Deoxy Androgens : Steric Mode of the C-19 Oxygenation and Clevage of the C_<10>-C_<19> Bond by Human Placental Aromatase.2005

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      Biochemistry 44

      Pages: 10839-10882

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Structure-Activity Relationships of 2-,4, or 6-Substituted Estrogens as Aromatase Inhibitors.2005

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      J Steroid Biochem.Molec.Biol. 96

      Pages: 51-58

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Gas Chromatography-Mass Spectrometric Analysis of Oxidative Reactions of [19,19^<-2>H_2] 19-Hydroxy-3-deoxy Androgens by Placental Aromatase. Absence of a Deuterium-Isotope Effect.2005

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      Steroids 70

      Pages: 831-839

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Structure-Activity Relationships of 2α-Substituted Androstenedione Analogs as Aromatase Inhibitors and Their Aromatization Reactions.2005

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      J.Steroid Biochem.Molec.Biol. 97

      Pages: 353-359

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Aromatase reaction of 3-deoxyandrogens : steric mode of the C-19 oxygenation and cleavage of the C_<10>-C_<19> bond by human placental aromatase2005

    • Author(s)
      沼沢 光輝
    • Journal Title

      Biochemistry 44

      Pages: 10839-10845

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Structure-activity relationships of 2-,4-, or 6-substituted estrogens as aromatase inhibitors2005

    • Author(s)
      沼沢 光輝
    • Journal Title

      J.Steroid Biochem.Molec.Biol 96

      Pages: 51-58

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Gas chromatography-mass spectrometric analysis of oxidative reactions of [19,19-^2H_2]19-hydroxy-3-deoxy androgens by placental aromatase. Absence of a deuterium-isotope effect2005

    • Author(s)
      沼沢 光輝
    • Journal Title

      Steroids 70

      Pages: 831-839

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Structure-activity relationships of 2α-substituted androstenedione analogs as aromatase inhibitors and their aromatization reactions2005

    • Author(s)
      沼沢 光輝
    • Journal Title

      J.Steroid Biochem.Molec.Biol 97

      Pages: 353-359

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 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.2004

    • Author(s)
      沼沢 光輝
    • Journal Title

      Chem. Pharm. Bull. 52

      Pages: 722-726

    • NAID

      110003615648

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] C(10)-C(19) Bond Cleavage Reaction of 19-oxygenated Androst-4-ene-3,6-dione Steroids under Various Conditions.2004

    • Author(s)
      沼沢 光輝
    • Journal Title

      Chem. Pharm. Bull. 52

      Pages: 983-985

    • NAID

      110003615701

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis and Biochemical Properties of 6-Bromoandrostenedione Derivatives with a 2,2-Dimethyl or 2-Methyl Group as Aromatase Inhibitors.2004

    • Author(s)
      沼沢 光輝
    • Journal Title

      Biol. Pharm. Bull 52

      Pages: 1878-1882

    • NAID

      110003608716

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Stereochemistry of NaBH_4 Reduction of a 19-Carbonyl Group of 3-Deoxy Androgens. Synthesis of [19S^<-3>H]-and [19R^<-3>H]-Labeled Aromatase Inhibitors Having a 19-Hydroxy Group.2004

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      Chem.Pharm.Bull. 52

      Pages: 722-726

    • NAID

      110003615648

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] C(10)-C(19) Bond Cleavage Reaction of 19-Oxygenated Androst-4-ene- 3,6-done Steroids under Various Conditions.2004

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      Chem.Pharm.Bull. 52

      Pages: 983-985

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis and Biochemical Properties of 6-Bromoandrostenedione Derivatives with a 2,2-Dimethyl or 2-Methyl Group as Aromatase Inhibitors.2004

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      Biol.Pharm.Bull. 27

      Pages: 1878-1882

    • NAID

      110003608716

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Stereochemistry of NaBH_4 reduction of a 19-carbonyl group of 3-deoxy androgens. Synthesis of [19R-^3 H]-labeled aromatase inhibitors having a 19-hydroxy group2004

    • Author(s)
      沼澤 光輝
    • Journal Title

      Chem.Pharm.Bull. 52

      Pages: 722-726

    • Related Report
      2004 Annual Research Report
  • [Journal Article] C(10)-C(19) Bond cleavage reaction of 19-oxygenated androst-4-ene-3,6-dione steroids under various conditions2004

    • Author(s)
      沼澤 光輝
    • Journal Title

      Chem.Pharm.Bull. 52

      Pages: 983-985

    • NAID

      110003615701

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Synthesis and biochemical properties of 6-brompandrostenedione derivatives with a 2,2-dimethyl or 2-methyl group as aromatase inhibitors2004

    • Author(s)
      沼澤 光輝
    • Journal Title

      Biol.Pharm.Bull. 27

      Pages: 1878-1882

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Analysis of Reversibli Inhibition of 16α-Hydroxyandrostenedione Aromatization in Human Placental Microsomes by Suicide Substrates of Androstenedione Aromatization.2003

    • Author(s)
      沼沢 光輝
    • Journal Title

      Biol. Pharm. Bull. 26

      Pages: 890-892

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Probing the Active Site of Aromatase with 2-Methyl-substituted Androstenedione Analogs.2003

    • Author(s)
      沼沢 光輝
    • Journal Title

      Steroids 68

      Pages: 503-513

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Structure-Activity Relationships of 3-Deoxy Androgens as Aromatase Inhibitors. Synthesis and Biochemical Studies of 4-Substituted 4-ene and 5-ene Steroids.2003

    • Author(s)
      沼沢 光輝
    • Journal Title

      Steroids 68

      Pages: 533-542

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Analysis of Reversible Inhibition of 16α-Hydroxyandrostenedione Aromatization in Human Placental Microsomes by Suicide Substrates of Androstenedione Aromatization.2003

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      Biol.Pharm.Bull. 26

      Pages: 890-892

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Probing the Active Site of Aromatase with 2-Methyl-substituted Androstenedione Analogs.2003

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      Steroids 68

      Pages: 503-513

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Structure-Activity Relationships of 3-Deoxy Androgens as Aromatase Inhibitors. Synthesis and Biochemical Studies of 4-Substituted 4-ene and 5-ene Steroids.2003

    • Author(s)
      Mitsuteru Numazawa, et al.
    • Journal Title

      Steroids 68

      Pages: 533-542

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Publications] 沼沢 光輝: "Kinetic analysis of reversible inhibition of 16α-hydroxyandrostenedione aromatization in human placental microsomes by suicide substrates of androstenedione aromatization"Biol.Pharm.Bull.. 26. 890-892 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 沼沢 光輝: "Probing the active site of aromatase with 2-methyl-substituted androstenedione analogs"Steroids. 68. 503-513 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 沼沢 光輝: "Structure-activity relationships of 3-deoxy androgens as aromatase inhibitors. synthesis and biochemical studies of 4-substituted 4-ene and 5-ene steroids"Steroids. 68. 533-542 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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