Synthesis of Cell-cycle Inhibitory Peptides and Their Development for Medicinal Use

细胞周期抑制肽的合成及其药用开发

基本信息

  • 批准号:
    11557171
  • 负责人:
  • 金额:
    $ 4.86万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    1999
  • 资助国家:
    日本
  • 起止时间:
    1999 至 2002
  • 项目状态:
    已结题

项目摘要

In this project, GE3 and Polyoxypeptins (A and B), novel 19-membered cyclic hexadepsipeptide antibiotics from Streptcmyces strains and Papuamides (A and B), novel cyclodepsipeptides with anti HIV and cytotoxic activies from the marine sponge genus Theonellawere synthetically studied. Stereoselective synthesis of the acyl side chain segment of GE3 has been achieved by using Sharpless's asymmetric dihydroxylation and stereoselective Evan's and Paterson's aldol methodologies. Stereoselective synthesis of the acyl side chain segment of Polyoxypeptins has been carried out through regioselective opening of chiral 2,3-epoxyalcohol. (2R,3R)-and (2S, 3S)-Hydroxyleucines, components of the cyclodepsipeptides, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuC_2(binap) catalyzed hydrogenation, Stereoselective synthesis of (2S,3R)-3-hydroxy-3-raethylproline (2), a component of polyoxypeptins, has been achieved by use of diastereoselective cyclization reaction using SmI_2 as a key step. (3S,4R)-3,4-Dimethy1-(S)-glutamine,a component Papuamides, was stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously confirmed to be (2S,3S,4R)-stereochemistry by comparisons of their spectra of the synthetic 3,4-dimethylpyroglutamic acid with the hydrolysate from the natural product. Β-Methoxytyrosine (β-OMeTyr) is a stereoundefined component of papuamides. For structural determination and total synthesis of papuamides, all stereoisomers of β-(MeTyr were stereoselectively prepared from (S)-and (R )-serine, respectively.Further studies on final construction of the three cyclodepsipeptides are under investigation in this laboratory.
本课题合成了从链霉菌菌株中分离得到的新型19元环六肽类抗生素GE3和聚氧多肽(A、B),以及从海洋海绵海绵属Theonellaa中分离得到的具有抗HIV活性的新型环肽类化合物和具有细胞毒活性的新型环肽类化合物。用夏普莱斯的不对称双羟基化和立体选择性的Evan和Paterson的Aldol方法实现了GE3的酰基侧链链段的立体选择性合成。通过手性2,3-环氧醇的区域选择性开环,立体选择性地合成了聚氧肽的酰基侧链链段。利用RuC_2(BINAP)催化的氢化反应,从相应的β-keto-α-氨基酸酯出发,通过动态动力学拆分,高效地合成了环多肽组分(2R,3R)-和(2S,3S)-羟亮氨酸及其非对映异构体,并以SnI_2为关键步骤,通过非对映选择性环化反应实现了(2S,3R)-3-羟基-3-乙基丙氨酸(2)的立体选择性合成。以(S)-焦谷氨酸为原料,立体选择性地合成了(3S,4R)-3,4-二甲基-(S)-谷氨酰胺。通过合成的3,4-二甲基焦谷氨酸与天然产物的水解物的光谱比较,明确地证实了天然二甲基谷氨酰胺的立体结构为(2S,3S,4R)-立体化学。Β-甲氧基酪氨酸(β-OMeTyr)是木瓜酰胺类化合物的立体结构成分。β-(MeTyr)的所有立体异构体都是从(S)-丝氨酸和(R)-丝氨酸分别立体选择性地合成的,用于木瓜酰胺的结构测定和全合成。这三个环去脂肽的最终结构研究正在实验室进行中。

项目成果

期刊论文数量(46)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Kazuishi Makino, Tatsuya Suzuki, Shinobu Awane, Osamu Hara, Yasumasa Hamada: "Synthesis of the acyl side chain segment of polyoxypeptins using regioselective ring-opening of chiral 2,3-epoxy alcohol."Tetrahedron Lett. 43. 9391-9395 (2002)
Kazuishi Makino、Tatsuya Suzuki、Shinobu Awane、Osamu Hara、Yasumasa Hamada:“利用手性 2,3-环氧醇的区域选择性开环合成聚氧肽的酰基侧链片段。”Tetrahedron Lett。
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    0
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Naoki Okamoto, Osamu Hara, Kasuishi Makino, Yasumasa Hamada: "Stereoselective Synthesis of (3S, 4R)-3,4-Dimethyl-(S)-glutamine and the Absolute Stereochemistry of Natural One from Papuamides and Callipeltin"Tetrahedron : Asymmetry. 12. 1353-1358 (2001)
Naoki Okamoto、Osamu Hara、Kasuishi Makino、Yasumasa Hamada:“(3S,4R)-3,4-二甲基-(S)-谷氨酰胺的立体选择性合成以及 Papuamides 和 Callipeltin 天然一物的绝对立体化学”四面体:不对称性。
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    0
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Kasuishi Makino, Naoki Okamoto, Osamu Hara, Yasumasa Hamada: "Efficiently Enantioselective Synthesis of (2R, 3R)-and (2S, 3S)-3-Hydroxyleucines and Their Diastereomers through Dynamic Kinetic Resolution"Tetrahedron : Asymmetry. 12. 1757-1762 (2001)
Kasuishi Makino、Naoki Okamoto、Osamu Hara、Yasumasa Hamada:“通过动态动力学拆分有效对映选择性合成 (2R, 3R)-和 (2S, 3S)-3-羟基亮氨酸及其非对映异构体”四面体:不对称性。
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    0
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Kazuishi Makino, Yoshiaki Hennmi, Yasumasa Hamada: "Synthetic Studies on a Cyclic Hexadepsipeptide GE3:Stereoselective Construction of the Acyl Side Chain"Synlett. 613-615 (2002)
Kazuishi Makino、Yoshiaki Hennmi、Yasumasa Hamada:“环状十六肽 GE3 的合成研究:酰基侧链的立体选择性构建”Synlett。
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    0
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Naoki Okamoto, Osamu Hara, Kazuishi Makino, Yasumasa Hamada: "Stereoselective Synthesis of (3S,4R)-3,4-Dimethyl-(S)-glutamine and the Absolute Stereochemistry of Natural One from Papuamides and Callipeltin"Tetrahedron : Asymmetry. 12. 1353-1358 (2001)
Naoki Okamoto、Osamu Hara、Kazuishi Makino、Yasumasa Hamada:“(3S,4R)-3,4-二甲基-(S)-谷氨酰胺的立体选择性合成以及 Papuamides 和 Callipeltin 天然一物的绝对立体化学”四面体:不对称性。
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    0
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HAMADA Yasumasa其他文献

HAMADA Yasumasa的其他文献

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{{ truncateString('HAMADA Yasumasa', 18)}}的其他基金

Discovery of new function of organophosphorus compounds and their applications to catalytic asymmetric synthesis
有机磷化合物新功能的发现及其在催化不对称合成中的应用
  • 批准号:
    24659002
  • 财政年份:
    2012
  • 资助金额:
    $ 4.86万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Development of highly efficient synthetic processes and their applications to natural products
高效合成工艺的开发及其在天然产物中的应用
  • 批准号:
    23390003
  • 财政年份:
    2011
  • 资助金额:
    $ 4.86万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of catalytic methods in organic synthesis and their applications to the synthesis of biologically interesting natural products
有机合成催化方法的发展及其在合成具有生物学意义的天然产物中的应用
  • 批准号:
    19390003
  • 财政年份:
    2007
  • 资助金额:
    $ 4.86万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of Transition-metal Catalysts and Their Applications to Asymmetric Catalysis
过渡金属催化剂的发展及其在不对称催化中的应用
  • 批准号:
    17390004
  • 财政年份:
    2005
  • 资助金额:
    $ 4.86万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of Rigid Tricyclic Ligands and their Application to Asymmetric Catalysis
刚性三环配体的开发及其在不对称催化中的应用
  • 批准号:
    13470467
  • 财政年份:
    2001
  • 资助金额:
    $ 4.86万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Design and development of monodentate chiral phosphines and their applications to asymmetric synthsese
单齿手性膦的设计、开发及其在不对称合成中的应用
  • 批准号:
    09470480
  • 财政年份:
    1997
  • 资助金额:
    $ 4.86万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Synthetic Studies on Hennoxazole A with Antivirus Activity
具有抗病毒活性的亨诺恶唑A的合成研究
  • 批准号:
    06672106
  • 财政年份:
    1994
  • 资助金额:
    $ 4.86万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
Total Synthesis of Cyclotheonamides, Potent Inhibitors of Thrombin
凝血酶强效抑制剂环草酰胺的全合成
  • 批准号:
    04671303
  • 财政年份:
    1992
  • 资助金额:
    $ 4.86万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
オキサソール環の構築、開裂反応を基盤とする生理活性物質の合成研究
基于恶唑环的构建和裂解反应合成生理活性物质的研究
  • 批准号:
    62570948
  • 财政年份:
    1987
  • 资助金额:
    $ 4.86万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)

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  • 批准号:
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  • 批准年份:
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