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Organic Chemical Investigation of Novel Biologically Active Compounds, Syntheses and Reactions, Evaluation of Biological Activities.

Research Project

Project/Area Number 09672161
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionTeikyo University

Principal Investigator

TAKAYAMA Hiroaki  Teikyo University, Pharmaceutical Sciences, Professor, 薬学部, 教授 (00012609)

Co-Investigator(Kenkyū-buntansha) SUHARA Yoshitomo  Teikyo University, Pharmaceutcial Sciences, Research Associate, 薬学部, 助手 (30297171)
FUJISHIMA Tosie  Teikyo University, Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (90286980)
SUZUKI Takayoshi  Teikyo University, Pharmaceutical Sciences, Assistant Professor, 薬学部, 講師(専) (10119589)
KONNO Katsuhiro  Teikyo University, Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (40215471)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsSolitary Wasp / Neuro-venom / Peptide / Mass Spectrometry / Synthesis of Active Vitamin D Derivatives / Conformation Analysis / Potency of HL-60 Differientiation / Vitamin D Receptor Affinity / ビタミンD誘導体合成 / ビタミンD活性 / 電解酸化 / 縮環スルホレン / デイールス・アルダー反応
Research Abstract

(1) The specimens of female solitary wasps were collected in Sagamiko, Ibaraki, and Kyoto. The lyophilized venom sacs were extracted and subjected repeatedly to reverse-phase HPLC, accompanied by testing neuro activity using neuromuscular preparations of walking leg of lobster, to give purified venoms. The structures of the isolated venoms were estimated mainly by the leading tequniques of mass spectrometry, MALDI-TOF-CID method andlor Ladder sequence method, and finally determined by solid phase synthesis based on the Fmoc- L-amino acid strategy. Eumenine mastoparan-AF was isolated from the venom of the Eumenine wasp. Anterhynchium flavomarginatum micado. Both the structure and theneuroactivity were similar to those ofmastoparan of a hornet wasp. Novel and uniqueneurotoxins, alpha- and beta-pompilidotoxins were isolated from the venoms of the Pompilidaewasps, Anoplius samariensis and Batozonellus maculifrons, These venoms potentiatessynaptic transmission of lobster leg muscle by the p … More resynaptic mechanisms.
(2) All eight possible A-ring diastereomers of both 2-methyl- and 4-methyl- 1,25-dihydroxyvitamin D_3 were synthesized to investigate the relationship of the A-ring conformation [alpha-form<double arrow>beta-form (active form ; lalpha-OH is equatorial)] to the biological activities C/DR affinity as an index). Also, all eight possible A- ring diastereomers of 2-methyl-20-epi-l, 25-dihydroxyvitamin D3 were synthesized. Introduction of 2-methyl- and 4-methyl-group would result in equibrium shift to either one way in certain extent. Starting from either (S)- or (R)-isomer of methyl 3-hydroxy-2-methyl-propionate, the A-ring portions(enynes) were obtained in good overall yields, which were subsequently coupled with the CD-ring-side chain portion by the Trost' Procedure to give the 2-methyl analogues. Similarly, starting from 1,3-propanediol, the A-ring portions of 4-methyl analogues were prepared as racemic forms, which, after separation, were subjected to the same procedure to give 4-methyl steroisomers. In VDR affinity using bovine thymus, the potency of 2-methyl isomers was highly dependent on the stereo-chemistry of the A-ring substituents. Thus, 2alpha-Me-1alpha-OH,3betaisomer showed 4-fold higher affinity than natural lalpha, 25-(OH)_2-D_3 (normalized, and so forth). This isomer also exhibited 4-fold higher potency in Ca mobilization, and 2-fold higher potency in HL-60 cell differentiation. Furthermore, double modified steroisomer of A-ring and side chain, 2alpha-Me-20-epi-1alpha, 25-(OH) _2-D_3 showed 12 fold higher in VDR affinity, 7 fold higher in Ca mobilization and 590 times higher potency in HL-60 cell differentiation, which is the most potent analogue reported to date. In contrast to 2-methyl series, VDR affinities of all diastereomers of 4-methyl-1,25-(OH) _2-D_3 were less than 10^21-10^3. From the conformational analysis by NMR spectroscopy, chair-wform is predominant in A-ring coconformation of 2alpha-Me-1alpha, 25-(OH) _2-D_3, while 2beta-Me isomer prefer half-boat-beta-form in A-ring. Further synthetic (various substituents in 2-position, conformational restricted) and biological (apotosis, transcriptional potency) studies are in progress. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] K.Konno, H.Takayama,: "α-Pompilidotoxin (α-PMTX), a novel neurotoxin from the venom of a solitary wasp, facilitates transmission in the crustacean neuromuscular synapse." Neuroscience Letters,. 238. 99-102 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Konno, H.Takayama: "Isolation and structure of Pompilidotoxins, novel peptide neurotoxins in solitary wasp venoms." Biochem. Biophy. Res. Commun.,. 250. 612-616 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] A.Harsch, K.Konnno,: "Effects of a pompilidotoxin on synchronized firing in networks of rat cortical neurons." Neuroscience Letters,. 252. 49-52 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] S.Maki, H.Takayama,: "Selective oxidation of terminal isopropyl groups to tertiary alcohols by electrochemical methodology." Tetrahedron Letters,. 38(40). 7067-7070 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Konno, H.Takayama,: "A novel and practical route to A-ring enyne synthon for 1α, 25-dihydroxy-vitamin D_3 analogs : Synthesis of A-ring diastereomers of 1α, 25-dihydroxy vitamin D_3 and 2-methyl-1,25-dihydroxyvitamin D_3." Bioorg. & Med. Chem. Letters.8(2). 151-156 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Fujishima, H.Takayama,: "Synthesis and biological activity of 2-methyl-20-epi analogues of 1α, 25-dihydroxyvitamin D_3." Bioorg. & Med. Chem. Letters,. 8(16). 2145-2148 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Iwasaki, H, Takayama,: "Improved and efficient synthesis of 1α-hydroxy-[6-^2H] and 1α-hydroxy-[6, 19, 19-^2H] vitamin D_3 derivatives." Steroid,. (in press). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Suzuki, H.Takayama,: "Synthesis of 4-substituted 3,5-dihydro-1H…thieno[3,4-c]pyrrole 2,2-dioxides and their Diels-Alder reactions." Heterocycles,. 46. 199-202 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Konno, H.Takayama,: "A novel approach to functionalized polycyclic systems ; Synthesis of tetracyclic compounds by sequential rearrangement-cycloaddition reactions of 7-oxa-2,3-dimethylenenorbornene derivative." Heterocycles,. 47(1). 167-170 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Konno, H.Takayama et.al.: "alpha-Pompilidotoxin (alpha-PMTX), a novel neurotoxin from the venom of a solitary wasp, facilitates transmission in the crustacean neuromuscular synapse" Neuroscience Letters. 238. 99-102 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Konno, H.Takayama et.al.: "solation and structure of Pompilidotoxins, novel peptide neurotoxins in solitary wasp venoms." Biochem.Biophy.Res Commun.250. 612-616 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] A.Harsch, K.Konno, et.al.: "Effects of a-pompilidotoxin on synchronized firing in networks of rat ortical neurons." Neuroscience Letters. 252. 49-52 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] S.Maki, H.Takayama, et.al.: "Selective oxidation of terminal isopropy1 groups to tertiary alcohols by electrochemical methodology." Tetrahedron Letters. 38 (40). 7067-7070 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Konno, H.Takayama, et.al.: "A novel and practical route to A-ring enyne synthon for 1 alpha, 25-dihydroxy vitamin D_3 analogs : Synthesis of A-ring diastereomers-of alpha, 25-dihydroxy vitamin D_3 and 2-methyl-1,25-dihydroxyvitamin D_3." Bioorg.& Med.Chem.Letters. 8 (2). 151-156 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Fujishima, H.Takayama, et., al.: "Synthesis and biological activity of 2-methyl-20-epi analogues of alpha, 25-dihydroxyvitamin D_3." Bioorg.& Med.Chem.Letters. 8 (16). 2145-2148 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Iwasaki, H.Takayama, et.al.: "Improved and efficient synthesis of 1alpha-hydroxy- [6-^2H] and 1alpha-hydroxy- [6,19,19-^2H] vitamin D_3 derivatives." Steroid. (in press.). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Suzuki, H.Takayama, et.al.: "Synthesis of 4-substituted 3,5-dihydro-1H--thieno [3,4-c] pyrrole 2,2-dioxides and their Diels-Alder reactions." Heterocycles. 46. 199-202 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Konno, H.Takayama, et.al.: "A novel approach to functionalized polycyclic systems ; Synthesis of etracyclic compounds by sequential rearrangement-cycloaddition reactions of 7-oxa-2,3-dimethylenenorbornene derivative." Heterocycles. 47 (1). 167-170 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Konno,H.Takayama et.al.,: "Isolation and structure of Pompilidotoxins,novel peptide neurotoxins in solitary wasp venoms." Biochem.Biophy.Res Commun.250. 612-616 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] A.Harsch,K.Konno,et.al.,: "Effects of a-pompilidotoxin onsynchronized firing in networks of rat cortical neurons." Neuroscience Letters,. 252. 49-52 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Fujishima,H.Takayama,et.,al.,: "Synthesis and biological activity of 2-methyl-20-epi analogues of 1α,25-dihydroxyvitamin D_3." Bioorg.& Med.Chem.Letters,. 8(16). 2145-2148 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Iwasaki,H.Takayama,et.al.,: "Improved and efficient synthesis of 1α-hydroxy-[6-^2H]and 1α-hydroxy-[6,19,19-^2H]vitamin D_3 derivatives." Steroid. (in press)(MS/10061). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Konno,H.Takayama,N.Kawai et al.: "α-Pompilidotoxin(α-PMTX)a novel neurotoxin from the venom of a solitary wasp,facilitates transmission in the crustacean neuromuscular synapse." Neuroscience Letters. 238. 99-102 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Konno,T.Fujishima,H.Takayama,et al.: "A novel and practical route to A-ring enyne synthon for 1 α,25-dihydroxyvitamin D_3 analogs:Synthesis of A-ring diastereomers of 1 α,25-dihydroxyvitamin D_3 and --------" Bioorg.& Med.Chem.Letters. 8(2). 151-156 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] S.Maki,K.Konno,H.Takayama: "Selective oxidation of terminal isopropyl groups to tertiary alcohols by electrochemical methodology." Tetrahedron Letters. 38(40). 7067-7070 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] T.Suzuki,H.Takatama,et al.: "Synthesis of 4-substituted 3,5-dihydro-1H-thieno[3,4-c]pyrrole 2,2-dioxides ans their Diels-Alder reactions." Heterocycles. 46. 199-202 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Konno,H.Takayama,et al.: "A novel approach to functionalized polycyclic systems;Synthesis of tetracyclic compounds by sequential rearrangement-cycloaddition reactions of 7-oxa-2,3- ---------" Heterocycles. 47(1). 167-170 (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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