1998 Fiscal Year Annual Research Report

実用化を指向した高効率且つ高選択的な抗腫瘍活性プソイド・ペプチド医薬品の開発

Research Project

Project/Area Number	09557179
Research Institution	Kyoto University
Principal Investigator	井深俊郎京都大学, 薬学研究科, 教授 (80025692)
Co-Investigator(Kenkyū-buntansha)	細谷亮京都大学, 医学研究科, 講師 (00139908) 玉村啓和京都大学, 薬学研究科, 講師 (80217182) 大高章京都大学, 薬学研究科, 助教授 (20201973) 藤井信孝京都大学, 薬学研究科, 教授 (60109014) 山本嘉則東北大学, 理学研究科, 教授 (60029519)
Keywords	有機銅化合物 / ボンベシン・アンタゴニスト / トリプトフアン・イソスター / アルケンイソスター / アジリジニル・エノエイト / ビニルアジリジン / 有機パラジウム化合物 / アリルパラジウム錯体
Research Abstract	1. パラジウム等の触媒量の遷移金属による異性化により不要な2-ビニル・アジリジン誘導体も必要な立体化学を持った2-ビニル・アジリジンに変換できる最適な方法を見い出すことが出来た。またアミノ基を有するアリルカルボナートにパラジウム等の触媒量の遷移金属を作用してアジリジン閉環を試みたところ、幸いにも目的物を高効率で合成できることを明らかにした。触媒量の遷移金属による目的の立体化学を持った異性体への変換が広範囲のイソスター合成に可能か否かに関し更に詳細な検討を加えたところ、種々のアミノ酸から出発し、様々なジペプチドイソスターがキラルなアジリジン誘導体を経て高効率かつ立体特異的合成できることも明らかにした。 2. 望ましくない立体化学を有するγ,δ-エピミノ-α,β-不飽和エステル類を触媒量のパラジウムを用いて必要な立体化学を有する化合物に変換する方法をほぼ確立することが出来た。通常の有機銅では合成困難なイソスターに関しては、有機銅による還元反応とアルキル化を連続的に行うことにより解決出来ることを明らかにした。更には亜鉛複合系試薬による合成ルートについて検討を加えたところ、本方法についても極めて有望であることが判明した。 3. 報告者らが開発した方法により大多数のイソスターの合成は可能であるがアスパラギン酸、システイン、およびメチオニン等を含むイソスターの合成は困難を伴う。これについては種々の検討を行ったところ、立体特異的にアルケン・イソスター合成が出来ること明らかにできた。 4. ジペプチドイソスターを組み込んだ物質を合成した。例えば、ボンベシン・アンタゴニスト類のアンタゴニスト活性は極めて高いことも判明した。またRas-Farnesyl化阻害ペブチド等の性抗腫瘍活性検討も現在進行中である。

Research Products

(18 results)

All Other

All Publications (18 results)

[Publications] Hirokazu Tamamura: "Unambiguous synthesis of stromal cell-derived factor-1 by regioselective disulfide bond formation using DMSO-aqueous HCl system" Chemical Communications. 1号. 151-152 (1998)
[Publications] Hirokazu Tamamura: "Effective lowly cytotoxic analogs of an HIV-cell fusion inhibitor,T22([Tyr5,12,Lys7]-polyphemusin II)" Bioorganic & Medicibnal Chemistry. 6巻. 231-238 (1998)
[Publications] Hirokazu Tamamura: "Convenient one-pot synthesis of cystine-containing peptides using the trimethylsilyl chloride-dimethylsulfoxide/trifluoroacetic acid system." J.Chem.Soc.,. 495-500 (1998)
[Publications] Toshiro Ibuka: "The Aza-Payne Rearrangement: A Synthetically Valuable Equlibration" Chemical Society Reviews. 27巻. 145-154 (1998)
[Publications] Hiromu Habashita: "A New Synthesis of the Central Substracture of Botryococcenes" Journal of Organic Chemistry. 63巻. 2391-2396 (1998)
[Publications] Hirokazu Tamamura: "Downsizing of an HIV-Cell Fusion Inhibitors,T22([Tyr5,12,Lys7]-Polyphemusin II),with the Maintenance of Anti-HIV Activity and Solution Streucture" Bioorganic & Medicinal Chemistry. 6巻. 473-479 (1998)
[Publications] Hirokazu Tamamura: "Pharmacophore identification of a chemokine receptor (CXCR4)antagonist,T22([Tyr5,12,Lye7]-plyphemusin II)." Bioorgic & Madicinal Chemistry. 6巻. 1033-1041 (1998)
[Publications] Asami Honda: "Rhodium(I)-or Iridium(I)-Mediated Equilibrated Reactions of Activated 2,3-cis and trans-3-Alkyl-2-vinylaziridines" Synlett. 969-970 (1998)
[Publications] Yoshiji Takemoto: "Utility of a diene-tricarbonyiron complex as mobile chiral auxiliary: iterative use for constructing contiguous chiral centers" Chemical Communications. 1911-1912 (1998)
[Publications] Hiroaki Ohno: "A 2,3-Cis Selective Synthesis of Aziridines bearing a Vinyl Group from Allyl Methyl Carbonates and Allyl Mesylates" J.Chem.Soc.,Perkin Trans.1. 3703-3716 (1998)
[Publications] Hiroaki Ohno: "A Convenient Synthesis of Activated Enantionerically Pure 2-Ethynylaziridines" Tetrahedron:Asymmetry. 9巻. 3929-3933 (1998)
[Publications] Yoshiji Takemoto: "Stereoselective synthesis of cis-fused chlorinated bicyclic ethers via CAN-mediated ring-opening of cycloprophysulfides" Tetrahedron Letters. 39巻. 7545-7548 (1998)
[Publications] Yoshiji Takemoto: "Asymmetric synthesis of (diene)Fe(CO)_3 complexes by a catalytic enantioselective alkylation using diakylzincs" Tetrahedron. 54巻. 15567-15580 (1998)
[Publications] Hirokazu Tamamura: "A low-molecular-weight inhibitor against the chemokine receptor CXCR4: A strong anti-HIV peptide T140" Biochem.Biophys.Res.Commun.253巻. 877-882 (1998)
[Publications] Hiroaki Ohno: "A Synthesis of Chiral Amino Allenes via an Organocyanocupreate-Mediated Ring-Opening Reaction of Enantiopure Ethynylaziridines" Tetrahedron Letters. 40巻. 349-352 (1999)
[Publications] Hiroaki Ohno: "Sterically Congested Activated Aziridines: Highyl Stereoselective Synthesis of Both 2,3-Cis- and 2,3-Trans-1-Alkenyl-3-alkylaziridines from Common Intermediates" Tetrahedron Letters. 40巻. 1331-1334 (1999)
[Publications] Hiroaki Ohno: "Selective Synthesis of Nonracemic 3-Pyrolines and 2,3-cis-2-vinylaziridines from(Z)- Amino Allylic Alcohols: New Synthetic Route to Chiral 3,4-Dehydroproline" Synlett. (in press). (1999)
[Publications] Hiroaki Ohno: "The first palladium-catalyzed aziridination reaction of amino allenes" Journal of Organic Chemistry. (in print). (1999)

1998 Fiscal Year Annual Research Report

実用化を指向した高効率且つ高選択的な抗腫瘍活性プソイド・ペプチド医薬品の開発

Principal Investigator

井深 俊郎 京都大学, 薬学研究科, 教授 (80025692)

Research Products

[Publications] Hirokazu Tamamura: "Unambiguous synthesis of stromal cell-derived factor-1 by regioselective disulfide bond formation using DMSO-aqueous HCl system" Chemical Communications. 1号. 151-152 (1998)

[Publications] Hirokazu Tamamura: "Effective lowly cytotoxic analogs of an HIV-cell fusion inhibitor,T22([Tyr5,12,Lys7]-polyphemusin II)" Bioorganic & Medicibnal Chemistry. 6巻. 231-238 (1998)

[Publications] Hirokazu Tamamura: "Convenient one-pot synthesis of cystine-containing peptides using the trimethylsilyl chloride-dimethylsulfoxide/trifluoroacetic acid system." J.Chem.Soc.,. 495-500 (1998)

[Publications] Toshiro Ibuka: "The Aza-Payne Rearrangement: A Synthetically Valuable Equlibration" Chemical Society Reviews. 27巻. 145-154 (1998)

[Publications] Hiromu Habashita: "A New Synthesis of the Central Substracture of Botryococcenes" Journal of Organic Chemistry. 63巻. 2391-2396 (1998)

[Publications] Hirokazu Tamamura: "Downsizing of an HIV-Cell Fusion Inhibitors,T22([Tyr5,12,Lys7]-Polyphemusin II),with the Maintenance of Anti-HIV Activity and Solution Streucture" Bioorganic & Medicinal Chemistry. 6巻. 473-479 (1998)

[Publications] Hirokazu Tamamura: "Pharmacophore identification of a chemokine receptor (CXCR4)antagonist,T22([Tyr5,12,Lye7]-plyphemusin II)." Bioorgic & Madicinal Chemistry. 6巻. 1033-1041 (1998)

[Publications] Asami Honda: "Rhodium(I)-or Iridium(I)-Mediated Equilibrated Reactions of Activated 2,3-cis and trans-3-Alkyl-2-vinylaziridines" Synlett. 969-970 (1998)

[Publications] Yoshiji Takemoto: "Utility of a diene-tricarbonyiron complex as mobile chiral auxiliary: iterative use for constructing contiguous chiral centers" Chemical Communications. 1911-1912 (1998)

[Publications] Hiroaki Ohno: "A 2,3-Cis Selective Synthesis of Aziridines bearing a Vinyl Group from Allyl Methyl Carbonates and Allyl Mesylates" J.Chem.Soc.,Perkin Trans.1. 3703-3716 (1998)

[Publications] Hiroaki Ohno: "A Convenient Synthesis of Activated Enantionerically Pure 2-Ethynylaziridines" Tetrahedron:Asymmetry. 9巻. 3929-3933 (1998)

[Publications] Yoshiji Takemoto: "Stereoselective synthesis of cis-fused chlorinated bicyclic ethers via CAN-mediated ring-opening of cycloprophysulfides" Tetrahedron Letters. 39巻. 7545-7548 (1998)

[Publications] Yoshiji Takemoto: "Asymmetric synthesis of (diene)Fe(CO)_3 complexes by a catalytic enantioselective alkylation using diakylzincs" Tetrahedron. 54巻. 15567-15580 (1998)

[Publications] Hirokazu Tamamura: "A low-molecular-weight inhibitor against the chemokine receptor CXCR4: A strong anti-HIV peptide T140" Biochem.Biophys.Res.Commun.253巻. 877-882 (1998)

[Publications] Hiroaki Ohno: "A Synthesis of Chiral Amino Allenes via an Organocyanocupreate-Mediated Ring-Opening Reaction of Enantiopure Ethynylaziridines" Tetrahedron Letters. 40巻. 349-352 (1999)

[Publications] Hiroaki Ohno: "Sterically Congested Activated Aziridines: Highyl Stereoselective Synthesis of Both 2,3-Cis- and 2,3-Trans-1-Alkenyl-3-alkylaziridines from Common Intermediates" Tetrahedron Letters. 40巻. 1331-1334 (1999)

[Publications] Hiroaki Ohno: "Selective Synthesis of Nonracemic 3-Pyrolines and 2,3-cis-2-vinylaziridines from(Z)- Amino Allylic Alcohols: New Synthetic Route to Chiral 3,4-Dehydroproline" Synlett. (in press). (1999)

[Publications] Hiroaki Ohno: "The first palladium-catalyzed aziridination reaction of amino allenes" Journal of Organic Chemistry. (in print). (1999)

井深俊郎京都大学, 薬学研究科, 教授 (80025692)