Combinatorial Synthesis of Peptide Mimetics Containing Unnatural Amino Acid Utilizing Homogeneous Catalyzed Reactions

利用均相催化反应组合合成含有非天然氨基酸的肽模拟物

基本信息

  • 批准号:
    11450344
  • 负责人:
  • 金额:
    $ 8.7万
  • 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 2001
  • 项目状态:
    已结题

项目摘要

The secondary structures (β-sheet, β-turn, α-helix) of protein play an important role in their interactions with receptors and enzymes to control a multitude of biological processes. Many researchers have been engaged in the development of mimics of these secondary structure motifs for drug discovery efforts and in particular the utilization of combinatorial libraries of these "templates" to probe biological structure-activity relationship. Much attention has been directed toward solid-phase methods development for the synthesis of libraries for use in biological discovery efforts.(i) Conformationally constrained 10-membered cyclic diamide was designed and synthesized. Sequential asymmetric hydrogenation of bis-cinnamic acid derivatives provided the core part of the HIV protease inhibitor in enantiomerically pure form.(ii) Palladium-catalyzed Mizoroki-Heck reaction of solid-supported dehydroalanine with various aryl iodides, followed by rhodium-catalyzed asymmetric hydrogenation afforded a library of peptides containing unnatural amino acids.(iii) Palladium-catalyzed carbonylation-cyclization of peptides including iodobenzyl amine derivatives furnished a library of cyclic peptides containing a benzene ring connecting at the ortho, metha, and para-positions.
蛋白质的二级结构(β-折叠、β-转角、α-螺旋)在其与受体和酶的相互作用中起着重要作用,从而控制了许多生物学过程。许多研究人员一直致力于开发这些二级结构基序的模拟物用于药物发现工作,特别是利用这些“模板”的组合文库来探测生物结构-活性关系。许多注意力已经指向固相方法的开发,用于合成用于生物发现工作的文库。(i)设计并合成了构象受限的10元环二酰胺。双肉桂酸衍生物的顺序不对称氢化提供了对映体纯形式的HIV蛋白酶抑制剂的核心部分。(ii)钯催化的Mizoroki-Heck反应的固体支持的脱氢丙氨酸与各种芳基碘,然后铑催化的不对称氢化提供了一个含有非天然氨基酸的肽库。(iii)钯催化的羰基化-环化的肽,包括碘苄基胺衍生物提供了一个图书馆的环肽含有苯环连接在邻位,甲基,和对位。

项目成果

期刊论文数量(35)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
N. Fuchi, T. Doi, B. Cao, M. Kahn, and T. Takahashi: "The Solid-Phase Parallel Synthesis of β-Strand Mimetic Template via 1,3-Dipolar Cyclization with Resin-bound Vinylsulfone"Synlett. (in press). (2002)
N. Fuchi、T. Doi、B. Cao、M. Kahn 和 T. Takahashi:“通过树脂结合乙烯基砜的 1,3-偶极环化固相平行合成 β-链模拟模板”Synlett。 (2002)
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    0
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N. Fuchi, T. Doi, T. Harada, J. Urban, B. Cao, M. Kahn, and T. Takahashi: "The Synthesis of β-Strand Mimetic Templates via Regioselective 1,3-Dipolar Cycloaddition with Vinylsulfone"Tetrahedron Lett.. 43. 1305-1308 (2001)
N. Fuchi、T. Doi、T. Harada、J. Urban、B. Cao、M. Kahn 和 T. Takahashi:“通过与乙烯基砜的区域选择性 1,3-偶极环加成合成 β-链模拟模板”莱特.. 43. 1305-1308 (2001)
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T. Doi, I. Hijikuro, and T. Takahashi: "An Efficient Solid Phase Synthesis of the Vitamin D_3 System"J. Am, Chem. Soc.. 121. 6749-6750 (1999)
T. Doi、I. Hijikuro 和 T. Takahashi:“维生素 D_3 系统的高效固相合成”J。
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    0
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Takayuki Doi: "Glycosidation of Solid-Supported Glycosyl Donors Tethered by a Trialkylsilane Linker" Tetrahedron Lett.40. 2141-2144 (1999)
Takayuki Doi:“由三烷基硅烷连接体束缚的固体支撑糖基供体的糖苷化”Tetrahedron Lett.40。
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    0
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Takayuki Doi: "A Novel Strategy for an Automated Synthesis of Bis-Amides of 1,2-Diamines"Synlett. (11). 1751-1753 (1999)
Takayuki Doi:“自动合成 1,2-二胺双酰胺的新策略”Synlett。
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